Cycle length: 21 days.
Duration of therapy: 6 cycles (pembrolizumab plus cisplatin and fluorouracil) then pembrolizumab alone to complete up to 35 cycles total or until disease progression or unacceptable toxicity*. |
| Drug | Dose and route | Administration | Given on days |
| 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 an 0.2- to 5-micron sterile, nonpyrogenic, low-protein-binding inline or add-on filter. | Day 1 |
| Cisplatin | 100 mg/m2 IV | Dilute in 250 mL NS¶ and administer over 60 minutes (or at 1 mg/min). Do not administer with aluminum needles or sets. Alternative: Dilute in 2 L 5% dextrose in one-half or one-third NS 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 |
| Fluorouracil (FU) | 1000 mg/m2 IV | Dilute in 500 to 1000 mL D5W¶ and administer as a continuous infusion over 24 hours per day for four days (96 hours). Begin each course after completion of cisplatin. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose can be diluted in 100 to 150 mL NS.¶ | Days 1 through 4 |
| 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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| Hydration | - Administer isotonic saline with electrolyte supplementation. Although clinical practice is variable, one approach is to administer isotonic saline with 20 mEq/L of potassium chloride and 2 grams/L of magnesium sulfate. Administer a minimum of 1000 mL over 2 to 3 hours prior to, and a minimum of 500 mL over the 2 hours following cisplatin administration.
- IV fluid should be sufficient to establish a urine flow of at least 100 mL/hour for at least 2 hours prior to and 2 hours after cisplatin administration[2].
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH on day 1, with substantial risk for delayed emesis on days 2 through 4, from cycle 1 through cycle 6.
- Minimal on day 1, with minimal risk for delayed emesis on days 2 through 4, from cycle 7 through cycle 35 of single-agent pembrolizumab.
- 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 pembrolizumab, cisplatin, or FU.
- Refer to UpToDate topics on 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 warranted (incidence of febrile neutropenia was 9% in this study).[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 | - The optimal approach to cisplatin therapy in patients with pre-existing kidney impairment is unknown. In the original protocol, cisplatin was not administered to patients with creatinine >1.5 × ULN or creatinine clearance less than 60 mL/min.[1]
- In the original protocol, patients were eligible for treatment if baseline total bilirubin was ≤1.5 × ULN or direct bilirubin was ≤ULN for those with bilirubin >1.5 × ULN; AST and ALT were <2.5 × ULN or <5 × ULN for those with liver metastases.[1] Lower starting doses of FU may be needed with severe liver impairment.[4]
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents; cisplatin nephrotoxicity; and chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents.
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| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of immunotherapy.
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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: |
- CBC with differential and platelet count every 3 weeks prior to each new cycle of treatment.
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- Assess electrolytes (including glucose) and liver and kidney function tests every 3 weeks prior to each new cycle of treatment.
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- Assess thyroid function tests prior to initiation of therapy and every 1 to 2 cycles during treatment, and/or as clinically indicated.
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- 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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- Monitor for infusion reactions during treatment. Interrupt infusion and permanently discontinue pembrolizumab for severe or life-threatening infusion-related reactions, as indicated in the United States Prescribing Information.[3]
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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- Monitor for diarrhea, stomatitis, and cutaneous toxicity during therapy (palmar-plantar erythrodysesthesia).
- Refer to UpToDate topics on management of acute chemotherapy-related diarrhea, oral toxicity associated with chemotherapy, cutaneous side effects of conventional chemotherapy agents, and management and prevention of complications during initial treatment of head and neck cancer.
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- Assess change in neurologic function prior to each chemotherapy course.
- Refer to UpToDate topics on prevention and treatment of chemotherapy-induced peripheral neuropathy and overview of neurologic complications of platinum-based chemotherapy.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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- Monitor for fluoropyrimidine-associated cardiotoxicity (chest pain, ECG changes, etc), and hyperammonemic encephalopathy.
- Refer to UpToDate topics on fluoropyrimidine-associated cardiotoxicity and overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - For grade 3 neutropenia, no dose reductions are required. For grade 4 neutropenia, reduce cisplatin and FU by 20% for subsequent cycles. In either case, consider G-CSF prophylaxis for subsequent cycles.[1]
- For grade 3 or 4 thrombocytopenia, reduce cisplatin and FU by 20% for subsequent cycles.[1]
- For a first febrile neutropenia (with documented infection) episode, reduce cisplatin and FU doses by 20% and consider use of prophylactic G-CSF for subsequent cycles. For a second episode of febrile neutropenia, reduce cisplatin and FU doses by another 20%.[1]
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| Mucositis or diarrhea | - Hold FU for grade ≥2 mucositis or diarrhea until it resolves to grade ≤1 and reduce FU dose by 20% for subsequent cycles.[1]
- NOTE: Severe diarrhea and mucositis after FU should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on chemotherapy-associated diarrhea, constipation and intestinal perforation; management and prevention of complications during initial treatment of head and neck cancer; and management of acute chemotherapy-related diarrhea.
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| Ototoxicity or sensory neuropathy | - Hold cisplatin for grade ≥2 toxicity.
- For grade 2 toxicity, the original protocol recommends changing from cisplatin to carboplatin AUC 5.[1]
- For grade 3 or 4 toxicity, the original protocol recommended a switch from cisplatin to carboplatin AUC 5 if toxicity resolved to grade ≤2 within 12 weeks of last infusion. If toxicity does not resolve to grade ≤2, then discontinue cisplatin. If already using carboplatin, then discontinue.[1]
- Even if the cisplatin dose had been modified prior to switching to carboplatin due to ototoxicity or sensory neuropathy, carboplatin may be started at a dose of AUC 5; patients are eligible to receive 2 additional carboplatin dose modifications.
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| Palmar-plantar erythrodysesthesia | - For grade 2 toxicity, no dose reductions required. For grade 3 or 4 toxicity, a reduce cisplatin and FU by 20% for subsequent cycles.[1]
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| Immune-mediated adverse events | - No pembrolizumab dose reductions are recommended; treatment is withheld or discontinued to manage toxicities.
- 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 or less, 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). Resume pembrolizumab only after resolution to grade ≤1 and glucocorticoid has been tapered.
- 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 × ULN), total bilirubin elevation >3 × ULN in patients with no hepatic tumor involvement, AST/ALT elevation to >10 × ULN for hepatitis with hepatic tumor involvement, grade 2 or greater 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 NCCN,[7] and from the SITC.[8]
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy and mucocutaneous toxicities associated with immune checkpoint inhibitors.
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.[4]
- Refer to UpToDate topics on fluoropyrimidine-associated cardiotoxicity.
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| Other toxicity | - For any other grade ≥3 toxicity, reduce cisplatin and FU doses by 20% for subsequent cycles once toxicity resolves to grade 1 (≤grade 2 for laboratory adverse events).[1]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
