Chapter. Contents Breast Cancer Adjuvant Epirubicin weekly. Docetaxel Copy No:

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1 Chapter 2: Breast Cancer Contents Chapter 2: Breast Cancer... 1 Breast Cancer... 2 Adjuvant Epi-CMF... 2 FEC / docetaxel... 3 FEC AC/EC/TC... 4 (neo) adjuvant HER2 positive: TCarboH... 6 NCRI recommendations for cardiac monitoring... 7 Neo-adjuvant... 8 AC/ECC... 8 Docetaxel... 9 Taxane allergy... 9 *Paclitaxel albumin (Abraxane )... 9 Advanced disease Doxorubicin AC/ECC Doxorubicin weekly Epirubicin weekly Docetaxel Paclitaxel Docetaxel / capecitabine Paclitaxel / gemcitabine Capecitabine Vinorelbine Gemcitabine / carboplatin Management of patients with HER2 positive cancers / pertuzumab / docetaxel 1 st line regimen only *Lapatinib and capecitabine Other CDF approved therapy *Bevacizumab *Everolimus and exemestanee Bone directed therapy Denosumab Bisphosphonate Page 1 of 24

2 Breast Cancer Adjuvant Epi-CMF Epi-CMF Epi 4 cycles n Epirubicin 100mg/m 2 IV bolus Followed by 4 cycles CMF Epi-CMF CMF Days 1 to 14 Every 28 Days Cyclophosphamide 100mg/m 2 4 cycles Orally, daily for 14 days in divided doses Days 1 and 8 Methotrexatee 40mg/m 2 IV bolus Days 1 and 8 Fluorouracill 600mg/m 2 IV bolus For patients unable to tolerate oral cyclophospha amide substitute: IV cyclophosphamide 600mg/m 2 days 1 and 8 Folinic acid rescue is not normally equired unless patient develop signs of methotrexate toxicity, add orally 15mg 6 hourly x 6 dosess starting 24 hours post methotrexatee with subsequent cycless LV ejection fraction prior to cycle 1 if history off cardiac problems butt methotrexate is hazardous in the presence of renal insufficiency, not required on day 8 Standard FBC limits for administration apply Page 2 of 24

3 FEC / docetaxel This protocol is available for node positive or high risk node negative patients. Patients should receive primary prophylaxis withh pegfilgrastim after each cycle FEC/docetaxel FEC Fluorouracil Epirubicin Cyclophosphamide 500mg/m 2 100mg/m 2 500mg/m 2 3 cycles n IV bolus IV bolus IV bolus Day 2 Pegfilgrastim 6mgg SC injection Followed by 3 cycles docetaxel FEC/docetaxel Docetaxel Dexamethasone 8mg BD Docetaxel 100mg/m h 3 cycles Orally for 3 days, commencing 24 hours before docetaxel IV infusion Day 2 Pegfilgrastim 6mg SC injection LV ejection fraction prior to cycle 1 if history off cardiac problems Standard FBC limits for administration apply For patients unable to tolerate 3 weekly docetaxel, weekly paclitaxel may be used as an alternative Weekly paclitaxel Every 7 days Chlorphenamine Dexamethasone Ranitidine Paclitaxel 10mg 8mgg 50mg 80mg/ /m 2 12 weeks Reducing to 4mg from week 2 Page 3 of 24

4 FEC100 As alternative to Epi-CMF regimen FEC 6 cycless Fluorouracil 500mg/m 2 Epirubicin 100mg/m 2 Cyclophosphamide 500mg/m 2 Day 2 Pegfilgrastim 6mgg SC injection LV ejection fraction prior to cycle 1 if history off cardiac problems Standard FBC limits for administration apply AC/EC/TC AC 4 cycless Doxorubicin 60mg/ /m 2 Cyclophosphamide 600mg/m 2 OR EC 4 cycless Epirubicin 90mg/ /m 2 Cyclophosphamide 600mg/m 2 AC for 4 cycles has been shown to be equivalent to 6 cycles of CMF Page 4 of 24

