| Cycle length: 28 days for four cycles. |
| Drug | Dose and route | Administration | Given on days |
| Irinotecan¶ | 60 mg/m2 IV | Dilute in 500 mL 5% dextrose in waterΔ and administer over 90 minutes. | Days 1, 8, and 15 |
| Cisplatin | 60 mg/m2 IV | Dilute in 250 mL normal saline and administer over 120 minutes. Do not administer with aluminum needles or sets. | Day 1 |
| 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.
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH on day 1 (90% frequency of emesis).
MODERATE on days 8 and 15 (30 to 90% frequency of emesis). - 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.
- 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 necrosis; avoid extravasation.[2]
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Primary prophylaxis with granulocyte colony stimulating factors is not recommended (risk of febrile neutropenia approximately 3%[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 renal dysfunction | - The optimal approach to cisplatin therapy in patients with preexisting renal impairment is unknown. Such patients were excluded from the original trial.[1] A lower starting dose of irinotecan may be needed for patients with hepatic or severe renal impairment.[3]
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
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- Electrolytes, liver and renal function prior to each cycle. Electrolytes may need to be assessed more frequently in patients with severe diarrhea.
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- Patients who develop diarrhea should be closely monitored and supportive care measures (eg, fluid and electrolyte replacement, loperamide, antibiotics, etc) provided as needed. Do not retreat until resolution of diarrhea for at least 24 hours without antidiarrheal medication.
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- Monitor for neurotoxicity prior to each treatment cycle.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
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- Irinotecan is associated with early and late diarrhea, both of which may be severe. For patients who develop abdominal cramping and/or diarrhea within 24 hours of receiving irinotecan, give atropine (0.3 to 0.6 mg IV) and premedicate with atropine during later cycles. Patients must be instructed in the early use of loperamide as a treatment for late diarrhea.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Each cycle should not begin until the ANC is >1500 cells/microL and platelets are >100,000/microL.[1] During treatment, withhold irinotecan for nadir ANC <500/microL, febrile neutropenia, or nadir platelet count ≤50,000/microL until recovery to ≤grade 1 toxicity. After recovery, omit the day 15 dose, reduce all subsequent irinotecan doses by 10 mg/m2, and administer further cycles with day 1 and 8 treatment only every 21 days.[1] In the original protocol, cisplatin doses were reduced by 25% in subsequent cycles for grade 4 neutropenia, febrile neutropenia, or grade 4 thrombocytopenia.[1]
|
| 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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| Nephrotoxicity | - Hold cisplatin until serum creatinine <1.5 mg/dL and/or blood urea nitrogen <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 if <60 mL/min.[2] In the original protocol, the cisplatin dose was reduced by 25% for grade 2 renal toxicity.[1]
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| Diarrhea | - Irinotecan is associated with early and late diarrhea, both of which may be severe. For patients who develop early diarrhea and/or cholinergic symptoms, premedication with atropine is an effective prophylaxis during later cycles. Do not retreat until resolution of diarrhea for at least 24 hours without antidiarrheal medication.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
- In the original protocol, patients with grade 3 or 4 diarrhea had irinotecan withheld until recovery to ≤grade 1.[1] After recovery, omit the day 15 dose, reduce all subsequent irinotecan doses by 10 mg/m2, and administer further cycles with day 1 and 8 treatment only every 21 days.
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| Other toxicity | - For other nonhematologic toxicities, if grade 2, hold treatment until ≤grade 1; if grade 3 or 4, hold treatment until ≤grade 2.[3]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
