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Epirubicin 90 / Cyclophosphamide 600, Breast Cancer, adjuvant

Protocol-ID: 579 V1.1 (Complete), EC (EPIR90/CYCL600), Breast Ca, adj.

Indication(s)

Breast Cancer; ICD-10 C50.-

Protocol classification

Classification: alternative
Intensity: Standard dose
Therapy phase:
Therapy intention: curative

Cycles

Cycle length 21 days, recommended cycles: 4

Protocol sequences

Risks

Emetogenicity (MASCC/ESMO): moderate (30-90%)
Neutropenia: very high (>41%)
Febrile Neutropenia: intermediate (10-20%)
Thrombocytopenia below 50 000/µl: low (<10%)
Anemia Hb below 8g/dl: low (<5%)
Dyspnea: CTC AE °3-4: 5%

Therapy

Day	Substance	Dosage	Appl.	Inf. time	Procedure
HYD Hydration: Balanced Crystalloid Solution
Access: peripheral venous
Hydration before, during, or after antitumor therapy
1	Balanced Crystalloid Solution	500 ml	i.v.	30 min	30 min before Epirubicin (d1)

Day	Substance	Dosage	Solution	Appl.	Inf. time	Procedure
AE Antiemesis: Emetogenicity high (AC), FOSAP, GRAN i.v., DEXA i.v
Access: peripheral venous
DGHO 2016, DKG 2016, MASCC/ESMO 2016, on combinations of anthracycline and cyclophosphamide
1	Fosaprepitant	150 mg	NaCl 0.9% 150 ml	i.v.	20 min	30 min before Epirubicin (d1)
1	Dexamethasone	12 mg	NaCl 0.9% 50 ml	i.v.	5 min	30 min before Epirubicin (d1)
1	Granisetron	1 mg	NaCl 0.9% 50 ml	i.v.	5 min	15 min before Epirubicin (d1)
or other 5-HT3 receptor antagonist

Day	Substance	Dosage	Appl.	Inf. time	Procedure
SUP Supportive therapy: Mesna i.v., hour 0 (pre), p.o. 2 h, 6 h after onset Cyclophosphamide
Access: peripheral venous
Mesna 0h,2h,6h, prophylaxis of urinary tract toxicity by cyclophosphamide. At the time of oxazaphosphorin injection, 20% of the oxazaphosphorin dose is injected simultaneously as mesna. 2 and 6 h after onset, oral intake of 40% of the oxazaphosporin dose.
1	Mesna	120 mg/m² BSA	i.v.	1 min	1 min before Cyclophosphamide (d1)
1	Mesna	240 mg/m² BSA	p.o.		90 min after Cyclophosphamide (d1)
1	Mesna	240 mg/m² BSA	p.o.		5 h after Cyclophosphamide (d1)
It is to be taken 6 hours after the start of the cyclophosphamide infusion.

Day	Substance	Dosage	Solution	Appl.	Inf. time	Procedure
CTX Antineoplastic therapy: EPIR/CYCL Breast Carcinoma (EC)
Access: central venous, port
1	Epirubicin	90 mg/m² BSA	Dextrose 5% 500 ml	i.v.	45 min	Sequence
1	Cyclophosphamide	600 mg/m² BSA	NaCl 0.9% 500 ml	i.v.	30 min	Sequence

Day	Substance	Dosage	Appl.	Inf. time	Procedure
HW Hematopoietic growth factors: FN risk 10-20%, G-CSF long-acting, pegylated
Access: - none -
Risk of febrile neutropenia (FN) 10-20% and 1 risk factor: age > 65 y, laboratory parameters (anemia, lymphocytopenia < 700/µl, hypalbuminemia, hyperbilirubinemia) previous chemotherapy, comorbidities, low performance status, advanced symptomatic tumor disease (DKG 2016)
2	Pegfilgrastim	6 mg	subc	Bolus	24 h after Cyclophosphamide (d1)
Use at risk: FN 10-20% and 1 risk factor, other long-acting G-CSF possible.

Warnings

Epirubicin: cardiac toxicity, maximum cumulative dose 900-1000 mg/m² KOF. For EPIR extravasation: dry cold (not just before or after Dexrazoxane infusion) on day of extravasation. Dexrazoxane i.v. for 3 days: 2 days 1000 mg/m², 3rd day 500 mg/m², do not use in parallel with DMSO. First infusion as soon as possible and within the first 6 hours.

Notes

This protocol was established based on a recommendation from the AGO to extrapolate from AC + paclitaxel to EC + paclitaxel and use in dose equivalent because of the more favorable side effect profile. In the work of Smith and Khasraw, the lower cardiotoxicity of EPIR vs DOXO is addressed. The side effect profile was based on the publication by Minckwitz for EC followed by docetaxel.

