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تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
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Chemotherapy regimens for RAS/BRAF wildtype metastatic colorectal cancer: FOLFIRI plus cetuximab[1]

Chemotherapy regimens for RAS/BRAF wildtype metastatic colorectal cancer: FOLFIRI plus cetuximab[1]
Cycle length: 14 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Cetuximab 500 mg/m2 IV The appropriate dose should be withdrawn from the vials (supplied in a concentration of 2 mg/mL) and aseptically transferred into an empty sterile IV bag without further dilution.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.Δ◊ Days 1 and 15
Irinotecan 180 mg/m2 IV§ Dilute in 500 mL D5W¥ and administer over 90 minutes after cetuximab; may be given concurrently with leucovorin via y-site connection. Days 1 and 15
Leucovorin‡ 400 mg/m2 IV Dilute in 250 mL D5W¥ and administer over two hours; may give concurrent with irinotecan via y-site connection. Days 1 and 15
Fluorouracil (FU), bolus 400 mg/m2 IV Slow IV push over five minutes (administer immediately after leucovorin). Days 1 and 15
FU, infusional 2400 mg/m2 IV† Dilute in 500 to 1000 mL D5W¥ and administer over 46 hours (begin immediately after FU bolus). 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 and 15
Pretreatment considerations:
Emesis risk
  • MODERATE (30 to 60% frequency of emesis).
  • Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions
  • Premedicate 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 G-CSF is not justified (risk of febrile neutropenia with this regimen was 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.
Dose adjustment for baseline liver or kidney dysfunction
  • A lower starting dose of FU and irinotecan may be needed for patients with liver impairment. A lower starting dose of irinotecan may be needed for patients with 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 insufficiency, 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.
  • NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.
  • Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
Monitoring parameters:
  • Obtain CBC with differential and platelet count prior to each treatment.
  • Assess electrolytes (including magnesium, calcium, and potassium) and liver and kidney function prior to each dose. Monitor serum calcium, magnesium, and potassium levels weekly for eight weeks after completion of therapy.[3]
  • 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.
Suggested dose modifications for toxicity:
Myelotoxicity
  • Delay treatment until ANC is >1500/microL and the platelet count is >100,000/microL. United States Prescribing Information suggests irinotecan dose reduction for grade 2 or worse hematologic toxicity during a prior cycle.[2]
  • A different approach is used by some clinicians. If treatment is delayed for two weeks or delayed for one week on two separate occasions, the day 1 FU bolus is eliminated. With the second occurrence, reduce the FU infusion dose by 20% and reduce irinotecan dose to 150 mg/m2.
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.[2]
  • 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) inhibitors.
Neurologic 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]
Cardiotoxicity
  • Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic 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]
Other toxicity
  • For other nonhematologic toxicities, if grade 2, hold treatment until ≤grade 1; if grade 3 or 4, hold treatment until ≤grade 2.[2] Withhold FU for grade 2 or worse diarrhea, and restart at a lower dose after complete resolution.[4] Reduce irinotecan dose for patients with grade 2 or worse other nonhematologic toxicities during a prior treatment cycle except alopecia, anorexia, and asthenia.[2] For grade 3 mucositis, eliminate FU bolus dose; prophylactic ice chips may be beneficial.
  • Refer to UpToDate topics on oral toxicity associated with chemotherapy.
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; CBC: complete blood count; DPD: dihydropyrimidine dehydrogenase; D5W: 5% dextrose in water; FDA: US Food and Drug Administration; G-CSF: granulocyte colony stimulating factors; IgE: immunoglobulin; IV: intravenous; NS: normal saline.

¶ The original protocol administered cetuximab 400 mg/m2 loading dose on day 1 followed by maintenance dosing 250 mg/m2 starting on day 8.[1] Results from a nonrandomized phase II trial[5] and a multicenter retrospective analysis[6] suggest that cetuximab at a dose of 500 mg/m2 initially followed by 500 mg/m2 every 2 weeks results in similar plasma concentrations and single-agent activity as does weekly dosing. This regimen is now approved by the FDA, and is easier to administer in conjunction with FOLFIRI.[3]
Δ Cetuximab should be administered with an infusion or syringe pump, using a low protein-binding 0.22-micron inline filter. Do not shake or dilute. Flush line with NS.
◊ 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-related reactions to therapeutic monoclonal antibodies used for 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.[2] Whether a reduced starting dose is needed in patients who are homozygous for the UGT 1A1*28 allele (Gilbert syndrome) and whether testing for this allele should be carried out prior to starting irinotecan are controversial. Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
¥ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).
‡ Leucovorin dose is given for d,l-racemic mixture.[7] Use half the dose for LEVOleucovorin (l-leucovorin).
† If there is no grade 1 or worse toxicity 1 in cycles 1 and 2, some clinicians increase the dose to 3000 mg/m2 starting with cycle 3.[1]

References:
  1. Van Cutsem E, Köhne C-H, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009; 360:1408.
  2. Irinotecan hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on July 23, 2018).
  3. 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).
  4. Fluorouracil injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on July 23, 2018).
  5. 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.
  6. Bouchahda M, Macarulla T, Liedo G, et al. Feasibility of cetuximab given with a simplified schedule every 2 weeks in advanced colorectal cancer: a multicenter, retrospective analysis. Med Oncol 2011; Suppl1:253.
  7. Leucovorin calcium injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on July 23, 2018).
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