| This chemotherapy regimen AC followed by T with H and P consists of (5) agents: doxorubicin, cyclophosphamide, paclitaxel, trastuzumab, and pertuzumab. Cycle length: AC is given every 2 weeks as a dose-dense schedule for 4 cycles followed by T given on days 1, 8, and 15 and H and P on day 1 every 21 days for an additional 4 cycles followed (no particular order of administration required) by H and P given every 21 days until the completion of one year of H and P therapy (13 cycles). |
| Drug | Dose and route | Administration | Given on days |
| Doxorubicin | 60 mg/m2 IV | Reconstitute with NS¶ to a concentration of 2 mg/mL and administer over at least three to five minutes.Δ◊ | Day 1 (Every two weeks for 4 cycles) |
| Cyclophosphamide | 600 mg/m2 IV | Mix with 250 mL NS or D5W¶ and administer over 0.5 to 1 hour. | Day 1 (Every two weeks for 4 cycles) |
| Pertuzumab (loading dose) | 840 mg IV | Dilute in 250 mL NS¶ and administer over 90 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycle 5 only) |
| Pertuzumab | 420 mg IV | Dilute in 250 mL NS¶ and administer over 30 to 60 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycles 6, 7, and 8) |
| Trastuzumab (loading dose)§ | 8 mg/kg IV | Dilute in 250 mL NS¶ and administer over 90 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycle 5 only) |
| Trastuzumab§ | 6 mg/kg IV | Dilute in 250 mL NS¶ and administer over 90 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycles 6, 7, and 8) |
| Paclitaxel | 80 mg/m2 IV | Mix in 250 mL NS or D5W¶ and administer over one hour.¥ | Weekly, after completion of AC, starting on cycle 5 day 1, and continuing through cycle 8 |
| Trastuzumab | 6 mg/kg IV | Dilute in 250 mL NS¶ and administer over 30 to 60 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycles 9, 10, 11, 12, and 13, to complete one full year of therapy) |
| Pertuzumab | 420 mg IV | Dilute in 250 mL NS¶ and administer over 30 to 60 minutes. Do not mix with D5W and do not infuse as an IVP or bolus. | Day 1 (Cycles 9, 10, 11, 12, and 13, to complete one full year of therapy) |
| Pretreatment considerations: |
| Emesis prophylaxis | - AC is considered a highly emetogenic chemotherapy regimen (>90% frequency of emesis). As such, we recommend prophylaxis with a combination of a 5HT3 receptor antagonist, dexamethasone, and aprepitant or fosaprepitant.
T is considered low-emetogenic chemotherapy (10 to 30% frequency of emesis); dexamethasone alone is usually adequate. - Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Paclitaxel may cause severe infusion reactions. Premedication for paclitaxel:[2] When paclitaxel is given weekly, dexamethasone 12 mg by mouth should be administered 4 to 6 hours prior to paclitaxel administration for day 1 and day 8 of first cycle at the least. If not administered by mouth, dexamethasone 12 mg IV may be used. If no reaction on day 1 and day 8, then dexamethasone can be deleted. H1 receptor antagonist should be administered for at least day 1 and day 8 of the first cycle; may be dropped in subsequent cycles.[1] Administer H2 antagonist of institution choice IV/by mouth prior to all paclitaxel administrations. Severe infusion reactions (eg, skin rash, flushing, dyspnea, urticaria, back pain, hypotension, chest pain, tachycardia) occur primarily during the first and second infusions, typically within the first hour after the start of the infusion. Premedications are not routinely used prior to the administration of trastuzumab or pertuzumab. However, patients may be instructed to self-administer acetaminophen or an NSAID if flu-like symptoms develop within 24 hours of drug administration.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy and infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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| Vesicant/irritant properties | - Doxorubicin is a vesicant and can cause significant tissue damage if extravasation occurs. For peripheral infusions, the IV line should be recently placed into a large, intact vein, with good blood return established immediately prior to starting the infusion. The IV or catheter site should be continuously monitored throughout the infusion.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
- Paclitaxel is classified as an irritant in most commonly used dilutions. However, tissue sloughing or necrosis has been reported with large-volume extravasations of concentrated solutions.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Hematopoietic growth factor support | - AC is given every two weeks, and hematopoietic growth factor support is needed during this portion: pegfilgrastim injection or on-body pegfilgrastim. No hematopoietic growth factor support is needed during later cycles of therapy.
