Chemotherapy regimens for metastatic, RAS/BRAF wildtype colorectal cancer: Cetuximab plus irinotecan^[1]

Chemotherapy regimens for metastatic, RAS/BRAF wildtype colorectal cancer: Cetuximab plus irinotecan^[1]

Cycle length: 28 days.
Drug	Dose and route	Administration	Given on days
Cetuximab	500 mg/m² IV	The appropriate dose should be withdrawn from the vials (supplied in a concentration of 2 mg/mL) and aseptically transferred into an empty sterile IV bag without further dilution. All doses should be infused over 120 minutes.^[2]^¶^Δ	Days 1 and 15
Irinotecan	180 mg/m²^◊	Dilute in 250 mL D5W^§ and administer over 30 minutes, one hour after the end of cetuximab for the first dose, thereafter can be given immediately after cetuximab.	Days 1 and 15
Pretreatment considerations:
Emesis risk	MODERATE (30 to 90% risk of emesis). Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Premedication with diphenhydramine with or without a glucocorticoid at least prior to the first infusion of cetuximab.^[2] In areas with a high frequency of infusion reactions (eg, middle-southeastern United States), testing for IgE antibodies to galactose-alpha-1,3 galactose should be considered. Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Infection prophylaxis	Primary prophylaxis with granulocyte colony stimulating factors is not justified (estimated risk of febrile neutropenia approximately 6%^[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 irinotecan may be needed for patients with liver impairment or severe kidney impairment. 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 kidney impairment, conventional cytotoxic agents.
Diarrhea	Irinotecan is associated with early and late diarrhea, both of which may be severe. For patients who develop abdominal cramps and/or diarrhea within 24 hours of treatment, administer 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.
Monitoring parameters:
Obtain CBC with differential and platelet count prior to each treatment.
Assess basic metabolic panel (including creatinine, magnesium, calcium, and potassium) prior to each treatment. Monitor serum calcium, magnesium, and potassium levels weekly for eight weeks after completion of therapy.^[2]
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 skin rash.
Suggested dose modifications for toxicity:
Myelosuppression	Delay treatment until absolute neutrophil count is >1500/microL and the platelet count is >100,000/microL. The United States Prescribing Information suggests irinotecan dose reduction for grade 3 or worse hematologic toxicity during a prior cycle.^[3] Refer to UpToDate topics on acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors.
Diarrhea	Withhold treatment until resolution of diarrhea for at least 24 hours off antidiarrheal medications. Reduce irinotecan dose for patients with grade 2 or worse diarrhea during a prior treatment cycle.^[3] Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
Dermatologic toxicity	Severe dermatologic reactions, such as acneiform rash, require delayed administration of cetuximab and/or dose reduction. Refer to UpToDate topics on acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors.
Other toxicity	If grade 2, hold treatment until less than or equal to grade 1; if grade 3 or 4, hold treatment until less than or equal to grade 2.^[3] Reduce irinotecan dose for grade 3 or worse other non-hematologic toxicities during a prior treatment cycle.
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.

CBC: complete blood count; IgE: immunoglobulin E; IV: intravenous.

¶ Cetuximab should be administered with an infusion or syringe pump, using a low protein-binding 0.22 micron in line filter. Do not shake or dilute. Flush line with normal saline.
Δ A slower infusion rate should be considered in areas with a high incidence of infusion reactions (such as the southeast United States). Refer to UpToDate topics on infusion reactions to the therapeutic monoclonal antibodies used in cancer therapy.
◊ A lower initial starting dose of irinotecan may be considered for patients with poor performance status, prior pelvic or abdominal radiotherapy, or increased bilirubin levels.^[3] Whether a reduced starting dose is needed in patients who are homozygous for the UGT 1A1*28 allele (Gilbert's syndrome) and whether testing for this allele should be carried out prior to starting irinotecan is controversial. Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
§ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibilities.

References:

Pfeiffer P, Nielsen D, Bjerregaard J, et al. Biweekly cetuximab and irinotecan as third-line therapy in patients with advanced colorectal cancer after failure to irinotecan, oxaliplatin and 5-fluorouracil. Ann Oncol 2008; 19:1141.
Cetuximab injection. United States Prescribing Information. US National Library of Medicine. (Available online at accessdata.fda.gov/drugsatfda_docs/label/2021/125084s277s280lbl.pdf, accessed on April 8, 2021).
Irinotecan hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on February 12, 2012).

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Chemotherapy regimens for metastatic, RAS/BRAF wildtype colorectal cancer: Cetuximab plus irinotecan[1]

Chemotherapy regimens for metastatic, RAS/BRAF wildtype colorectal cancer: Cetuximab plus irinotecan^[1]