FOLFIRI is a widely used chemotherapy regimen that contains folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan (Camptosar). Administered in 2-week cycles, these medications work together to target and destroy rapidly dividing cancer cells, slowing tumor growth and improving survival. FOLFIRI is primarily used for treating metastatic colorectal cancer, but is also used for other gastrointestinal cancers.

What Does FOLFIRI Stand For?

FOLFIRI is an acronym that stands for the three medications is contains:

• FOL – Folinic acid (leucovorin): Enhances the effectiveness of 5-FU by helping it attach more effectively to its target protein.
• F – Fluorouracil (5-FU): An antimetabolite that disrupts DNA synthesis, preventing cancer cell division and ultimately leading to cell death.
• IRI – Irinotecan: Inhibits topoisomerase I, blocking DNA replication and causing cancer cell death.

Each drug in the combination plays a distinct role in targeting cancer cells.

When Is FOLFIRI Chemotherapy Used?

FOLFIRI is primarily used in the treatment of advanced or metastatic colorectal cancer, particularly in the following scenarios:

• First-Line Therapy for Metastatic Colorectal Cancer: FOLFIRI is one of the standard options for patients with stage IV (metastatic) colorectal cancer. It can be used as an initial (first-line) treatment, often chosen based on patient characteristics, comorbidities, and the side effect profiles of available regimens.
• Second-Line Therapy: FOLFIRI is commonly used as a second-line regimen for metastatic colorectal cancer in patients who have progressed after first-line treatment with oxaliplatin-based regimens such as FOLFOX or XELOX. In this setting, FOLFIRI is considered a standard of care.

FOLFIRI may also be used in certain cases of advanced or metastatic gastric, gastroesophageal, cholangiocarcinoma, gallbladder, pancreatic, or ampullary cancers, often after other treatments have failed. It may be used in combination with targeted therapies (e.g., bevacizumab or cetuximab). FOLFIRI is generally not used with the goal of cure in metastatic settings, but aims to shrink tumors, control symptoms, and prolong survival.

How Is FOLFIRI Administered?

FOLFIRI is typically given intravenously (IV), often through a central line, PICC line, or portacath. It is usually administered in cycles, with each cycle lasting 2 weeks. Patients may undergo up to 12 cycles, spanning about 6 months.

Below is a typical FOLFIRI chemotherapy cycle. Your healthcare provider may give you different instructions than what is outlined below.

Day 1	Irinotecan is administered intravenously over 30-120 minutes Leucovorin is administered intravenously over 2 hours Fluorouracil is injected as an IV bolus, and then administered as an IV infusion for over 46 hours through a portable pump.
Day 2	Continue fluorouracil infusion via pump.
Day 3	You will have your portable pump disconnected.
Days 4 to 14	No treatment.

How Effective Is FOLFIRI Chemotherapy?

FOLFIRI is an effective and standard chemotherapy regimen for metastatic colorectal cancer, offering similar survival outcomes to FOLFOX in the first-line setting. Its effectiveness decreases when used as a second-line therapy. Combining FOLFIRI with targeted agents like bevacizumab can further improve survival for selected patients. Success rates vary based on genetic mutations (e.g., KRAS, NRAS status) and prior treatments.

Efficacy in Metastatic Colorectal Cancer

First-Line Therapy

• FOLFIRI is as effective as FOLFOX (another standard regimen) for previously untreated metastatic colorectal cancer, with similar overall response rates (31–34%), time to progression (7 months), and overall survival (14–15 months). When combined with bevacizumab, FOLFIRI achieves a median progression-free survival (PFS) of 12 months and overall survival (OS) of 31 months, comparable to FOLFOX plus bevacizumab.

Second-Line Therapy

• As a second-line option (after failure of other regimens), FOLFIRI is less effective, with response rates dropping to around 7% and median PFS of 3–4 months. Median OS in second-line settings can vary but is generally lower than in first-line use.
• A review of 11 studies of patients treated with FOLFIRI plus bevacizumab as second-line treatment of patients with advanced colorectal cancer found that the pooled overall response rate was 26%, median PFS was 8 months, and OS was 7 months.

