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CRBPDOCETRAS
Adjuvant
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.
Neo-adjuvant or adjuvant treatment for node-positive or high risk node-negative, and HER-2 positive early breast cancer
trastuzumab
New Drug Funding Program
(Trastuzumab (Biosimilar) - Adjuvant Treatment for Breast Cancer)
Note: Different trastuzumab products are not interchangeable.
Q3 Weekly Chemotherapy:
| DOCEtaxel | 75 mg /m² | IV | Day 1 |
|
CARBOplatin 1 | AUC 6 | IV | Day 1 |
|
1Adjust Carboplatin dose to AUC target (using Calvert formula) as outlined in "Other Notes" section. PLUS Q3 Weekly Trastuzumab Dosing
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| trastuzumab | 8 mg /kg | IV over 90 minutes | Day 1 (Loading dose - first cycle only) |
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then |
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| trastuzumab | 6 mg /kg | IV over 30 minutes* | Day 1 (starting second cycle) |
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*if loading dose is well-tolerated
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REPEAT EVERY 21 DAYS
Docetaxel and Carboplatin: For a usual total of 6 cycles unless disease progression or unacceptable toxicity occurs
Trastuzumab: To be given concurrently with docetaxel and carboplatin and continued for up to 1 year, unless disease progression or unacceptable toxicity occurs
Moderate + NK1 antagonist (Carboplatin AUC ≥ 5)
High
Consider G-CSF prophylaxis for patients at high risk of febrile neutropenia. See G-CSF recommendations.
Other Supportive Care:
- Dexamethasone 8 mg bid po for 3 days starting 1 day prior to docetaxel (prevent anaphylaxis / fluid retention.)
- Trastuzumab: To prevent recurrence of infusion-associated reactions, acetaminophen and diphenhydramine may be given as pre-medication. Refer to Trastuzumab drug monograph for full details.
- Consider antibiotic prophylaxis or G-CSF according to local guidelines.
Also refer to CCO Antiemetic Recommendations.
Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.
In general, the dose of trastuzumab should be delayed if the chemotherapy cycle is delayed for scheduling convenience; if the delay is > 1 week, loading dose should be repeated.
Dosage with toxicity
|
Toxicity Type/ Counts x109/L
|
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Toxicity Type/ Counts x109/L
|
Carboplatin1
|
Docetaxel (% previous) 1 |
|
Febrile Neutropenia / Thrombocytopenic bleeding
|
OR
|
Grade 4 ANC ≥ 7 d or grade 4 platelets |
↓ 1 AUC1 or GCSF |
75%1 or GCSF |
|
Grade 3 non-hematologic/ organ
|
|
|
↓ 1 AUC1 |
75%1; discontinue if recurs |
| Any occurrence of cystoid macular edema | No change | Hold and investigate; refer patient promptly to an ophthalmic examination. Discontinue if confirmed. | ||
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Grade 4 non-hematologic / organ
|
|
|
Discontinue
|
Discontinue
|
Trastuzumab:
Product Monograph Recommendations
- Trastuzumab should be held with a fall in LVEF (if LVEF falls ≥10 points from baseline and/or if LVEF falls to < 50%). Repeat LVEF in 3 weeks and consider discontinuing. Discontinue if clinically significant cardiac dysfunction or cardiac failure develops.
Canadian Consensus Guidelines
- Discontinue if symptomatic.