5 In patients at significant risk of cardiac problems: TC TC 4 6 cycles Dexamethasone Docetaxel 8mg BD 75mg/ /m 2 Orally for 3 days, commencing 24 hours before docetaxel Cyclophosphamide 600mg/m 2 LV ejection fraction prior to cycle 1 if history off cardiac problems, standard FBC limits for administration apply (neo) adjuvantt For patients with HER2 positive cancers (IHC 3+ + and / or FISH positive): Non-metastatic potentially operable primary invasive breast cancer Given after completion of (neo) adjuvant anthracyclines, it can be givenn in combination with trastuzumab ECOG PS 0 or 1 Baseline LVEF normal after completing anthracycline chemotherapy, no n serious cardiac illness Subcutaneous Herceptin Herceptin SC 600mg 18 cycles Subcutaneous injectionn over 2 to 5 minutes 18 cycles Cycle 1 8mg/kg IV infusion over 90 minutes Subsequent IV infusion over 60 minutes, reduced to t 30 mins if 6mg/kg cycles tolerated May be given concurrently with docetaxel in FEC/docetaxel regimen Stop at any time if CCF develops (see NCRI recommendations for cardiac monitoring) Page 5 of 24

6 In patients at significant risk of cardiac problems: HER2 positive: TCarboH TCarboH Dexamethasone Docetaxel 8mg BD 75mg/ /m 2 6 cycles Orally for 3 days, d commencing 24 hours before docetaxel Carboplatin AUC6 Day 2 Pegfilgrastim 6mgg SC injection Cycle 1 Subsequent cycles (2 to 6) 8mg/kg 6mg/kg Loading dose IVV over 90 mins Subsequent doses IV overr 60mins, then reduce to 30 mins if tolerated Continue with trastuzumab maintenance to 18 cycles in total. Subcutaneous Herceptin Subsequent cycles Herceptin SC (6 to 18) 600mg To complete 18 cycles Subcutaneouss injection over 2 to 5 minutes OR To complete 18 cycles Subsequent cycles (6 to 18) 6mg/kg IV infusion over 30 mins Page 6 of 24

7 NCRI recommendations for cardiac monitoring Ref: British Journal of Cancer : Page 7 of 24 Authorised by: Dr Susan O Reilly

8 Neo-adjuvant Indication / treatment plan Patients with locally advanced disease or to alloww less radical surgery in patients withh operable tumours. Options include six cycles of EC/AC or four cycles EC/AC followed by four cycles docetaxel at 100mg/m 2 HER-2 positive patients may commence trastuzumab following completion of anthracycline based treatment i.e. concurrently with docetaxel if this is being given providedd LVEF normal after completion of the anthracycline. Patients should then have the remaining 14 cycles of trastuzumab as adjuvant treatment. AC/EC AC Upto 6 cycles n Doxorubicin 60mg/ /m 2 IV bolus Cyclophosphamide 600mg/m 2 IV bolus Day 2 Pegfilgrastim 6mgg SC injection OR EC Upto 6 cycles n Epirubicin 90mg/ /m 2 IV bolus Cyclophosphamide 600mg/m 2 IV bolus Day 2 Pegfilgrastim 6mgg SC injection LV ejection fraction prior to cycle 1 if history off cardiac problems Standard FBC limits for administration apply Page 8 of 24

9 Docetaxel Docetaxel 4 cycles Dexamethasone Docetaxel 8mg BD 100mg/m 2 Orally for 3 days, d commencing 24 hours before docetaxel Day 2 Pegfilgrastim 6mgg SC injection Standard FBC limits for administration apply For patients unable to tolerate 3 weekly docetaxel, weekly paclitaxel may be used as an alternative Weekly paclitaxel Every 7 days Chlorphenamine Dexamethasone Ranitidine Paclitaxel 10mg 8mgg 50mg 80mg/ /m 2 12 weeks Reducing to 4mg from week 2 Taxane allergy *Paclitaxel albumin (Abraxane ) Paclitaxell albumin Paclitaxell albumin 260mg/m 2 Until disease progression IV infusion over 30 minutes Consider if no longer safe to continue with paclitaxel or docetaxel. Patients may be able to receive Abraxane with premedication and appropriate precautions. Page 9 of 24

10 Criteria: Adjuvant breast cancer Situations where taxanes are Normal FBC limits for administration apply Page 10 of 24

11 Advancedd disease Doxorubicin Doxorubicin single agent 6 cycless Doxorubicin 75mg/ /m 2 AC/EC AC Upto 6 cycles Doxorubicin 60mg/ /m 2 Cyclophosphamide 600mg/m 2 OR EC Upto 6 cycles Epirubicin 90mg/ /m 2 Cyclophosphamide 600mg/m 2 LV ejection fraction prior to cycle 1 if history off cardiac problems Normal FBC limits for administration apply Page 11 of 24