Efficacy in Other Cancers

In advanced gastric cancer and high-grade neuroendocrine carcinomas, FOLFIRI as a second-line therapy has shown lower response rates (around 9%–31%) and modest disease control, with median OS ranging from about 6 to 18 months depending on factors like tumor type.

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What Are the Side Effects of FOLFIRI Chemotherapy?

The FOLFIRI chemotherapy regimen can cause a range of side effects, from mild to severe. Most side effects can be managed at home, but it is important to know when to seek prompt medical attention.

Common Side Effects

• Increased risk of infection: Due to low white blood cell counts, leading to symptoms such as fever, chills, cough, or feeling generally unwell. Infections can sometimes be life-threatening.
• Bruising and bleeding: Lower platelet counts can cause easy bruising, bleeding gums, or nosebleeds.
• Anemia: Low red blood cells may cause breathlessness and paleness.
• Sore mouth: Mouth sores and ulcers are common and may be painful.
• Diarrhea: A hallmark side effect of irinotecan, which can be severe and lead to dehydration. It may be accompanied by abdominal cramps, bloating, and sore skin in the anal area.
• Fatigue: Profound tiredness and lack of energy, often worsening after each treatment cycle.
• Nausea and vomiting: Typically worse 2–3 days after treatment and can last several days.
• Hair loss or thinning: Some patients experience hair loss, which is usually temporary.
• Loss of appetite and weight loss
• Pain at the infusion site

Serious Side Effects

• Allergic reactions
• Heart problems, such as abnormal heart rhythm
• Liver function changes
• Lung toxicity

These are not all possible side effects from FOLFIRI chemotherapy. Discuss your risk for side effects with your healthcare provider, including what symptoms to watch out for and when to get medical help.

Special Considerations and Monitoring

FOLFIRI chemotherapy requires careful monitoring and management to balance efficacy with patient safety. Key considerations include:

Pre-Treatment Testing and Education

• DPD and UGT1A1 enzyme testing: A baseline blood test for dihydropyrimidine dehydrogenase (DPD) and UGT1A1 may be done before administering 5FU and irinotecan. A low DPD level increases your risk of side effects, and may necessitate dose reductions or alternative treatments. UGT1A1 polymorphisms are one of the risk factors for increased toxicity from irinotecan.
• Baseline blood work: Complete blood count (CBC), electrolytes, liver, and kidney function tests are performed to establish baseline health metrics.
• Infusion pump education: Your healthcare provider will teach you about your infusion pump.

Ongoing Monitoring

• Blood tests: Repeated before each cycle to track CBC, electrolytes, liver/renal function, and infection risks. White blood cell counts are closely monitored between days 7–14 post-treatment due to heightened infection susceptibility.
• Cardiac assessment: Regular heart function checks are advised, as 5FU may rarely cause arrhythmias, heart failure, or heart attacks. Report chest pain, palpitations, or shortness of breath immediately.
• Clinical evaluations: At each visit, your healthcare provider may assess for diarrhea, dehydration, mouth sores, nausea/vomiting, and fatigue.

Side Effect Management

• Diarrhea: Typically managed with antidiarrheals (e.g., loperamide), hydration, and dietary adjustments (avoiding lactose, spicy foods, and caffeine). Severe cases require urgent medical attention.
• Infection risks: Fever ≥37.5°C or flu-like symptoms warrant immediate intervention. Prophylactic antibiotics may be used. Wash your hands often and avoid crowds or people who are sick.
• Eye effects: Watery eyes or conjunctivitis may occur; preservative-free eye drops are usually recommended. Vision changes or eye pain require prompt evaluation.
• Harm to babies and fertility problems: FOLFIRI can cause harm to babies, so it is not recommended during pregnancy or breastfeeding. It can also make it harder to have children. Speak to your healthcare provider about fertility preservation before starting treatment.

