Cycle length: 21 days.
Duration of therapy: Maximum 35 cycles or until disease progression. |
| Drug | Dose and route | Administration | Given on days |
| Trastuzumab | Loading dose: 8 mg/kg IV | Dilute in 250 mL NS¶ and administer over 90 minutes for the loading dose. 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 to 90 minutes. Do not mix with D5W and do not infuse as an IV push or bolus. | Day 1 of every subsequent cycle, starting with cycle 2 |
| OxaliplatinΔ | 130 mg/m2 IV | Dilute in 500 mL D5W¶ and administer over two hours. Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[2] | Day 1 |
| Capecitabine◊ | 1000 mg/m2 orally per dose | Twice daily (total dose 2000 mg/m2 per day), rounded to the nearest tablet size; 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.§ | Days 1 to 14 |
| Pembrolizumab | 200 mg IV | Dilute in NS or D5W¶ to a final concentration between 1 and 10 mg/mL and infuse over 30 minutes through a 0.2- to 5-micron sterile, nonpyrogenic, low-protein-binding inline or add-on filter. | Day 1, every 3 weeks |
| OR |
| Pembrolizumab | 400 mg IV | Dilute in NS or D5W¶ to a final concentration between 1 and 10 mg/mL and infuse over 30 minutes through a 0.2- to 5-micron sterile, nonpyrogenic, low-protein-binding inline or add-on filter. | Day 1, every 6 weeks |
| Pretreatment considerations: |
| Immune status | - Anti-PD-1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as pembrolizumab in patients with an underlying autoimmune disorder.[3] Pembrolizumab should be used with extreme caution in such individuals.
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| Emesis risk | - Oxaliplatin: MODERATE.
- Oral capecitabine: LOW.
- Pembrolizumab and trastuzumab: LOW TO MINIMAL.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - There is no standard premedication regimen for oxaliplatin or pembrolizumab. 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 | - Oxaliplatin is classified as an irritant, but can cause significant tissue damage (rare); 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 justified (estimated risk of febrile neutropenia <20%[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 liver or kidney dysfunction | - Lower starting doses of oxaliplatin and capecitabine may be needed for kidney impairment.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy and periodically during treatment.
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| Maneuvers to prevent neurotoxicity | - Counsel patients to avoid exposure to cold during and for approximately 72 hours after each infusion of oxaliplatin. Prolongation of the oxaliplatin infusion time from two to six hours may mitigate acute neurotoxicity.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| Cardiopulmonary issues | - Prolongation of the QTc interval and ventricular arrhythmias have been reported after oxaliplatin. ECG monitoring is recommended if therapy is initiated in patients with heart failure, bradyarrhythmias, coadministration of drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid oxaliplatin in patients with congenital long QT syndrome. Correct hypokalemia and hypomagnesemia prior to initiating oxaliplatin. Pulmonary toxicity is rarely reported with oxaliplatin.
- Trastuzumab is associated with cardiomyopathy; assess baseline LVEF prior to therapy and at least every three months during therapy.[4] Patients with heart failure, coronary artery disease, myocardial infarction in the prior six months, or baseline LVEF <50% were excluded from one study.[1] Trastuzumab may also cause serious pulmonary toxicity and should be used with caution in patients with pre-existing pulmonary disease.
- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents and fluoropyrimidine-associated cardiotoxicity.
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| Regulatory issues | - An FDA-approved patient medication guide, which is available with the United States Prescribing Information,[3] must be dispensed with pembrolizumab.
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| Monitoring parameters: |
- Obtain CBC with differential and platelet count prior to each treatment.
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- Assess electrolytes and liver and kidney function every three weeks prior to each new treatment.
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- Assess changes in neurologic function prior to each treatment.
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- All patients should be closely monitored and evaluated for immune-mediated adverse effects at least every three weeks during therapy.
- Monitor for fatigue, colitis, hepatotoxicity, hypophysitis, adrenal insufficiency, hypo- or hyperthyroidism, nephrotoxicity, pneumonitis, hyperglycemia, and skin rash. Many other clinically relevant immune-mediated toxicities have been observed, which may involve any organ system or tissue, and may be severe or fatal.
- While immune-mediated toxicities generally occur during treatment with pembrolizumab, adverse reactions, including infusion-related reactions, may also develop weeks to months after therapy discontinuation.
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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- Assess cardiac function every three months during therapy or as clinically indicated.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents and fluoropyrimidine-associated cardiotoxicity.
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- Monitor for infusion reactions during pembrolizumab infusion and during trastuzumab infusion. For pembrolizumab, interrupt infusion and permanently discontinue for severe or life-threatening infusion-related reactions, as indicated in the United States Prescribing Information.[3]
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- Monitor for mucositis, diarrhea, and palmar-plantar erythrodysesthesia during treatment.