12 For patients with compromised liver or marrow function due to tumour infiltration Doxorubicin weekly Doxorubicin weekly Every 7 days Doxorubicin 20mg/m 2 Usually 6 to 8 weeks, increasing to 21 day cycles where possible. IV bolus Maximum doxorubicin total dose 450mg/m 2 Epirubicin weekly Epirubicin weekly Every 7 days Epirubicin 20 to 30mg/ /m 2 Usually 6 to 8 weeks initially IV bolus Ensure normal renal function priorr to cycle 1 and repeat during subsequent cycles if clinically Patients with abnormal hepatic function shouldd be treated cautiously LV ejection fraction prior to cycle 1 if history off cardiac problems. Normal limits for administration apply with the exception that for patients with marrow infiltrationn treatment may be continued at lower platelett and neutrophil counts at treating physician discretion. Docetaxel Docetaxel 3 cycles Dexamethasone Docetaxel 8mg BD 75 to 100mg/m 2 n Orally for 3 days, commencing 24 hours before docetaxel Page 12 of 24

13 Normal FBC limits for administration apply Paclitaxel Weekly paclitaxel Every 7 days Chlorphenamine Dexamethasone Ranitidine Paclitaxel 10mg 8mgg 50mg 80mg/ /m 2 Until disease progression Reducing to 4mg from week 2 Paclitaxel weekly: for patients with compromised d liver or marrow functionn who have previously received anthracyclines. investigations Ensure normal renal function priorr to cycle 1 and repeat during subsequent cycles if clinically Patients with abnormal hepatic function shouldd be treated cautiously. Normal limits for administration apply with the exception that for patients with marrow infiltrationn treatment may be continued at lower platelett and neutrophil counts at treating physician discretion. Docetaxel / capecitabine Docetaxel / capecitabine Dexamethasone Docetaxel to 14 Capecitabine 8mg BD 75mg/ /m mg/mm 2 BD Upto 6 cycles n Orally for 3 days, commencing 24 hours before docetaxel Twice daily (morning and evening) orally, for 14 dayss followed byy 7 days off NB Capecitabine is contra-d when creatinine clearance is below 30mL/min. See capecitabine renal function recommendations (chapter 1) Criteria PS 0-1 NB very fit patients only where rapid symptomatic control is required Recurrent following adjuvant anthracycline therapy Page 13 of 24

14 Normal FBC limits for administration apply Paclitaxel / gemcitabine Paclitaxell / gemcitabine Chlorphenamine 10mg Upto 6 cycles Dexamethasone 16mg Ranitidine 50mg Paclitaxel 175mg/m 2 IV infusion overr 3 hours Gemcitabine 1250mg/m 2 IV infusion over 30 minutes Day 8 Gemcitabine 1250mg/m 2 IV infusion over 30 minutes Criteria PS 0-1 NB very fit patients only Recurrent following adjuvant anthracycline therapy Normal FBC limits for administration apply Capecitabine Capecitabine orally Days 1 to 14 Capecitabine 1000 to 1250mg/m Upto 6 cycles n Tw wice daily (morning and evening) orally, for 14 dayss followed byy 7 days off In elderly patients consider a starting dose of 850mg/m 2 BD Page 14 of 24

15 can be reduced further to mg/m 2 twice daily for 14 days followed by 7 days off if heavily pre- treated or poorer PS NB Capecitabine is contra-d when creatinine clearance is below 30mL/min See capecitabine renal function recommendations (chapter 1) Criteria Failed or unsuitable for anthracycline and/or taxane PS 0-2 Normal FBC limits for administration apply *Eribulin Eribulin Until disease progression Eribulin 1.23 mg/m 2 IV infusion over 2 too 5 minutes Day 8 Eribulin 1.23 mg/m 2 IV infusion over 2 too 5 minutes *NB available via the Cancer s fund CDF Criteria (as at 23 rd September 2013) The treatment of advanced breast cancer wheree all the following criteria are met: 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. Advancedd breast cancer 3. At least 2 prior chemotherapy regimens for advanced disease Impaired liver function due to metastases: The recommended dose of eribulin in patients with mild hepatic impairment (Child-Pugh A) is 0.97 mg/m 2 administered intravenously over 2 to 5 minutes on Days 1 and 8 of a 21-day cycle. The recommended dose of eribulin in patients with moderate hepatic c impairment (Child-Pugh B) is 0.62 mg/m 2 administered intravenously over 2 to 5 minutes on Dayss 1 and 8 of a 21-day cycle. Page 15 of 24

