Drug Formulary information is intended for use by healthcare professionals. It is not intended to be medical advice. Some of the information, including information about funding for cancer drugs, does not apply to all patients. Cancer treatment plans are unique to each patient. If you are a patient, please speak with your healthcare team to understand how this information applies to you.
PACL(W)+TRAS
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.
Treatment of HER2-positive breast cancer
Note: The clinical trial included patients with negative nodes (a single axillary lymph node micrometastasis was allowed) and tumor size < 3 cm.
trastuzumab
New Drug Funding Program
(Trastuzumab (Biosimilar) - Adjuvant Treatment for Breast Cancer)
(NDFP Website
)
Note: Different trastuzumab products are not interchangeable.
Paclitaxel Weekly for 12 weeks1:
| PACLitaxel | 80 mg /m² | IV (1 hour infusion) | Day 1 |
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PLUS Trastuzumab2 to be given for one year, starting concurrently with Paclitaxel.
Weekly Trastuzumab Schedule - LOADING DOSE: |
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| trastuzumab | 4 mg /kg | IV over 90 minutes | Day 1 (week 1) |
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THEN, Weekly Trastuzumab - MAINTENANCE DOSE: |
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| trastuzumab | 2 mg /kg | IV over 30 minutes* | Day 1 (starting week 2) |
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Q7 Days
OR Alternative Trastuzumab Schedule:
Q21 Day Trastuzumab Schedule - LOADING DOSE: |
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| trastuzumab | 8 mg /kg | IV over 90 minutes | Day 1 (Cycle1) |
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THEN, Q21 Day Trastuzumab - MAINTENANCE DOSE:
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| trastuzumab | 6 mg /kg | IV over 30 minutes* | Day 1 (starting cycle 2) |
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Q21 Days |
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*if loading dose was well-tolerated
1 If a dose of paclitaxel is missed, it should be made up (trastuzumab should be given even if paclitaxel missed). Up to 3 doses can be made up and should be completed within 16 weeks of starting treatment.
2 In the clinical trial (Tolaney et al), patients were given weekly trastuzumab during the paclitaxel phase (x 12 weeks), then they either continued on the weekly schedule or switched to the Q21 day schedule. A repeat loading dose was not needed as long as the trastuzumab monotherapy is started 1 to 3 weeks after the completion of combination therapy.
WEEKLY (Paclitaxel) x 12 doses
unless disease progression or unacceptable toxicity occurs
Trastuzumab is given for one year treatment duration and may start concurrently with paclitaxel treatment.
Low
Low
Other Supportive Care:
- Weekly Paclitaxel: Patients should be pretreated with a corticosteroid as well as an antihistamine and a H2 blocker. For example:
- Dexamethasone 10mg IV 30 minutes before paclitaxel
- Diphenhydramine 50mg IV 30 minutes before paclitaxel
- Ranitidine 50mg IV 30 minutes before paclitaxel
- Trastuzumab: Nausea and vomiting are usually symptoms that are 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.
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.
Dosage with toxicity
Paclitaxel:
- Patients should not be treated until neutrophil ≥ 0.8 x 109/L and platelet counts ≥ 100 x 109/L.
- If trastuzumab is held or discontinued during paclitaxel treatment, paclitaxel may continue at the discretion of the physician
Suggested dose levels:
| Dose level | Dose of Paclitaxel (mg/m2) per week |
| ideal starting dose | 80 |
| -1 | 70 |
| -2 | 60 |
| -3 | 50 |
| -4 | 40 |
- Missed doses should be made up. Once the dose has been decreased, it should not be re-escalated.
- Discontinue treatment if toxicity recurs after 4 dose reductions (or specified in the table below).
