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CMF(PO)+TRAS

Cancer Type: Breast  Intent: Adjuvant, Neoadjuvant, Palliative
Regimen Category: Evidence-Informed
Funding:
ODB - General Benefit
    cyclophosphamide - oral tablets
New Drug Funding Program
    Trastuzumab - Adjuvant Treatment for HER2_neu-Overexpressing Primary Breast Cancer
Evidence Building Program
    Trastuzumab (EBP) - Adjuvant Treatment for Breast Cancer
New Drug Funding Program
    Trastuzumab - Second Line - Metastatic Breast Cancer
A - Regimen Name

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
  • 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 - 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 PO Days 1 to 14
(Outpatient prescription in multiples of 25mg tablets)
methotrexate
40 mg /m² IV Day 1 and 8
fluorouracil
600 mg /m² IV 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 IV Cycle 1, day 1 ONLY

Maintenance Dose (starting cycle 2):

trastuzumab
6 mg /kg IV Day 1
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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

Adjuvant: - For a usual treatment duration of one year unless limited by cardiotoxicity risk (may be funded for up to 18 treatments over a maximum period of 14 months)

Palliative - 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: 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
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, fluorouraciltrastuzumab 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

  • 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
     

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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

May 2019 Updated emetic risk category


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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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.