Regimen:
Indication
Adjuvant treatment for early breast cancer in patients who are unsuitable for
anthracycline based chemotherapy
Regimen detail
Administration
Classical CMF (IV) for Early Breast Cancer
Day
1&8
1&8
1&8
Drug
Cyclophosphamide
Methotrexate
Fluorouracil (5-FU)
Dose
600mg/m2
40mg/m2
600mg/m2
Route
IV
IV
IV
Fluorouracil, methotrexate and cyclophosphamide are given by slow intravenous
bolus into the side arm of a fast flowing drip of 0.9% sodium chloride.
Cyclophosphamide may be given in 250-500ml 0.9% sodium chloride over 30
minutes
Frequency
Every 28 days
Maximum 6 cycles
Extravasation
Fluorouracil and methotrexate are inflammatants (Group 2)
Cyclophosphamide is a neutral agent (Group 1)
Premedication
Not usually required.
Emetogenicity
This regimen has moderate emetogenic potential – refer to local protocol
Additional
recommended
supportive medication
Mouthwashes as per local policy
Loperamide 4mg po stat then 2mg prn for diarrhoea
Consider folinic acid (calcium folinate/leucovorin) rescue 15mg po 6 hourly x 6
doses, starting 24 hours post methotrexate D1&D8 (only for patients with
severe toxicities such as mucositis, sore eyes, diarrhoea, severe renal
impairment or “third – space” fluid collection)
Pre- treatment
evaluation
FBC
LFT
U&E (inc. SrCr)
Baseline - results valid for 4 weeks
Baseline - results valid for 4 weeks
Baseline - results valid for 4 weeks
Regular investigation
FBC
LFT
U&E (inc SrCr)
Clinical
Assessment
Pre D1 – results valid for 72 hours,
Pre D1 – results valid for 7 days
Pre D1 – results valid for 7 days
Clinically assess patient prior to each cycle,
particularly focusing on whether the patient has
developed stomatitis or haemorrhagic cystitis
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within range, authorisation to
administer must be given by
prescriber/consultant
Dose modifications
•
Haematological
toxicity
≥ 1 x 109/l
≥100 x 109/l
≥ 80ml/min
<1.5 x ULN
<2.5 x ULN
Neutrophil count
Platelet count
Creatinine Clearance
Bilirubin
ALT
Standard limits for
administration to go
ahead – if blood results not
Reduce the dose of methotrexate if the patient has a pleural effusion or ascites
(Is this done empirically or is there a defined dose reduction?)
Delay 1 week if neutrophils <1.0 x 109/l and/or platelets <100 x 109/l.
Dose reduction should be considered if myelosuppression results in delay of
subsequent courses.
In adjuvant treatment, dose reduction and delays can compromise outcome. GCSF should be considered if more than one delay and/or before dose reduction.
Contact relevant consultant.
•
•
Renal
impairment
Hepatic
impairment
CrCl
(ml/min)
>80
60-80
50-59
30-50
10-30
Cyclophosphamide
dose
100%
100%
100%
100%
75%
Methotrexate
dose
100%
65%
50%
50%
Contraindicated
<10
50%
Contraindicated
Bilirubin
ALT
< 1.5 x
ULN
1.5 – 3 x
x ULN or
<2.5 x
ULN
2.5 - 5 x
ULN
Fluorouracil (5FU)
dose
100%
100%
100%
100%
100%
Consider dose
reduction
Cyclophosphamide
dose
Methotrexate
dose
Fluorouracil
(5FU) dose
100%
100%
100%
100%*
75%
67%
Consider dose
>5x
reduction / use
> 3x ULN
Contraindicated Contraindicated
ULN
alternative regimen*
* Cyclophosphamide is not recommended in patients if bilirubin > 1.5 x ULN or
AST/ALT >2–3xULN, but exposure to active metabolites may not be increased
and therefore a dose reduction may not be necessary. Consultant decision
•
NCI Common
Toxicity Criteria
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Last printed 02/12/2010
Toxicity
Febrile
neutropenia
Definition
ANC <0.5 x 109/l plus
fever requiring IV
antibiotics +/hospitalisation
Stomatitis & for Grade III painful
Mucositis
erythema or ulcers
requiring rehydration
resolving to Grade I or
less painless ulcers of
mild soreness
Other
Grade III/IV toxicity
toxicities
(except alopecia)
Dose adjustment
20% reduction of cyclophosphamide
only
20% dose reduction of methotrexate
and fluorouracil. Consider folinic acid
rescue (see above)
Continue with 20% dose reduction of
suspected causative agent(s)
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provided toxicity has resolved to
Grade I or less
If further toxicity occurs, an
additional reduction may be made
after discussion with consultant.
• Defer treatment for any grade III/IV non-haematological toxicity (excluding
alopecia)
• If a delay of more than 3 weeks is required for recovery, or more than 2 dose
reductions are necessary, the patient should discontinue treatment
Adverse effects – the
contents of the table indicate
the adverse effects that should
be included in consent to
treatment forms
Rare or Serious Side Effects
Frequently occurring Side Effects
Grade 3/4 febrile neutropenia
Nausea and vomiting
Myelosuppression
Fatigue
Risk of second malignancy e.g.
