Cycle length: 28 days.
Duration of therapy: Disease progression or unacceptable toxicity. |
| Drug | Dose and route | Administration | Given on days |
| Liposomal irinotecan¶ | 50 mg/m2 IV | Dilute in 500 mL D5W or NSΔ and administer over 90 minutes. | Days 1 and 15 |
| Oxaliplatin | 60 mg/m2 IV◊§ | Dilute in 500 mL D5WΔ and administer over 2 hours, after the completion of liposomal irinotecan. | Days 1 and 15 |
| Leucovorin¥ | 400 mg/m2 IV | Dilute in 250 mL D5WΔ and administer over 30 minutes. Start 30 minutes after the completion of oxaliplatin. | Days 1 and 15 |
| Fluorouracil (FU) | 2400 mg/m2 IV | Dilute in 500 to 1000 mL NS or D5WΔ and administer within 60 minutes of leucovorin as a continuous IV infusion over 46 hours. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose diluted in 100 to 150 mL NS.Δ | Days 1 and 15 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
|
| Prophylaxis for infusion reactions | - Although infusion reactions have been reported with oxaliplatin, no standard premedication is required for this regimen.[2]
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
|
| Vesicant/irritant properties | - Oxaliplatin◊ and FU are irritants, but oxaliplatin can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Primary prophylaxis with granulocyte colony stimulating factor (G-CSF) is not required.
- Primary prophylaxis is allowed in high-risk individuals, but the decision to use hematopoietic growth factors must be individualized.[3]
- Secondary prophylaxis is an option after one episode of febrile neutropenia, infection associated with neutropenia, or neutropenic sepsis.[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.
|
| Dose adjustment for baseline liver or kidney dysfunction | - A lower starting dose of FU may be needed for patients with liver impairment.[4]
- Oxaliplatin may require a lower starting dose for severe kidney impairment.[2]
- Refer to UpToDate topics on hepatotoxicity of chemotherapy and other cytotoxic agents and nephrotoxicity of chemotherapy and other cytotoxic agents.
|
| Cardiopulmonary issues | - QT prolongation 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.[2]
- Oxaliplatin is rarely associated with pulmonary toxicity.[2]
- Refer to UpToDate topics on pulmonary toxicity associated with chemotherapy and other cytotoxic agents.
|
| Maneuvers to prevent neurotoxicity | - Pharmacologic methods to prevent/delay the onset of oxaliplatin-related neuropathy are controversial due to the absence of large clinical trials proving benefit. Counsel patients to avoid exposure to cold during and for approximately 48 hours after each infusion.
- Refer to UpToDate topics on neurologic complications of platinum-based chemotherapy.
|
| Maneuvers to prevent diarrhea | - To reduce the risk of severe diarrhea, it is recommended that patient should stop lactose-containing products, eat frequent small meals, eat a low-fat diet and maintain adequate hydration with 8 to 10 glasses of water per day.[1,5-7]
- Refer to UpToDate topic on management of acute chemotherapy-related diarrhea.
|
| UGT1A1*28 allele polymorphism | - Patients with homozygous recessive UGT1A1*28 alleles are at increased risk for severe or life-threatening neutropenia with irinotecan due to increase exposure to SN-38 (active metabolite) because of poor metabolism of UGT1A1. However, grade 3 and 4 neutropenia rates for homozygous UGT1A1*28 alleles compared with non-homozygous UGT1A1*28 alleles were similar at liposomal irinotecan 70 mg/m2 and 50 mg/m2 doses.[1,5] This regimen utilizes liposomal irinotecan 50 mg/m2; therefore, no upfront dose adjustment is required for patients with homozygous UGT1A1*28 alleles.
|
| Strong CYP3A4 inducers and inhibitors; UGT1A1 inhibitors | - Avoid the use of strong CYP3A4 or UGT1A1 inhibitors, if possible, during treatment with liposomal irinotecan. Otherwise, discontinue strong CYP3A4 inhibitors at least 1 week and strong CYP3A4 inducers at least 2 weeks prior to starting liposomal irinotecan.[1,5]
|
| Monitoring parameters: |
- Obtain CBC with differential and platelet count on days 1 and 8 of each treatment cycle and more frequently if clinically indicated.
