regimen-monograph

CMF(PO)+TRAS; CMF(PO)

Regimen Category

Evidence-Informed

Funding Program

ODB - General Benefit

Drugs Used

cyclophosphamide , methotrexate , fluorouracil , trastuzumab

A - Regimen Name

CMF(PO) Regimen

Cyclophosphamide (oral)-Methotrexate-Fluorouracil

CMF(PO)+TRAS Regimen

Cyclophosphamide (oral)-Methotrexate-Fluorouracil, Trastuzumab

Disease Site

Breast

Intent

Adjuvant
Neoadjuvant
Palliative

Regimen Category

Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.

Rationale and Uses

Neoadjuvant treatment for locally advanced breast cancer or adjuvant therapy for node-positive and high risk node-negative breast cancer patients, in whom an anthracycline and taxane is contraindicated.

Trastuzumab may be used concurrently with or after completion of CMF(PO) if applicable (e.g. HER-2 positive, adequate cardiac function).

Supplementary Public Funding

cyclophosphamide
ODB - General Benefit (cyclophosphamide - oral tablets) (

ODB Formulary

)

trastuzumab
New Drug Funding Program (Trastuzumab - Adjuvant Treatment for HER2_neu-Overexpressing Primary Breast Cancer) (NDFP Website)

trastuzumab
Evidence Building Program (Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer) (EBP Website)

trastuzumab
New Drug Funding Program (Trastuzumab - Second Line - Metastatic Breast Cancer) (NDFP Website)

B - Drug Regimen

cyclophosphamide

100 mg /m²

Days 1 to 14

_{(Outpatient prescription in multiples of 25mg tablets)}

methotrexate

40 mg /m²

Day 1 and 8

fluorouracil

600 mg /m²

Day 1 and 8

For patients with HER2 positive tumours, Trastuzumab may be given for one year, starting either concurrently with or after completion of CMF(PO).

trastuzumab

Refer to TRAS (Breast - Adjuvant) regimen for details.

C - Cycle Frequency

REPEAT EVERY 28 DAYS

For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs

Trastuzumab: Refer to TRAS (Breast - Adjuvant) regimen for details.

D - Premedication and Supportive Measures

Antiemetic Regimen:

Moderate (Days 1 and 8)

Other Supportive Care:

Also refer to CCO Antiemetic Summary

• Trastuzumab: Nausea and vomiting may be related to infusion-associated reactions. To prevent recurrence of infusion-associated reactions, acetaminophen and diphenhydramine may be given as pre-medication. Refer to Trastuzumab drug monograph for full details.

E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. The following recommendations are in use at some centres.

Dosage with toxicity

Hematologic Toxicities:

Worst Toxicity Type / Counts x 10⁹/L in Prior Cycle	Cyclophosphamide (% previous dose)	Methotrexate (% previous dose)	Fluorouracil (% previous dose)
Febrile Neutropenia, or Thrombocytopenic bleeding, or Grade 4 ANC ≥ 7 d	75% * (or consider GCSF for isolated neutropenia)
Grade 3 related organ	75% for suspect drug(s)*.
Grade 4 related organ, Any grade pneumonitis, cardiac or viral reactivation	Discontinue suspect drug (s)

_{*Do not retreat until toxicity has recovered to ≤ grade 2, platelets ≥ 100 x 10⁹/L, and ANC ≥ 1.5 x 10⁹/L.}

Hepatic Impairment

AST/ALT		Bilirubin	Methotrexate (% previous)	Fluorouracil (% previous)	Cyclophosphamide (% previous)
2-4 x ULN	OR	2-4 x ULN	50% or Discontinue	No change	No change
>4 X ULN	AND	< 4 X ULN	Discontinue	No change	Caution
		> 4 X ULN	Discontinue	Discontinue	Caution

Renal Impairment

Creatinine Clearance (mL/min)	Cyclophosphamide (% previous dose)	Methotrexate (% previous dose)	Fluorouracil (% previous dose)
>50 – 80	100%	50-75%	100%
>30 – 50	100%	OMIT	100%
10 – 30	50-75%	OMIT	Consider dose ↓

Dosage in the Elderly

No dose modification routinely required, but should be used with cautiion and monitored closely.

Methotrexate has not been well studied in the elderly. It should be used with extreme caution because of likely renal and hepatic impairment and reduced folate stores in the elderly.

F - Adverse Effects

Refer to cyclophosphamide, methotrexate, fluorouracil drug monograph(s) for additional details of adverse effects

Refer to trastuzumab drug monograph for adverse effect details (not listed below).

Most Common Side Effects

Less Common Side Effects, but may be
Severe or Life-Threatening

Myelosuppression ± infection / bleeding
Cystitis
Nausea and vomiting
Diarrhea
Stomatitis, anorexia
Alopecia
Nephrotoxicity
↑ LFTs
Reproductive risk
Conjunctivitis

· SIADH

· Cardiac, AMI, arrhythmia

· Thromboembolism, DIC, HUS, VOD, hemolysis

· Secondary malignancies

· Pneumonitis

· Leukoencephalopathy (may be delayed)

· Severe rash, photosensitivity

· Rhabdomyolysis

· Pancreatitis

G - Interactions

Refer to cyclophosphamide, methotrexate, fluorouracil drug monograph(s) for additional details

H - Drug Administration and Special Precautions

Refer to cyclophosphamide, methotrexate, fluorouracil drug monograph(s) for additional details

I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

Clinical toxicity assessment (including GI, cystitis, cardiac, infection).
CBC before each cycle
Baseline and regular liver function tests
Baseline and regular renal function tests and urinalysis
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

J - Administrative Information

Approximate Patient Visit

CMF(PO)

0.5 hour

CMF(PO)+TRAS

CMF: 0.5 hour
Trastuzumab: 1.5 hours (first dose); 0.5 hour (subsequent doses)

Pharmacy Workload (average time per visit)

CMF(PO)

18.742 minutes

CMF(PO)+TRAS

24.379 minutes

Nursing Workload (average time per visit)

CMF(PO)

41.667 minutes

CMF(PO)+TRAS

47.083 minutes

K - References

Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10.

Cyclophosphamide, methotrexate, fluorouracil drug monographs, Cancer Care Ontario.

Fisher B, Brown AM, Dimitrov NV, et al. Two months of Doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of Cyclophosphamide, Methotrexate, and 5-Fluorouracil in positive-breast cancer patients with tamoxifen-nonresponsive tumors: results from the NSABP B-15, J. Clin Oncol 1990 Sep:8(9): 1483-1496

Paik S, Bryant J, Tan-Chiu E, et al. HER2 and Choice of Adjuvant Chemotherapy for Invasive Breast Cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst 2000; 92: 1991-1998.

PEBC Advice Documents or Guidelines

Optimal Systemic Therapy for Early Female Breast Cancer

M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability.
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Last Updated: July 21, 2026

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