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IRIN+CETU; IRIN(Q2W)+CETU
Small bowel and appendix
Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR). Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.
Third-line treatment of EGFR-expressing metastatic colorectal, small bowel or appendiceal cancer, in patients with wild-type KRAS after failure of oxaliplatin and irinotecan-containing chemotherapy regimens.
Cetuximab is not indicated in mCRC patients with RAS mutant tumours (exon 2, codons 12, 13; 3, codons 59, 61; or 4, codons 117, 146) or in tumours with unknown mutation status. Assessment of RAS mutation status should be performed prior to treatment using a validated test.
cetuximab
New Drug Funding Program
(Cetuximab with Irinotecan - Metastatic Colorectal, Small Bowel, or Appendiceal Cancer)
(NDFP Website
)
IRIN(Q2W)+CETU Schedule:
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cetuximab 1 | 500 mg /m² | IV * | Day 1; q14 days |
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* over 2 hours for the first dose, then over 1 to 2 hours for subsequent doses (if no infusion reactions observed in previous cycle) 1 maximum infusion rate 10 mg/min |
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| irinotecan | 180 mg /m² | IV | Day 1; q14 days |
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Cetuximab (loading dose): |
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cetuximab 1 | 400 mg /m² | IV | Cycle 1, day 1 ONLY |
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cetuximab 1 | 250 mg /m² | IV | Cycle 1, day 8 and then weekly thereafter |
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1 maximum infusion rate 10 mg/min Irinotecan every 3 weeks: |
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| irinotecan | 350 mg /m² | IV | Day 1 only |
IRIN(Q2W)+CETU:*
Cetuximab and Irinotecan REPEAT EVERY 14 DAYS
IRIN+CETU:*
Cetuximab REPEAT EVERY 7 DAYS
AND
Irinotecan REPEAT EVERY 21 DAYS
*Continue until evidence of disease progression or unacceptable toxicity
Moderate (D1)
Minimal (D8, 15)
Other Supportive Care:
Irinotecan:
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Unless contraindicated, atropine 0.25-1mg IV/SC may be used for cholinergic adverse effects (early diarrhea)
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Diarrhea may be severe and delayed with irinotecan; use loperamide 4mg at the onset of diarrhea, then 2mg q2h until patient is diarrhea-free for 12 hours
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Patients with ileus, fever or febrile neutropenia should receive antibiotics
Cetuximab:
- An H1 antagonist (e.g. 50 mg of diphenhydramine IV) is recommended with each dose
Also refer to CCO Antiemetic Recommendations.
Doses should be modified according to the protocol by which the patient is being treated. The following recommendations have been adapted from clinical trials or product monographs and could be considered.
Dosage with toxicity
Patients should not be re-treated with irinotecan until recovery (to baseline) from GI toxicity (without loperamide for at least 24 hours) has occurred, platelets ≥ 100 x 109/L, and ANC ≥ 1.5 x 109/L. All dose adjustments should be based on the worst preceding toxicity.
Patients with ileus, fever or febrile neutropenia should receive antibiotics.
Do not use in patients with ECOG PS of 3 or 4, nor in patients with moderate or severe increases in bilirubin
Consider a reduction in the starting dose described below for elderly patients (≥ 70 years), patients with prior abdominal or pelvic irradiation, patients with a poor performance status (ECOG of 2), patients with mild increases in bilirubin (including Gilbert’s syndrome), patients homozygous for UGT1A1*28 allele or patients with a history of myelosuppression with previous treatment.
Suggested dose levels for irinotecan:
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Regimen
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Drug
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Starting dose (mg/m2)
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Dose level -1 (mg/m2)
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Dose Level -2 (mg/m2)
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Dose Level -3 (mg/m2) |
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Q2W
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Irinotecan
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180
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140-150
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110-120
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Q3W
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Irinotecan
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350
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300
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250
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200 |
Irinotecan: Dose Modification for Toxicity
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Toxicity grade3
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At start of subsequent cycle1,2 |
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1
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No change
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2
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Diarrhea alone – no change
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Hematologic alone – no change
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Other 3: ↓ 1 dose level
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3
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↓ 1 dose level
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4 or febrile neutropenia
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↓ 1 dose level
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| Pneumonitis | Hold; investigate and if confirmed, discontinue. |
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1 Relative to the starting dose used in the previous cycle.