| Worst Toxicity Type / Counts x 109/L in the Previous Cycle | Paclitaxel (% previous dose) |
| Febrile Neutropenia; Infection with or without neutropenia; Thrombocytopenic bleeding; Grade 4 ANC ≥7 days |
First occurrence: May consider GCSF (if neutropenia) and restart at previous dose 2nd occurrence: *Give with GCSF (if neutropenia) and restart by ↓ 1 dose level 3rd occurrence: *Give with GCSF (if neutropenia) and restart by ↓ 1 dose level 4th occurrence: *Discontinue paclitaxel |
| Grade 3 neurotoxicity | Hold*; restart at ↓ 1 dose level |
| Worsening neurotoxicity (even if grade 2) | may consider ↓ 1 dose level |
| Grade 3 nausea/vomiting |
Hold until ≤ grade 2; restart at 80% dose; Discontinue if grade 3 recurs despite dose reduction |
| Grade 2 mucositis or diarrhea on day of treatment | Hold until ≤ grade 1; restart at same dose |
| ≤ Grade 3 mucositis or diarrhea | Hold until ≤ grade 1; restart at ↓ 1 dose level (lowest dose level = 60 mg/m2) |
| Grade 3 related organ | Hold*, then 80% |
| Grade 4 related organ, neurotoxicity | Discontinue |
| *Do not retreat until toxicity has recovered to ≤ grade 2 (or indicated in table), platelets ≥ 100 x 109/L, and ANC ≥ 0.8 x 109/L. Discontinue paclitaxel if delay for > 21 days (or > 14 days for neurotoxicity). Missed paclitaxel doses (up to 3) can be made up; all paclitaxel doses must be given within 16 weeks of starting treatment. | |
- No dose adjustment required for hematological toxicity.
- Trastuzumab may be continued if paclitaxel is delayed (other than for cardiotoxicity or severe hypersensitivity reactions that occurred when both drugs were given).
- For maintenance treatment, if a patient has not had a dose for ≥ 28 days, a loading dose should be given (Tolaney et al).
Cardiotoxicity:
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Relationship of LVEF to Lower Limit of Normal (LLN)
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Trastuzumab dose modification
based on asymptomatic LVEF decrease from baseline
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< 10 percentage points
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10-15 percentage points
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≥ 16 percentage points
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Within facility’s normal limits
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Continue
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Continue
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Hold and repeat MUGA/ECHO after 4 weeks
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1-5% below LLN
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Continue 1
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Hold and repeat MUGA/ECHO after 4 weeks 1, 2
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Hold and repeat MUGA/ECHO after 4 weeks 2, 3
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≥ 6% below LLN
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Continue and repeat MUGA/ECHO after 4 weeks 3
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Hold and repeat MUGA/ECHO after 4 weeks 2, 3
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Hold and repeat MUGA/ECHO after 4 weeks 2, 3
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2 After 2 holds, consider permanent trastuzumab discontinuation
3 Start ACEI therapy and refer to cardiologist
Management of Hypersensitivity:
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Toxicity |
Action |
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Mild hypersensitivity reaction (Grade 1): flushing, rash, pruritus |
Consider ↓ infusion rate; complete infusion and observe patient. Consider premedication for next infusion. |
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Moderate hypersensitivity reaction (Grade 2): moderate rash, flushing, mild dyspnea, chest discomfort |
Hold and use beta-agonists, antihistamines, antipyretics, and/or corticosteroids as appropriate; complete infusion at ↓ rate if possible. Use premedication for next infusion. May resume infusion at a rate of 10% of original rate for 15 minutes, then at 25% of original rate for 15 minutes, and if no further symptoms develop, continue at original rate until infusion is complete. |
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Severe hypersensitivity reaction (Grade 3): hypotension, angioedema, respiratory distress, generalized urticaria |
Hold and manage symptoms aggressively with beta-agonists, antihistamines, antipyretics, and/or corticosteroids. Re-challenge at a slower rate, only after premedication with at least a corticosteroid and antihistamine. |
Hepatic Impairment
Trastuzumab: No adjustment required.
Paclitaxel: Caution and dose reduction advised in patients with moderate to severe hepatic impairment. Patients with hepatic impairment may be at risk of toxicity, especially severe myelosuppression. Suggested are:
| Bilirubin and/or AST/ALT | Paclitaxel Dose |
| 1.5-3 x ULN | Hold for 1 week; restart at same dose if ≤ grade 1; restart by ↓ 1 dose level if remains at grade 2 (may re-escalate if recover to ≤ grade 1.) |
| >3 x ULN | Hold; then restart with 50% dose or discontinue |
Renal Impairment
Trastuzumab and Paclitaxel: No adjustment required.
Dosage in the Elderly
No adjustment of paclitaxel required, but elderly patients are more at risk for severe toxicity.
No adjustment of trastuzumab is 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 PACLitaxel, trastuzumab drug monograph(s) for additional details of adverse effects
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Very common (≥ 50%) |
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
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'
Refer to PACLitaxel, trastuzumab drug monograph(s) for additional details
- Monitor INR in patients receiving warfarin; warfarin dosage adjustment may be required.