Long term risk of early menopause,
leukaemia
reduced fertility
Cardiac toxicity
Stomatitis and mucositis
Teratogenicity
Diarrhoea
Other side effects include: alopecia (partial), loss of appetite, taste disturbance,
skin sensitivity, gritty eyes, blurred vision, nail changes, bladder irritation
(including haemorrhagic cystitis), allergic reactions and altered liver and kidney
function.
Significant drug
interactions –
Co-trimoxazole/trimethoprim – Avoid if possible – enhances antifolate effect.
If essential, monitor FBC regularly.
NSAIDs – Monitor renal function and FBC if used concomitantly as may reduce
renal excretion of methotrexate (increased risk in renal impairment).
Probenecid – avoid – increases methotrexate toxicity 3-4 fold.
Antibacterials – Monitor FBC – penicillins, tetracyclines, sulphonamides,
doxycycline and ciprofloxacin may reduce methotrexate clearance.
For full details consult product
literature/ reference texts
Comments
Dihydropyrimidine dehydrogenase (DPD) deficiency can result in severe toxicity
secondary to reduced fluorouracil metabolism – avoid use in patients with
known DPD deficiency
Cardiotoxicity has been associated with fluoropyrimidine therapy, with adverse
events being more common in patients with a prior history of coronary artery
disease. Caution must be taken in patients with a history of significant cardiac
disease, arrhythmias or angina pectoris.
Methotrexate accumulates in 3rd space fluids (pleural effusions, ascites) leading
to prolonged elimination time and potentially increased toxicity. Consider folinic
acid rescue (as above) starting 24 hours after each dose.
Methotrexate can cause acute or chronic interstitial pneumonitis, which is often
associated with blood eosinophilia. Monitor patients for dyspnoea, cough
(especially dry, non-productive) and fever. Deaths have been reported.
Cumulative Doses
References
None
• Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et
al. Two months of doxorubicin-cyclophosphamide with and without interval
reinduction therapy compared with 6 months of cyclophosphamide,
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Document title
Document number
Approval date
Written by
Checked by
Authorised by
Review date
Document reviewed by
Version number
Summary of changes
Controlled document
Last printed 02/12/2010
methotrexate, and fluorouracil in positive-node breast cancer patients with
tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant
Breast and Bowel Project B-15. J Clin Oncol. 1990; 8:1483-96.
Tancini G, Bonadonna, G, Valagussa P, Marchini S and Veronesi U. Adjuvant
CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin
Oncol. 1983;1:2-10.
Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla
C et al. Combination chemotherapy as adjuvant treatment in operable breast
cancer. N Engl JMed 1976;294:405-10.
Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M et
al. Ten year experience with CMF-based adjuvant chemotherapy in
resectable breast cancer. Breast Cancer Res Treat.1985;5:95-115.
Daniels S. North London Cancer Network, Dose adjustment of cytotoxics for
hepatic impairment [internet]. accessed 16/04/2009 available at
http://www.bopawebsite.org/tiki-download_file.php?fileId=621
Daniels S. North London Cancer Network, Dose adjustment of cytotoxics for
renal impairment [internet]. 16/04/2009 available at
http://www.bopawebsite.org/tiki-download_file.php?fileId=620
Baxter K, editor. Stockley’s Drug Interactions. Pharmaceutical Press; 2009.
Accessed on line on 06/05/09 available at
https://www.medicinescomplete.com/mc/
Summary of Product Characteristics Fluorouracil 50mg/ml injection (Hospira)
[internet] accessed 16/04/2009 available from
http://emc.medicines.org.uk/document.aspx?documentId=636
Summary of Product Characteristics Methotrexate 100mg/ml injection
(Hospira) [internet] accessed 16/04/2009 available at
http://emc.medicines.org.uk/document.aspx?documentId=11588
Summary of Product Characteristics Cyclophosphamide 500mg injection
(Baxter) [internet] accessed 11/11/2009 available from
http://www.ecomm.baxter.com/ecatalog/loadResource.do?bid=44228
Allwood M, Stanley, A, Wright P, editors. The cytotoxics handbook. 4th ed.
Radcliffe Medical Press 2002.
Trissel LA. Handbook of Injectable Drugs. 15th ed. American Society for
Health-Systems Pharmacists 2009. Accessed on line on 06/05/09 available at
http://www.medicinescomplete.com/mc/hid/current/
Classical CMF (IV) for Breast Cancer
ASWCS10 BR016
Jeremy Braybrooke, Consultant Medical Oncologist,
BHOC, and Chair, ASWCS Drugs and Therapeutics
Committee
Becky Bagnall, Consultant Pharmacist, NBT
Jeremy Braybrooke, Chair, ASWCS Drug+Therapeutics
Committee
15/10/2011
Jeremy
Braybrooke
Digitally signed by Jeremy Braybrooke
DN: cn=Jeremy Braybrooke, o, ou,
email=james.carr@aswcs.nhs.uk, c=GB
Date: 2010.12.02 15:59:59 Z
Becky Bagnall
Digitally signed by Becky Bagnall
DN: cn=Becky Bagnall, o, ou, email=james.carr@aswcs.nhs.
uk, c=GB
Date: 2010.12.02 16:00:32 Z
Digitally signed by Jeremy Braybrooke
cn=Jeremy Braybrooke, o, ou,
Jeremy Braybrooke DN:
email=james.carr@aswcs.nhs.uk, c=GB
Date: 2010.12.02 16:01:09 Z
1.1.a
Version
Document No
Version Number
ASWCS10 BR016
1.1.a
*ONLY VALID ON DATE OF PRINTING*
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