2 Patients should not be retreated until GI toxicity resolved to baseline (without loperamide for at least 24 h), platelets ≥ 100 x 109/L, and ANC ≥ 1.5 x 109/L. If no recovery after a 2-week delay, consider discontinuing treatment. 3 Excludes alopecia, anorexia, and fatigue
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Cetuximab: Dosage Modification for Dermatologic Toxicity and Related Disorders
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Grade 3 or 4 Acneiform Rash
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Action
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Outcome
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Cetuximab
(weekly dosing)
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1st occurrence
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Delay infusion 1 to 2 weeks |
Improvement
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Continue at 250mg/m2
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No improvement |
Discontinue
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2nd occurrence
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Delay infusion 1 to 2 weeks |
Improvement
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Reduce: 200mg/m2
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No improvement |
Discontinue
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3rd occurrence
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Delay infusion 1 to 2 weeks |
Improvement
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Reduce: 150mg/m2
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No improvement |
Discontinue
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4th occurrence OR any occurrence of SJS/TENS
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Discontinue
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Cetuximab: Infusion Rate Modification for Infusion Reactions
Mild to moderate infusion reactions can be managed with slowing the infusion rate of cetuximab and with continued use of antihistamine medications (e.g. diphenhydramine) in subsequent doses.
| Grade |
Infusion rate |
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Grade 1 or 2
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5 mg/min
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Grade 3 or 4
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Discontinue
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Other Toxicities
Hepatic Impairment
| Transaminases | Bilirubin1 | Irinotecan |
| 1-1.5 x ULN or Gilbert's | Consider ↓ | |
| > 3 x ULN* | 2-4 x ULN | Omit |
| ≥ 4 x ULN | Omit |
1 Consider investigating for reversible causes such as biliary obstruction and re-evaluate after stent
Renal Impairment
Dosage in the Elderly
No dosage adjustment is required for cetuximab. Elderly patients receiving irinotecan may be at increased risk of diarrhea and should be monitored closely. Consider reducing the irinotecan starting dose in patients aged 70 and older.
Refer to cetuximab, irinotecan drug monograph(s) for additional details of adverse effects
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Very common (≥ 50%) |
Common (25-49%) |
Less common (10-24%) |
Uncommon (< 10%), but may be severe or life-threatening |
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Refer to cetuximab, irinotecan drug monograph(s) for additional details
- Additive skin toxicity may occur when cetuximab is given in combination with radiation
- Azole antifungals are contraindicated with irinotecan (discontinue one week before the first dose of irinotecan)
- Avoid concomitant use of strong CYP3A4 inhibitors and inducers with irinotecan
- Avoid concomitant use of prochlorperazine, turmeric and azatanavir with irinotecan
Refer to cetuximab, irinotecan drug monograph(s) for additional details.
Administration:
Cetuximab:
- Do not shake or further dilute the solution.
- DO NOT ADMINISTER AS AN IV PUSH OR BOLUS.
- Transfer undiluted solution into an empty Viaflex bag or an empty syringe, if using a syringe pump.
- Administer the undiluted solution via a low protein binding 0.22-micrometer in-line filter. Piggybacking to the patient’s infusion line, infuse initial loading dose over 2 hours, and maintenance dose over 1 hour (maximum rate 10 mg/min). (May require infusion at slower rate in those who experienced infusion reactions).
- Prime administration line with drug solution before infusion and may use NS to flush line at the end of infusion.
- A 1-hour observation period is recommended following each cetuximab infusion. Longer observation periods may be required in those who experienced infusion reactions.
- Should not be mixed or diluted with other drugs.
- Discard any unused portion left in a vial 12 hours under refrigeration or 8 hours at room temperature, as the product contains no preservatives.