Management of trastuzumab therapy in adjuvant breast cancer patients with asymptomatic decreases in LVEF (Mackey et al 2008):
|
Relationship of LVEF to Lower Limit of Normal (LLN) |
Trastuzumab dose modification based on asymptomatic LVEF decrease from baseline |
||
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≤ 10 percentage points |
10-15 percentage points |
≥ 15 percentage points |
|
|
Within facility’s normal limits |
Continue |
Continue |
Hold and repeat MUGA/ECHO after 4 weeks |
|
1-5% below LLN |
Continue 1 |
Hold and repeat MUGA/ECHO after 4 weeks 1, 2 |
Hold and repeat MUGA/ECHO after 4 weeks 2, 3 |
|
≥ 6% below LLN |
Continue and repeat MUGA/ECHO after 4 weeks 3 |
Hold and repeat MUGA/ECHO after 4 weeks 2, 3 |
Hold and repeat MUGA/ECHO after 4 weeks 2, 3 |
1 Consider cardiac assessment and starting ACEI therapy
2 After 2 holds, consider permanent trastuzumab discontinuation
3 Start ACEI therapy and refer to cardiologist
Hypersensitivity:
|
Toxicity
|
Trastuzumab
|
Docetaxel
|
|
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Mild hypersensitivity reaction
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↓ infusion rate (and/ or hold) and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate. Consider premedication for next infusion. |
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Moderate hypersensitivity reaction
|
Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion. |
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Severe hypersensitivity reaction or Pulmonary Toxicity
|
Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids. Discontinue permanently and do not rechallenge. |
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Hepatic Impairment
|
|
AST and/or ALT |
|
Alk Phosp |
|
Bilirubin |
Docetaxel (% previous dose) |
Carboplatin or Trastuzumab |
|
Mild-moderate |
> 1.5 X ULN |
AND |
> 2.5 x ULN |
|
|
Do not treat |
No change |
|
Severe |
> 3.5 x ULN |
OR |
> 6 x ULN |
OR |
> ULN |
Do not treat. Discontinue if treatment already started. |
Renal Impairment
|
Creatinine Clearance (mL/min)
|
DOCEtaxel
(% previous dose)
|
CARBOplatin
(% previous dose)
|
trastuzumab
(% previous dose)
|
|
20 - 50
|
No adjustment appears to be required. |
Use Calvert formula (Refer to "Other Notes" section) |
No adjustment appears to be required. |
|
<20
|
Discontinue
|
Dosage in the Elderly
For docetaxel, no adjustment required, but caution should be exercised in elderly patients with poor performance status.
For carboplatin, caution should be exercised and dose reduction considered as elderly patients may have more severe myelosuppression and neuropathy.
For trastuzumab, no adjustment required; the risk of cardiac dysfunction and myelosuppression may be increased in elderly patients. The reported trials did not determine differences in efficacy between patients > 65 years versus younger patients.
Refer to trastuzumab, DOCEtaxel, CARBOplatin drug monograph(s) for additional details of adverse effects
|
Most Common Side Effects |
Less Common Side Effects, but may be |
|
|
Refer to trastuzumab, DOCEtaxel, CARBOplatin drug monograph(s) for additional details
Refer to trastuzumab, DOCEtaxel, CARBOplatin drug monograph(s) for additional details.
Note: Different trastuzumab products are not interchangeable.
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
- 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; also as clinically indicated
- CBC; baseline and regular
- Liver and renal function tests; baseline and routine
- Electrolytes (including magnesium); baseline and regular
- Clinical toxicity assessment for neurotoxicity, ototoxicity, bleeding, infection, nausea and vomiting, pulmonary toxicity, diarrhea, infusion reactions, fluid retention, cutaneous reactions, thromboembolism, musculoskeletal pain, ophthalmic effects.
-
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
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Carboplatin, docetaxel, trastuzumab drug monographs, Cancer Care Ontario.
Mackey JR, Clemons M, Cote, MA, et al. Cardiac management during adjuvant trastuzumab therapy: recommendations of the Canadian trastuzumab working group. Current Oncology 2008; 15: 24-35.
Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365(14):1273-83.
February 2022 Removed trastuzumab EBP forms; updated Rationale and uses section
Calvert Formula
DOSE (mg) = target AUC X (GFR + 25)
- Target AUC of 4 to 6 mg/mL·min (previously treated patients) or 6 to 8 mg/mL·min (previously untreated patients)
- AUC = product of serum concentration (mg/mL) and time (min)
- GFR (glomerular filtration rate) expressed as measured Creatinine Clearance or estimated from Serum Creatinine (by Cockcroft and Gault method or Jelliffe method)
(Calvert AH, Newell DR, Gumbrell LA, et al, Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol, 1989; 7: 1748-1756)
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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