Cycle diagram

Hydration: Balanced Crystalloid Solution

Substance	1	2	3	4	5	6	7
	Week 1 / d
Balanced Crystalloid Solution (i.v.)

Antiemesis: Emetogenicity high (AC), FOSAP, GRAN i.v., DEXA i.v

Substance	1	2	3	4	5	6	7
	Week 1 / d
Fosaprepitant (i.v.)
Dexamethasone (i.v.)
Granisetron (i.v.)

Supportive therapy: Mesna i.v., hour 0 (pre), p.o. 2 h, 6 h after onset Cyclophosphamide

Substance	1	2	3	4	5	6	7
	Week 1 / d
Mesna (i.v.)
Mesna (p.o.)
Mesna (p.o.)

Antineoplastic therapy: EPIR/CYCL Breast Carcinoma (EC)

Substance	1	2	3	4	5	6	7
	Week 1 / d
Epirubicin (i.v.)
Cyclophosphamide (i.v.)

Hematopoietic growth factors: FN risk 10-20%, G-CSF long-acting, pegylated

Substance	1	2	3	4	5	6	7
	Week 1 / d
Pegfilgrastim (subc)

Cycles

Cycle length 21 days, recommended cycles: 4

Controls:

Blood count: on day 1 and subsequently weekly
ECG Cardiotoxicity of epirubicin, check cardiac function before/under therapy recommended. See technical info
Day 1: GOT, GPT, GGT, Bilirubin, AP, Cholinesterase Epirubicin: continuous liver monitoring is necessary during therapy. In case of elevated bilirubin, dose adjustment, if necessary, see summary of product characteristics. Cyclophosphamide: dose reduction is recommended in case of impaired liver function.
Day 1: Creatinine, glomerular filtration rate (GFR) Epirubicin: If serum creatinine levels are elevated (> 5 mg/dl), the dose should be reduced. Cyclophosphamide: In case of impaired renal function, dose reduction is recommended.
Day 1: Urine status Urinary sediment must be checked regularly for erythrocytes and other signs of uro/nephrotoxicity.
Day 1: Na⁺, K⁺, Ca²⁺, Mg²⁺ Cyclophosphamide: exclusion of electrolyte disturbances before use.

Pharmacokinetics

Epirubicin: hepatischer Abbau, 50% biliäre Elimination Cyclophosphamid: hepatischer Abbau, hauptsächlich renale Elimination

Original indication

Paclitaxel weekly, Breast Cancer, adjuvant

Original author

Sparano JA (2008)

Origin

The Eastern Cooperative Oncology Group, Southwest Oncology Group, Cancer and Leukemia Group, Noth Central Cancer Treatment Group

References

Sparano JA, Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med 2008 Apr 17;358(16):1663-71. doi: 10.1056/NEJMoa0707056. PMID: 18420499. [PMID]
von Minckwitz G, Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol 2010 Apr 20;28(12):2015-23. doi: 10.1200/JCO.2009.23.8303. PMID: 20308671. [PMID]
De Laurentiis M, Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008 Jan 01;26(1):44-53. doi: 10.1200/JCO.2007.11.3787. PMID: 18165639. [PMID]
Smith LA, Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer 2010 Jun 29;10:337. doi: 10.1186/1471-2407-10-337. PMID: 20587042. [PMID]
Khasraw M, Epirubicin: is it like doxorubicin in breast cancer? A clinical review. Breast 2012 Apr;21(2):142-9. doi: 10.1016/j.breast.2011.12.012. PMID: 22260846. [PMID]
Jones RL, A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer. Br J Cancer 2009 Jan 27;100(2):305-10. doi: 10.1038/sj.bjc.6604862. PMID: 19165198. [PMID]

Recommendations

12/2023: European Society for Medical Oncology

Status

Valid since 2023-09-18, Version 1.1, last updated 2023-09-09

Last modification: V1.1: Protocol name changed according to current standard V1.0: Cato test successful. Use this scheme for first 4 cycles, then use protocol EC x 4 followed by PACL, Breast Ca, adj., B. V0.1: Cyclophosphamide duration and sequence according to primary literature. Epirubicin duration is according to carrier solution volume.

Important notice

The copyrighted protocols are treatment recommendations. The information contained in this compilation on cytostatic drugs, concomitant medication and other therapeutic procedures, as well as dosage and application information, is continuously reviewed with all due care by the authors and editors involved. Nevertheless, the publishers and authors do not assume any liability for the correctness - also with regard to possible printing errors.

The protocols may not be changed in terms of content.

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The publishers and authors assume no liability for the accuracy of the contents. The application is at the own responsibility of the treating physician. ©Onkopti.