16 Normal FBC limits for administration apply Vinorelbinee Vinorelbine intravenous Upto 6 cycles Vinorelbine 25 to 30mg/m 2 IVV infusion over 5 mins Day 8 Vinorelbine Maximum single dose 60mg 25 to 30mg/m 2 IVV infusion over 5 mins Vinorelbine oral Upto 6 cycles Vinorelbine 60 to 80mg/m 2 Orally O as a single dose Day 8 Vinorelbine 60 to 80mg/m 2 Orally O as a single dose Maximum dose 120mg for 60mg/m 2 dose and 160mg for 80mg/m 2 dose Reassess after every 2 cycles, maximum 6 cycles Criteria: WHO performance status 0-1 Endocrine resistant Prior alkylating agent therapy Normal FBC limits for administration apply Page 16 of 24

17 Gemcitabine / carboplatin Gemcitabine / carboplatin Carboplatin Gemcitabine Day 8 Gemcitabine AUC mg/m mg/m 2 Course C length Upto 6 cycles IV infusion over 30 minutes IV infusion over 30 minutes Ensure normal hepatic function prior to cycle 1 and repeat during subsequent cycles if clinically NB: transaminases may rise during treatment Calculate or measure creatinine clearance prior to first cycle and before subsequent cycles if clinically Normal FBC limits for administration apply, if outside limits on day 8 then omit treatment and re-start chemotherapy again on day 1 as scheduled For patients with significant previous chemotherapy treatment or underlying thrombocytopenia the split dose regimen should be considered Gemcitabine / carboplatin split dose Carboplatin Gemcitabine AUC mg/m Course C length Upto 6 cycles IV infusion over 30 minutes Day 8 Carboplatin AUC 2.5 Day 8 Gemcitabine 1250mg/m 2 IV infusion over 30 minutes Cycle interval can be increased to 28 days if clinically Ensure normal hepatic function prior to cycle 1 and repeat during subsequent cycles if clinically NB: transaminases may rise during treatment Calculate or measure creatinine clearance prior to first cycle and before subsequent cycles if clinically Page 17 of 24

18 , normal FBC limits for administration apply Page 18 of 24

19 Management of patients with HER2 positive cancers Subcutaneous Herceptin (trastuzumab) Herceptin SC 600mg Until disease progression Subcutaneous injectionn over 2 to 5 minutes OR Until disease progression Cycle 1 Subsequent cycles 8mg/kg 6mg/kg IV infusion over 90 minutes IV infusion over 60 minutes, reduced to t 30 mins if tolerated Criteria: Strongly HER2 positive (HER2 3+ by IHC or FISH positive) given together with non-anthracycline based chemotherapyy or as a single agent. LVEF: baseline ECHO/MUGA and repeated as algorithm in adjuvant section. Page 19 of 24

20 / pertuzumab / docetaxel 1 st line regimen only / pertuzumab / docetaxel Until disease progression n Cycle 1 Cycle 1 Dexamethasone 8mg BD 8mg/kg Orally for 3 days, commencing 24 hours before docetaxel IV infusion over 90 minutes Cycle 1 Pertuzumab* 840mg Cycle 1 Cycle 2 Cycle 2 onwards Cycle 2 onwards Cycle 2 to 6 Docetaxel Dexamethasone Pertuzumab* Docetaxel 75mg/ /m 2 8mg BD 6mg/kg 420mg 75mg/ /m 2 Orally for 3 days, commencing 24 hours before docetaxel IV infusion 30 to 60 minutes IV infusion over 30 to 60 minutes Docetaxel dose may be increased to 100mg/m 2 if well tolerated from cycle 2 onwards. and pertuzumab continue after docetaxel course is completed. to remain intravenous administration. Criteria: Strongly HER2 positive (HER2 3+ by IHC or FISH positive) LVEF: baseline ECHO/MUGA and repeated as algorithm (in adjuvant section). Review LFTs at each cycle If unacceptable toxicity from docetaxel at reduced dose of 60mg/m 2 then paclitaxel may be used as alternative. If the time between 2 pertuzumab doses is 6 weeks or more than a re-loading dose of 840mg needs to be administered. *NB available via the Cancer s fund CDF Criteria (as at 23 rd September 2013) The first line treatment of locally advanced or metastatic breast cancer where w all the following criteria are met: 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. Locally advanced or metastatic breast cancer 3. HER-2 3+ or FISH positive 4. PS Any adjuvant HER2 therapy should have beenn completed more than 12 months prior to metastatic diagnosis 6. No prior treatment with chemotherapy of HER2 therapy for metastatic disease 7. To be given as first line treatmentt in combination with docetaxel and trastuzumab NOTE: not to be used beyond first disease progression Page 20 of 24