|
- Assess electrolytes (especially potassium and magnesium) and liver and kidney function prior to each treatment.
|
- Monitor for diarrhea. 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.
|
- Monitor for palmar-plantar erythrodysesthesia.
|
- Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy.
|
- Liposomal irinotecan can cause severe and fatal interstitial lung disease. Withhold the drug in patients with new or progressive dyspnea, cough, fever, pending diagnostic evaluation, and permanently discontinue if interstitial lung disease is confirmed.
|
- Severe diarrhea, mucositis, and/or myelosuppression after the first dose of FU and/or liposomal irinotecan should prompt evaluation for DPD deficiency for FU and UGT1A1*28 allele polymorphism for liposomal irinotecan.
- Refer to UpToDate topics on clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation.
|
| Suggested dose modifications for toxicity: |
| If there is a dose reduction due to toxicity, then the doses should remain reduced. Dose escalation is not permitted. Leucovorin is not dose reduced for any toxicities.[1] |
| Myelotoxicity | - Do not treat unless ANC is ≥2000/microL and platelets are ≥100,000/microL.[1]
- For grade 3 or 4 neutropenia or febrile neutropenia and/or thrombocytopenia, reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 20%. For second occurrence reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 15% to administer 65% of original doses. A third occurrence requires another 15% dose reduction (ie, 50% of original doses) of the three chemotherapy agents before discontinuation of treatment is recommended.[1]
|
| Diarrhea | - For grade 1 or 2 diarrhea, no dose reductions are required.[1]
- For grade 3 or 4 diarrhea, reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 20%. For second occurrence reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 15% to administer 65% of original doses. A third occurrence requires another 15% dose reduction (ie, 50% of original doses) of the three chemotherapy agents before discontinuation of treatment is recommended.[1]
- Refer to UpToDate topics on management of acute chemotherapy-related diarrhea.
|
| Palmar-plantar erythrodysesthesia | - For grade 2 hand-foot syndrome, reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 20%. For second occurrence reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 15% to administer 65% of original doses. A third occurrence requires another 15% dose reduction (ie, 50% of original doses) of the three chemotherapy agents before discontinuation of treatment is recommended.[1]
- For grade 3 or 4 hand foot syndrome, discontinuation of treatment is recommended.[1]
- Refer to UpToDate topics on toxic erythema of chemotherapy (hand-foot syndrome) and drug eruptions.
|
| Neurocerebellar toxicity | - There is no recommended dose for resumption of FU administration following development of hyperammonemic encephalopathy, acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances; the drug should be permanently discontinued.[4]
|
| Sensory neuropathy | - For grade 2, persistent sensory neuropathy, reduce oxaliplatin dose by 20%.[1]
- For grade 3 that resolves prior to next dose, then reduce oxaliplatin dose by 35%. For recurrent grade 3, then dose reduce oxaliplatin by another 15% (ie, 50% total dose reduction).[1]
- For grade 4, discontinuation of oxaliplatin is recommended.
|
| Hepatic or kidney toxicity | - For grade 3 or 4 hepatic or renal toxicity, reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 20%. For second occurrence reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 15% to administer 65% of original doses. A third occurrence requires another 15% dose reduction (ie, 50% original doses) of the three chemotherapy agents before discontinuation of treatment is recommended.[1]
|
| Pulmonary toxicity | - Withhold liposomal irinotecan and oxaliplatin for unexplained pulmonary symptoms until interstitial lung disease or pulmonary fibrosis is excluded. Permanently discontinue both agents if interstitial lung disease is confirmed.
- For grade 3 or 4 other pulmonary toxicity, reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 20%. For second occurrence reduce all doses of liposomal irinotecan, oxaliplatin, and FU by 15% to administer 65% of original doses. A third occurrence requires another 15% dose reduction (ie, 50% of original doses) of the three chemotherapy agents before discontinuation of treatment is recommended.[1]
|
| Cardiac toxicity | - 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: incidence, clinical manifestations, mechanisms, and management.
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
September 2025