- Refer to UpToDate topics on oral toxicity associated with chemotherapy, cutaneous side effects of conventional chemotherapy agents, and enterotoxicity of chemotherapeutic agents.
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- More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy.
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| Suggested dose modifications for toxicity: |
| Immune-mediated toxicity | - No dose reductions of pembrolizumab are recommended; treatment is withheld or discontinued to manage toxicities.[1]
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Based on the type and severity of the reaction, withhold treatment and administer systemic glucocorticoids. Upon resolution to ≤grade 1, initiate glucocorticoid taper. Immune-mediated adverse reactions that do not resolve with systemic glucocorticoids may be managed with other systemic immunosuppressants (based on limited data). Discontinue pembrolizumab permanently for any grade 4 or recurrent grade 3 immune-mediated adverse event or one that is life threatening, grade 3 pneumonitis, AST/ALT elevation >8 times ULN, total bilirubin elevation >3 times ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 times ULN for hepatitis with hepatic tumor involvement, grade ≥2 myocarditis, grade 3 neurologic toxicity, suspected exfoliative dermatologic condition, severe (grade 3) or life-threatening (grade 4) infusion reactions, or if there is an inability to reduce glucocorticoid dose to 10 mg or less of prednisone equivalent per day within 12 weeks of initiating glucocorticoids.[3]
- Most pembrolizumab-associated rashes can be managed with topical corticosteroid creams.
- Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for pembrolizumab,[3] from ASCO,[5] from the MASCC,[6] from the NCCN,[7] and from the SITC.[8]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
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| Myelotoxicity | - A new cycle of treatment should not start until neutrophils recover to >1500/microL and platelets recover to >75,000/microL.[1] Interrupt capecitabine for any grade 2 or worse hematologic toxicity and delay treatment with both capecitabine and oxaliplatin until complete recovery or improvement to ≤grade 1.[9] Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of a grade 2 or grade 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event.[10] After recovery, reduce oxaliplatin to 100 mg/m2 for any intracycle grade 3 or 4 neutropenia or thrombocytopenia. Discontinue capecitabine and oxaliplatin permanently if, despite dose reduction, hematologic toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.
|
| Neurotoxicity | - Withhold oxaliplatin for grade 3 to 4 paresthesias/dysesthesias and reduce dose by 25% upon resolution to grade 0 to 2.[1] The United States Prescribing Information recommends a dose reduction in oxaliplatin to 65 mg/m2 for persistent grade 2 neurosensory events that do not resolve, and permanent discontinuation for persistent grade 3 neurosensory events.[11]
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
|
| Gastrointestinal toxicity | - Interrupt capecitabine and delay oxaliplatin for any grade 2 or worse gastrointestinal toxicity; restart treatment only after complete recovery or improvement to ≤grade 1.[1,4,6] After recovery, reduce the dose of oxaliplatin to 100 mg/m2 after the first episode of grade 2 or worse diarrhea or mucositis. Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of grade 2 or 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event.[10] Discontinue capecitabine permanently if, despite dose reduction, a given toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.[1,6]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for DPD deficiency. Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Cardiotoxicity | - Assess LVEF at least every three months during trastuzumab.[4] In the original protocol, published as a supplement to the clinical report,[1] patients with any signs or symptoms of heart failure had trastuzumab held while receiving heart failure treatment. Asymptomatic declines in LVEF of ≥16 percentage points or ≥10 points to below the lower limit of normal had trastuzumab held. Reinitiation of treatment was allowed for symptom resolution and/or return of LVEF to baseline, without a specific timeline. The United States Prescribing Information suggests withholding trastuzumab for at least four weeks for LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline and repeat LVEF 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 interruptions for cardiomyopathy.[4]
- There is no recommended dose for the resumption of capecitabine following development of cardiac toxicity, and the drug should be discontinued.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents and fluoropyrimidine-associated cardiotoxicity.
|
| Pulmonary toxicity | - Discontinue trastuzumab for serious pulmonary toxicity. Withhold oxaliplatin for unexplained pulmonary symptoms until interstitial lung disease or pulmonary fibrosis is excluded.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents and pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
|
| Other toxicities (including hepatotoxicity) | - Interrupt capecitabine and delay oxaliplatin for any grade 2 or worse other non-neurologic toxicity (except alopecia); restart treatment only after complete recovery or improvement to ≤grade 1.[1,4,6] Patients with grade 3 or 4 hyperbilirubinemia may resume capecitabine once toxicity has reduced to grade ≤2, but at a reduced dose.[10]
- Reduce the dose of oxaliplatin for subsequent cycles to 100 mg/m2 for drug-related grade 3 toxicity. Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of a grade 2 or grade 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event.[10] Discontinue capecitabine permanently if, despite dose reduction, a given toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.
|
| Doses of capecitabine and trastuzumab omitted for toxicity are not replaced or restored; instead the patient should resume with the next planned treatment cycle.[1] |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