21 *Lapatinib and capecitabine Lapatinib and capecitabine Days 1 to 14 Capecitabine Daily Lapatinib Until disease progression n 1000 mg/ /m 2 Tw wice daily (morning and evening) orally, for 14 dayss followed byy 7 days off 1250mgg Daily, continuously NB see capecitabine renal function recommendations (chapter 1) Capecitabine may be reduced to 850mg/m 2 twice daily for 14 days followed by 7 days off if heavily pre- treated or poorer PS For some responding patients continuing with lapatinib alone may be thee right approach if capecitabine toxicity becomes unacceptable. Normal FBC limits for administration apply *NB available via the Cancer s fund CDF Criteria (as at 23 rd September 2013) The treatment of advanced breast cancer wheree all the following criteria are met: 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. Progressing advanced or metastatic breast cancer 3. HER-2 over-expression 4. Previous treatment with anthracyclines or anthracyclines contra-indica ated 5. Previous treatment with taxanes 6. Previous treatment with trastuzumab in the metastatic setting 7. Use in combination with capecitabine Page 21 of 24

22 Other CDF approved therapy *Bevacizumab Bevacizumab Every 14 Days Bevacizumab 10mg/ /kg Until disease progression IV infusion over 90 minutes for first infusion, then 60 and 30 minutes as tolerated To be given in combination with paclitaxel *NB available via the Cancer s fund CDF Criteria (as at 23 September 2013) The treatment of advanced breast cancer wheree all the following criteria are met: 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. Advancedd Breast Cancer 3. Triple negative disease (ER, PR, and HER2 negative) 4. a) 1st line indication OR b) 2nd line indication 5. To be given in combination with paclitaxel Proteinuria monitoring BP at each cycle, normal FBC limits for administration apply *Everolimus and exemestane Everolimus and exemestane Continuous, supplied every 28 days Daily Everolimus 10mg Until disease progression / toxicity Orally, daily Daily Exemestane 25mg Orally, daily (may be obtained via GP) *NB available via the Cancer s fund CDF Criteria (as at 23 rd September 2013) Page 22 of 24

23 The treatment of advanced breast cancer wheree all the following criteria are met: 1. Application made by and first cycle of systemic anti-cancer therapy to be prescribed by a consultant specialist specifically trained and accredited in the use of systemic anti-cancer therapy 2. ER +ve, HER2 ve metastatic breast cancer 3. No symptomatic visceral disease 4. In combination with exemestane 5. Previous treatment with a non-steroidal aromatase inhibitor 6. No previous treatment with exemestane for metastatic breast cancer 7. No more than one line of chemotherapy for the treatment of advanced breast cancer Normal FBC limits for administration apply Blood glucose and triglycerides at baseline, then as Page 23 of 24

24 Bone directed therapy Denosumab Denosumab Every 28 Days Continuous Denosumab 120mg Subcutaneouss injection Daily Adcal D3 1 to 2 daily Orally daily Calcium supplements: Supplementation of at least 500 mg calcium and 4004 IU vitamin D daily is required in all patients, unless hypercalcaemia is present. Patients should have their serum calcium measured every four weeks and the dose of Adcal D3 tablets adjusted as necessary. Bisphosphonate Zoledronic acid Every 28 Days (range 21 42) Zoledronic acid 4mg* Continuous n IV infusion over 15 minutes Daily Adcal D3 1 to 2 daily Orally daily Criteria: Performance status 0-2 Symptomatic / extensive bone metastases Calcium supplements: Supplementation of at least 500 mg calcium and 4004 IU vitamin D daily is required in all patients, unless hypercalcaemia is present. Patients should have their serum calcium measured every four weeks and the dose of Adcal D3 tablets adjusted as necessary. *Renal impairment Cr clearance >60 4.0mg mg mg mg < 30 no treatment Cockcroft and Gault formula to be used for calculating creatinine clearance, see chapter 1 Serum creatinine should be repeated every 4 weeks and if it rises significantly duringg treatment zoledronic acid should be witheld until the creatinine has returned to within 10% of the t baseline prior to starting. Page 24 of 24