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| Dose adjustment for liver or renal dysfunction | - The need for cyclophosphamide dose reduction in renal insufficiency is controversial. While some advocate a 25% dose decrease in patients with a CrCl <10 mL/min, others suggest 10 and 20% dose reductions for CrCl values <55 and 20 mL/min, respectively. The FDA-approved manufacturer's package insert provides no specific guidelines for dose reduction.[3] Dose adjustments are not necessary for doxorubicin or paclitaxel in renal impairment.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Hydration | - Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day) and void frequently to reduce the risk of hemorrhagic cystitis.[3] A 500-mL hydration is given prior to cyclophosphamide infusion.
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Pre-existing cardiopulmonary disease | - Doxorubicin is associated with significant cardiotoxicity, the incidence of which is related to the cumulative dose of anthracycline administered. The risk is increased in patients with underlying heart disease, when anthracyclines are used concurrently with other cardiotoxic agents or radiation, and in patients previously treated with mediastinal or chest wall irradiation. Doxorubicin is contraindicated for patients with recent MI, severe myocardial dysfunction, severe arrhythmia, and previous therapy with high cumulative doses of doxorubicin.[4] Trastuzumab and pertuzumab are associated with cardiotoxicity; assess baseline LVEF prior to therapy.[5,6] Further information on anthracycline-associated cardiotoxicity, including discussion about prevention and treatment, is available.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines, cardiotoxicity of trastuzumab and other HER2-targeted agents, clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity, and prevention and management of anthracycline cardiotoxicity.
- Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with pre-existing pulmonary disease.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
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- Serum electrolytes and liver and renal function tests prior to each treatment cycle.
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- Assess changes in neurologic function prior to each treatment cycle.
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- Assess line site periodically during infusion of chemotherapy for signs and symptoms of extravasation.
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- Assess cardiac function prior to initiation of AC then periodically throughout the entire treatment duration.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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- It is recommended to observe the patient for one hour after the initial dose of pertuzumab and for 30 minutes after all subsequent doses for signs of infusion reactions.[5]
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Treatment with AC should be delayed until the ANC is >1000/microL and platelet count is >100,000/microL.[1] For weekly T, treatment should be delayed until the ANC is >1000/microL (>1500/microL for every-three-week T).[1] With both AC and T, a 20% dose reduction with subsequent cycles is recommended for patients with severe, prolonged neutropenia (ANC <500/microL for seven days or longer).[2,4] If patients have an episode of febrile neutropenia or have persistent neutropenia that prevents treatment on schedule, secondary prevention with hematopoietic growth factor support is suggested.[7]
- Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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| Neurologic toxicity | - For patients who develop severe neuropathy (grade 3 or 4) for a week or longer, the dose of paclitaxel should be reduced by 20% for subsequent courses of paclitaxel.[2]
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Renal/hepatic toxicity | - Guidelines for managing doxorubicin, cyclophosphamide, and paclitaxel in patients with symptomatic renal/hepatic dysfunction or asymptomatic changes in renal/hepatic function tests during therapy are addressed in detail separately.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
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| Cardiotoxicity | - Guidelines for managing doxorubicin in patients with symptomatic cardiac dysfunction or asymptomatic changes in LVEF during therapy are addressed in detail separately; however, LVEF should be evaluated prior to and during HP therapy.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
- Hold both trastuzumab and pertuzumab if the LVEF drops to <50% with a 10% or greater absolute decrease below baseline. Repeat LVEF in three weeks; if LVEF drops to <50% with a confirmed 10% or greater absolute decrease below baseline, stop treatment.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
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| Pulmonary toxicity | - Discontinue trastuzumab for serious pulmonary toxicity.[6]
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
