Cycle length: 21 days.
Duration of therapy: 6 cycles. |
| Drug | Dose and route | Administration | Given on days |
| Cisplatin | 80 mg/m2 IV | Dilute in 250 mL NS* and administer over 30 minutes or at a rate of 1 mg/min. Alternative: Dilute in 2000 mL 5% dextrose in half NS (0.45%)* containing 37.5 g of mannitol and infuse over a six to eight hour period.[2] Do not administer with aluminum needles or sets. | Day 1 |
| Capecitabine¶ | 1000 mg/m2 per dose by mouth | Twice daily; swallow whole with water within 30 minutes after a meal, with each dose as close to 12 hours apart as possible. Do not cut or crush tablets.Δ | Days 1 through 14 |
| Trastuzumab◊ | 8 mg/kg IV loading dose | Dilute in 250 mL NS* and administer over 90 minutes. Do not mix with D5W and do not infuse as an IV push or bolus. | Day 1, cycle 1 only |
| Trastuzumab◊ | 6 mg/kg IV | Dilute in 250 mL NS* and administer over 30 minutes. Do not mix with D5W and do not infuse as an IV push or bolus. | Day 1, starting with cycle 2§ |
| Pretreatment considerations: |
| Hydration | - IV fluid to establish a urine flow of at least 100 mL/hour for at least two hours prior to and two hours after cisplatin administration.
- Alternative: Pretreatment hydration with 1 to 2 L of fluid infused for 8 to 12 hours prior to each dose of cisplatin.[2]
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH (>90% risk of emesis); prophylaxis for acute and delayed nausea and emesis through days 1 to 4 is warranted.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
- According to the NCCN Antiemesis Guidelines, cisplatin doses >50 mg/m2 are considered of high emetic risk. While it is true the capecitabine given on days 2 through 14 is low risk, it may be confusing for practitioners to state that antiemetic risk is only high on day 1, since the period of nausea may last for several days.
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| Prophylaxis for infusion reactions | - Routine prophylaxis not indicated for cisplatin. Most clinicians do not routinely premedicate prior to the first trastuzumab dose. 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-related reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Cisplatin is an irritant but can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not indicated (estimated risk of febrile neutropenia is 5%[1]).
- Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
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| Dose adjustment for baseline renal dysfunction | - The optimal approach to cisplatin therapy in patients with preexisting renal impairment is unknown. A lower starting dose of capecitabine may be needed for patients with renal impairment.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Cardiopulmonary issues | - Trastuzumab is associated with cardiotoxicity; assess baseline LVEF prior to therapy. Patients with baseline LVEF <50% were excluded from this study.[1] Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease.[3]
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents and pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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| Monitoring parameters: |
- Obtain CBC with differential and platelet count prior to each new treatment cycle.
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- Assess electrolytes and liver and renal function prior to each new treatment cycle.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
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- Monitor for infusion reactions, especially during the first two courses of trastuzumab.
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- Monitor for diarrhea and cutaneous toxicity (palmar-plantar erythrodysesthesias) due to capecitabine.
- Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents.
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- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Hold new course of treatment until ANC is ≥1500/microL and platelet count is ≥100,000/microL.[2]
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| Nephrotoxicity | - Hold cisplatin until serum creatinine is <1.5 mg/dL and/or BUN is <25 mg/dL. For grade ≥2 nephrotoxicity during treatment (creatinine >1.5 times normal value despite adequate hydration), creatinine clearance should be determined prior to next cycle, and cisplatin dose reduced (or switch to carboplatin) if <60 mL/min. While this is clinically appropriate, there is not a specific reference in the United States Prescribing Information outlining a change to carboplatin based on creatinine clearance of <60 mL/min.
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| Cardiotoxicity | - Assess LVEF at least every three months during trastuzumab.[3] The United States Prescribing Information recommends withholding trastuzumab for at least four weeks for LVEF ≥16% decrease from baseline or LVEF below lower limit of normal and ≥10% decrease from baseline; repeat LVEF assessment every four weeks. May resume trastuzumab treatment if LVEF returns to normal limits within four to eight weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruption for cardiomyopathy.
- 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.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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| Neurologic toxicity | - Neuropathy usually is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Patients with mild neuropathy can continue to receive full cisplatin doses. However, if the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| Hand-foot syndrome and diarrhea/stomatitis | - Hold capecitabine for grade 3 toxicity, and following recovery, reduce the dose by 25% for recurrent grade 2 or worse toxicity.
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
|
| Other toxicity (including hepatotoxicity) | - Recommended dose modification guidelines for capecitabine are listed in the United States Prescribing Information.[4]
- Grade 2: For the first, second, and third occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment (first occurrence, no dosage adjustment; second occurrence, 75% of the starting dose; third occurrence, 50% of the starting dose).[4] For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy.
- Grade 3: For the first and second occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment at a reduced dose (first occurrence, 75% of the starting dose; second occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine therapy.
- Grade 4: Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy, and begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or less; discontinue treatment for first recurrence of grade 4 toxicity.
- Patients with grade 3 or 4 hyperbilirubinemia may resume capecitabine once toxicity has reduced to grade ≤2, but at a reduced dose.
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| Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume with the next planned treatment cycle.[4] |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