- Concurrent use with radiation may increase the risk of radiation pneumonitis
- Caution and monitor with CYP3A4 and CYP 2C8 inducers , inhibitors, and substrates
- Avoid concomitant use of cardiotoxic drugs as additive effects may occur
Refer to PACLitaxel, trastuzumab drug monograph(s) for additional details
Note: Different trastuzumab products are not interchangeable.
Administration
Paclitaxel:
- In order to minimize patients’ exposure to DEHP leaching from PVC bags or sets, use polyolefin or polypropylene infusion bags and polyethylene-lined administration sets (with a 0.22 micron in-line filter).
- Dilute in 250-500 mL Normal Saline or 5% Dextrose, in a final concentration of 0.3-1.2 mg/mL.
- For weekly dosing, infuse over 1 hour
- Excessive shaking, agitation, or vibration may induce precipitation and should be avoided.
Trastuzumab:
- NOTE: Herceptin® (trastuzumab) and Kadcyla® (trastuzumab emtansine) are NON-INTERCHANAGEABLE. There have been fatal reports where the incorrect trastuzumab product was administered to patients with breast cancer in the clinical trials setting.
- Mix in 250 mL bag NS. Do not use D5W as it causes protein aggregation. Do not shake.
- Infuse loading dose IV over 90 minutes; subsequent infusions may be given over 30 minutes if the initial loading dose is well-tolerated.
- DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
- Should not be mixed or diluted with other drugs.
- Diluent supplied - Bacteriostatic Water for Injection (BWFI) - contains benzyl alcohol 1.1%; if patient is hypersensitive to benzyl alcohol, may reconstitute with Sterile Water for Injection, but must be used immediately and discard unused portion.
- Solution reconstituted with the supplied BWFI is stable up to 28 days refrigerated.
- Do not freeze the reconstituted solution.
Contraindications:
- Patients with a history of severe hypersensitivity reactions to paclitaxe, trastuzumab, drugs formulated in Cremophor EL (polyethoxylated castor oil), Chinese Hamster Ovary (CHO) cell proteins, or any components of these products
- Patients with severe baseline neutropenia
- Trastuzumab should only be used in patients whose tumours overexpress HER
Other Warnings/Precautions:
- Severe arrhythmias may occur during infusion; patients should be appropriately managed and undergo continuous ECG monitoring during subsequent infusions. Congestive heart failure (including LVEF decrease) has been reported in patients who have received other chemotherapy agents, especially anthracyclines.
- Paclitaxel contains ethanol, and is administered with agents such as antihistamines which cause drowsiness. Patients should be cautioned regarding driving and the use of machinery.
- The risk of cardiotoxicity must be weighed against the potential benefits of treatment, especially in older patients, patients with pre-existing cardiac disease (including LVEF < 55%) and patients who have had prior cardiotoxic therapy. Note: in the adjuvant trials, patients with cardiac risk factors were excluded from the trials.
- Exercise caution in patients with pre-existing pulmonary disease or patients with extensive pulmonary tumour involvement, as they may experience more severe lung toxicities.
- Use with caution before or after anthracyclines (for up to 24 weeks after trastuzumab discontinuation due to long half-life).
- Life-threatening infusion-related reactions associated with the administration of trastuzumab may occur. See Adverse Effects for recommended precautions, monitoring, and treatment.
Pregnancy and Lactation:
- Trastuzumab and paclitaxel are not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 7 months after the last dose (for women of child-bearing potential).
- Breastfeeding is not recommended.
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 paclitaxel treatment
- Liver function tests; Baseline and before each cycle
- Blood pressure and pulse rate monitoring during paclitaxel infusion, cardiac monitoring with prior arrhythmia
- 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 of bleeding, infection, diarrhea, musculoskeletal, neurologic (sensory), infusion reactions, flu-like symptoms, cardiotoxicity, lung toxicity; at each visit
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Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Suggested Clinical Monitoring
Renal function tests; baseline and as indicated
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Tolaney SM, Barry WT, Dang CT, et al. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med 2015 Jan 8;372(2):134-41.
Paclitaxel and trastuzumab drug monographs, Cancer Care Ontario.
February 2022 Removed trastuzumab EBP forms
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.
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