regimen-monograph

CMF(PO)+TRAS

Intent

Palliative

Regimen Category

Evidence-Informed

Funding Program

ODB - General Benefit New Drug Funding Program

Drugs Used

cyclophosphamide , methotrexate , fluorouracil , trastuzumab

A - Regimen Name

CMF(PO)+TRAS Regimen

Cyclophosphamide (oral)-Methotrexate-Fluorouracil, Trastuzumab

Disease Site

Breast

Intent

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

Treatment of advanced breast cancer

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 (Biosimilar) - Second Line - Metastatic Breast Cancer)

B - Drug Regimen

Note: Different trastuzumab products are NOT INTERCHANGEABLE.

cyclophosphamide

100 mg /m²

Days 1 to 14

methotrexate

40 mg /m²

Day 1 and 8

fluorouracil

600 mg /m²

Day 1 and 8

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

Loading Dose (cycle 1):

trastuzumab

8 mg /kg

Cycle 1, day 1 ONLY

Maintenance Dose (starting cycle 2):

trastuzumab

6 mg /kg

Day 1

C - Cycle Frequency

CMF(PO):

REPEAT EVERY 28 DAYS

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

Trastuzumab:

REPEAT EVERY 21 DAYS

Until disease progression or unacceptable toxicity

D - Premedication and Supportive Measures

Antiemetic Regimen:

Low
Consider prophylaxis daily for cyclophosphamide PO

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Trastuzumab: Routine pre-medication is not recommended. Refer to the "Management of Infusion-Related Reactions" table on pre-medications at re-challenge.

E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated.

Refer to TRAS regimen for details on trastuzumab.

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.}

Trastuzumab: Management of Infusion-related reactions:

Also refer to the CCO guideline for detailed description of Management of Cancer Medication-Related Infusion Reactions.

Grade

Management (trastuzumab)

Re-challenge

1 or 2

Stop or slow the infusion rate.
Manage the symptoms.

Restart:

Once symptoms have resolved, if IR was not severe, consider resuming the infusion at a slower rate.

Restart and re-challenge with pre-medications (e.g. H1-receptor antagonist and corticosteroid).

3 or 4

Stop treatment.
Aggressively manage symptoms.

Discontinue permanently (do not re-challenge).

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 ↓
<10	50% or OMIT	OMIT	Consider dose ↓

Dosage in the Elderly

No dose modification of cyclphosphamide 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, trastuzumab drug monograph(s) for additional details

H - Drug Administration and Special Precautions

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

Note: Different trastuzumab products are NOT INTERCHANGEABLE.

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.

Refer to TRAS regimen for details on trastuzumab.

Recommended Clinical Monitoring

CBC; baseline and before each cycle
Liver function tests; Baseline and before each cycle
Renal function tests; Baseline and before each cycle
Urinalysis; Baseline and as clinically indicated
Cardiac assessment, including evaluation of left ventricular function (Echocardiogram or MUGA scan); more frequent with asymptomatic reductions in LVEF; baseline, q3 months during treatment, then q6 months after trastuzumab discontinuation x2 years (and annually up to 5 years after last trastuzumab dose in adjuvant breast cancer patients who received anthracyclines), also as clinically indicated
Clinical assessment and grading of stomatitis, diarrhea, bleeding, infection, GI, pulmonary, CNS, cystitis,and local site toxicity, skin effects (rash or hand-foot-syndrome), cardiovascular or ophthalmic effects, infusion reactions, thromboembolism; At each visit
Toxicity ratings of infusion-associated symptoms (especially first infusion); Close monitoring at each visit
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Lung function tests if pulmonary toxicity suspected;
CXR; Baseline
Hepatitis B and Hepatitis C infection testing; Baseline

J - Administrative Information

Cyclophosphamide: Outpatient prescription for home administration

Approximate Patient Visit

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

Pharmacy Workload (average time per visit)

24.379 minutes

Nursing Workload (average time per visit)

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, trastuzumab drug monographs, Cancer Care Ontario.

Engelsman E, Klijn JCM, et al, “Classical” CMF vs. a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer. Eur J Cancer, 1991; 27: 966-970.

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.

Semiglazov V, Eiermann W, Zambetti M, et al. Surgery following neoadjuvant therapy in patients with HER2-positive locally advanced or inflammatory breast cancer participating in the NeOAdjuvant Herceptin (NOAH) Study. EJSO 2011: 856-863.

PEBC Advice Documents or Guidelines

Optimal Systemic Therapy for Early Female Breast Cancer

June 2020 Removed neoadjuvant and adjuvant intents - De-iisted from ST-QBP March 31, 2020; Added trastuzumab infusion reactions management info

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
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Last Updated: July 21, 2026

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