Irinotecan:
- Mix in 500mL bag (D5W-preferred or NS) in a concentration range between 0.12 to 3 mg/mL; infuse IV over 90 minutes
- Do not refrigerate admixtures in NS (may result in precipitation)
- Avoid freezing irinotecan and its admixtures since this may result in drug precipitation.
- Do not admix with other drugs
- Protect from light
- Prior to the initial irinotecan treatment, patients should be given a sufficient supply of loperamide and instructed on its appropriate use.
- Avoid grapefruit, starfruit, Seville oranges, their juices or products during irinotecan treatment
Contraindications:
- Patients with known hypersensitivity to cetuximab, murine protein or any components of this product
- Treatment of colorectal cancer in patients with RAS mutations (exon 2, 3, 4) or RAS unknown status
- Patients with ECOG performance status of 3 or 4
- Patients with moderate to severe hepatic dysfunction
- Avoid in patients with hereditary fructose intolerance since the product contains sorbitol
- Avoid the use of live or live attenuated vaccines
Warnings/precautions:
- Patients with a history of, or pre-existing keratitis, dry eyes or contact lens use
- Patients with poor performance status, or cardiopulmonary disease are at increased risk of severe hypersensitivity
- Elderly patients, patients with poor performance status (= 2), limited marrow reserve, 3rd space accumulation, Gilbert’s syndrome and patients with reduced UGT1A1 activity may be more susceptible to the toxic effects of irinotecan; they should be carefully monitored and dose reduction considered.
- The concurrent administration of irinotecan with irradiation is not recommended.
- This regimen is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
- Breastfeeding is not recommended.
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
Recommended Clinical Monitoring
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CBC, liver & renal function tests; baseline and at each cycle
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Electrolytes, including serum magnesium, potassium and calcium; baseline, at each cycle and as clinically indicated, and monthly for 2 months following completion of therapy
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Clinical toxicity assessment including infection, bleeding, hypersensitivity, diarrhea and other GI effects, pancreatitis, cholinergic symptoms, respiratory, skin and CNS toxicity, thromboembolism and fatigue; at each visit
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Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
Suggested Clinical Monitoring
- Blood glucose, especially in patients with diabetes; baseline and at each visit
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Cetuximab and irinotecan drug monographs, Cancer Care Ontario.
Cunningham D et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. NEJM 2004; 351(4): 337-45.
Martın-Martorell P, Rosello S, Rodrıguez-Braun E, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer 2008; 99: 455-8.
Mbrati H, De la Fourchardiere C, Desseigne F, et al. Irinotecan associated with cetuximab given every 2 weeks versus cetuximab weekly in metastatic colorectal cancer. Journal of Cancer Research and Therapeutics 2009; 5(4): 272-6.
National Comprehensive Cancer Network. Colon Cancer (Version 2.2017). https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Accessed June 30, 2017.
Pfeiffer P, Nielsen D, Bierregaard 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: 1141–5.
Roca JM, Alonso V, Pericay C, et al. Cetuximab given every 2 weeks plus irinotecan is an active and safe option for previously treated patients with metastatic colorectal cancer. Chemotherapy. 2010;56(2):142-6.
Sobrero A, et al. EPIC: Phase III trial of cetuximab plus irinotecan After fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. JCO 2008; 28(14): 2311-9.
Tabernero J, Ciardiello F, Rivera F, et al. Cetuximab administered once every second week to patients with metastatic colorectal cancer: a two‐part pharmacokinetic/pharmacodynamics phase I dose‐escalation study. Ann Oncol 2010;21:1537–45
Wilke H et al. Cetuximab plus irinotecan in heavily pretreated metastatic colorectal cancer progressing on irinotecan: MABEL Study. JCO 2008; 26(33): 5335-43.
June 2022 IRIN(Wx4)+CETU de-listed starting 2022-23; removed related info from Drug regimen, Cycle frequency, Dose modifications and Monitoring sections
Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph. Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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