Chemotherapy regimens for diffuse large B cell lymphoma: Rituximab, ifosfamide, carboplatin, and etoposide (R-ICE)^[1]

Cycle length: 21 days.
Drug	Dose and route	Administration	Given on days
Rituximab	375 mg/m² IV^*	Dilute in NS or D5W^¶ to a final concentration of 1 to 4 mg/mL. Initial infusion: Start at 50 mg/hour; escalate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour, as tolerated.^[2] In the absence of a severe infusion reaction, for subsequent infusions, administer 20% of the total dose over the first 30 minutes and the remaining 80% over 60 minutes, as tolerated. The 90-minute infusion schedule should not be used in patients who have clinically significant cardiovascular disease or a circulating lymphocyte count ≥5000/mm³. For patients not meeting these criteria, the recommended infusion rate for subsequent doses is 100 mg/hour, increased by 100 mg/hour every 30 minutes until a maximum infusion rate of 400 mg/hour is reached.	Day minus 2 of cycle 1 (48 hours prior to initiation of cycle 1), then day 1 of cycles 2 to 4 (four total doses).
Ifosfamide	5000 mg/m² continuous IV infusion	Dilute in NS or D5W^¶ to a final concentration of 0.6 to 20 mg/mL and infuse over 24 hours.	Day 4
Mesna^Δ	5000 mg/m² continuous IV infusion	Add to ifosfamide bag and administer over 24 hours. Total concentration of mesna should not exceed 20 mg/mL.	Day 4
Carboplatin	AUC^◊ = 5 mg/mL per min IV (maximum dose = 800 mg)	Dilute in 250 mL NS^¶ and administer over 30 minutes.	Day 4
Etoposide	100 mg/m² IV daily	Dilute in 500 mL NS or D5W^¶ to final concentration <0.4 mg/mL. Infuse over 30 to 60 minutes; if infused more rapidly, severe hypotension may occur.	Days 3 to 5
Pretreatment considerations:
Emesis risk	High (>90% frequency of emesis) on day 4; minimal to low on days 1, 3, and 5.^§ Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity; it is avoided at many institutions. Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Hydration	Adequate hydration (at least 2 liters of oral or IV fluids per day) should be maintained with ifosfamide to reduce the risk of bladder toxicity.^[3] Refer to UpToDate topics hemorrhagic cystitis in cancer patients.
Prophylaxis for infusion reactions	Premedicate with acetaminophen and diphenhydramine, with or without an H2 blocker, 30 minutes prior to at least the first and second infusions of rituximab.^[2] Premedication not routinely required for ifosfamide, carboplatin, or etoposide. Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Infection prophylaxis	Primary prophylaxis with G-CSF is administered as a routine component of this regimen.^[1] Refer to UpToDate topics on use of G-CSFs 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 etoposide and ifosfamide doses may be needed for pre-existing kidney or liver dysfunction.^[3,4] Carboplatin dose is calculated based upon kidney function; dose adjustment is not necessary for liver dysfunction.^[5] Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions.^[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; dosing of anticancer agents in adults; and hemorrhagic cystitis in cancer patients.
Hepatitis screening	Patients should be screened for hepatitis B and C prior to starting rituximab, and if positive, considered for hepatitis B prophylaxis. 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 hepatitis B virus.
Monitoring parameters:
CBC with differential and platelet count weekly during treatment.
Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 grams/m².^[3] Clinical manifestations may include hypophosphatemia, kidney potassium wasting, metabolic acidosis with a normal ion gap, and, rarely, polyuria due to nephrogenic diabetes insipidus. Assess creatinine and electrolytes, including potassium and phosphate, daily during treatment and prior to each new treatment cycle. Refer to UpToDate topics on ifosfamide nephrotoxicity.
Assay for liver function prior to each treatment cycle.
Mesna does not prevent ifosfamide-related hemorrhagic cystitis in all patients. Perform urinalysis on a morning specimen of urine daily, on days 4 and 5.^[3]
Monitor for ifosfamide-related neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily, on days 4 and 5.^[3] CNS side effects may be especially problematic for those over age 60. Refer to UpToDate topics on overview of neurologic complications of conventional nonplatinum cancer chemotherapy.
Monitor vital signs during etoposide infusion.^[5]
Carriers of hepatitis B or C should be monitored for clinical and laboratory signs of active infection during and following completion of therapy. Rituximab should be discontinued if reactivation occurs. 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.
Suggested dose modifications for toxicity:
Myelotoxicity	Delay treatment cycle until the ANC is >1000/microL and platelet count is >50,000/microL.^[1] Dose reduction not indicated for intracycle hematologic toxicity.
Neurotoxicity	Discontinue ifosfamide treatment for encephalopathy. Refer to UpToDate topics on overview of neurologic complications of conventional nonplatinum cancer chemotherapy.
Urotoxicity	If microscopic hematuria (greater than 10 RBCs per high-power field) is present during therapy, then subsequent administration of ifosfamide should be withheld until complete resolution.^[3] Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ANC: absolute neutrophil count; AUC: area under the concentration × time curve; CBC: complete blood count; CNS: central nervous system; D5W: 5% dextrose in water; GFR: glomerular filtration rate; G-CSF: granulocyte colony stimulating factors; IV: intravenous; NCCN: National Comprehensive Cancer Network; NS: normal saline; RBC: red blood cell.

* A subcutaneous formulation (rituximab-hyaluronidase) that uses a shorter administration time is an acceptable alternative for patients who have tolerated at least one full dose of IV rituximab.^[6] Dosing for the subcutaneous formulation varies by histology, and clinicians should refer to the United States Prescribing Information for details.

¶ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).

Δ Due to a longer half-life of ifosfamide and associated metabolites at higher doses, some references recommend continuation of mesna for 12 to 24 hours beyond completion of ifosfamide to reduce the risk of hemorrhagic cystitis. If necessary, oral mesna may be used at a dose twice that of IV mesna.

◊ AUC is converted to a patient-specific carboplatin dose (in mg) according to renal function by using the Calvert formula. The Calvert formula is total dose (mg) = (target AUC) × (GFR + 25). If using measured serum creatinine, limit the maximal GFR for the calculation to 125 mL/min. Refer to UpToDate topics on dosing of anticancer agents in adults.

§ Consensus-based guidelines from the NCCN classify higher carboplatin doses (AUC ≥4) as highly emetogenic; by contrast, the American Society of Clinical Oncology and the Multinational Association for Supportive Care in Cancer guidelines consider all carboplatin doses to be moderately emetogenic. Although many institutions classify carboplatin-containing regimens as moderately emetogenic, a benefit for adding a neurokinin 1 receptor antagonist on day 1 has been shown in many studies; additional prophylaxis beyond day 1 for delayed emesis is not needed for most patients. Refer to UpToDate topics on prevention and treatment of chemotherapy-induced nausea and vomiting in adults.

References:

Gisselbrecht C, Glass B, Mounier N, et al. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol 2010; 28:4184.
Rituximab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed October 23, 2012).
Ifosfamide injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed October 23, 2012).
Etoposide injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed October 23, 2012).
Carboplatin injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 23, 2012).
Rituximab and hyaluronidase human injection for subcutaneous use. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on June 30, 2017).

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Chemotherapy regimens for diffuse large B cell lymphoma: Rituximab, ifosfamide, carboplatin, and etoposide (R-ICE)[1]

Chemotherapy regimens for diffuse large B cell lymphoma: Rituximab, ifosfamide, carboplatin, and etoposide (R-ICE)^[1]