Key Points

• FOLFIRI is a combination chemotherapy regimen used mainly for metastatic colorectal cancer. The name FOLFIRI stands for folinic acid (leucovorin), fluorouracil (5-FU), and irinotecan.
• It combines drugs that attack cancer cells by disrupting their DNA synthesis and replication.
• The regimen is given in cycles, with rest periods to allow the body to recover.
• While effective, FOLFIRI can cause significant side effects due to its impact on healthy rapidly dividing cells.
• Always consult with your oncology team for specific details and management of side effects during FOLFIRI treatment.

References

1. American Cancer Society. 2024. Treatment of Colon Cancer, by Stage. Accessed on May 16, 2025 at https://www.cancer.org/cancer/types/colon-rectal-cancer/treating/by-stage-colon.html
2. Beretta, G. D., et. al. 2013.FOLFIRI + bevacizumab as second-line therapy for metastatic colorectal cancer pretreated with oxaliplatin: a pooled analysis of published trials. [Review]. In: Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet]. Accessed on May 16, 2025 at https://www.ncbi.nlm.nih.gov/books/NBK164635/
3. Cancer Research UK. 2024. Folinic acid, fluorouracil and irinotecan (FOLFIRI). Accessed on May 16, 2025 at https://www.cancerresearchuk.org/about-cancer/treatment/drugs/folfiri
4. Colucci, G., et. al. 2005. Phase III Randomized Trial of FOLFIRI Versus FOLFOX4 in the Treatment of Advanced Colorectal Cancer: A Multicenter Study of the Gruppo Oncologico Dell’Italia Meridionale. In: Journal of Clinical Oncology. DOI: https://doi.org/10.1200/JCO.2005.07.113
5. EviQ. 2022. Patient information - Advanced or metastatic - FOLFIRI modified (fluorouracil, leucovorin, irinotecan). Accessed on May 16, 2025 at https://www.eviq.org.au/medical-oncology/upper-gastrointestinal/gastric-and-oesophageal-metastatic/4043-advanced-or-metastatic-folfiri-modified-fl/patient-information
6. Fluorouracil injection [package insert]. Updated 2024. Accord Healthcare, Inc. Accessed on May 17, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=66d451fe-2436-494c-80c5-4528c8e34369
7. Hentic, O., et. al. 2012. FOLFIRI regimen: an effective second-line chemotherapy after failure of etoposide-platinum combination in patients with neuroendocrine carcinomas grade 3. Endocrine-related cancer, 19(6), 751–757. https://doi.org/10.1530/ERC-12-0002
8. Irinotecan [package insert]. Updated 2025. BluePoint Laboratories. Accessed on May 17, 2025 at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b66dbd6d-6ccb-ce9d-e053-2995a90a4c3c
9. Jeon, E. K., et. al. 2011. Modified FOLFIRI as Second-Line Chemotherapy after Failure of Modified FOLFOX-4 in Advanced Gastric Cancer. Cancer research and treatment, 43(3), 148–153. https://doi.org/10.4143/crt.2011.43.3.148
10. Karas, S., et. al. 2021. All You Need to Know About UGT1A1 Genetic Testing for Patients Treated With Irinotecan: A Practitioner-Friendly Guide. In: JCO Oncology Practice. DOI: https://doi.org/10.1200/OP.21.00624
11. Macmillan Cancer Support. 2024. Irinotecan with 5FU and folinic acid. Accessed on May 18, 2025 at https://www.macmillan.org.uk/cancer-information-and-support/treatments-and-drugs/irinotecan-with-5fu-and-folinic-acid-folfiri
12. National Cancer Institute. 2023. FOLFIRI. Accessed on May 16, 2025 at https://www.cancer.gov/about-cancer/treatment/drugs/folfiri
13. Neugut, A. I., et. al. 2019. FOLFOX and FOLFIRI Use in Stage IV Colon Cancer: Analysis of SEER-Medicare Data. Clinical colorectal cancer, 18(2), 133–140. https://doi.org/10.1016/j.clcc.2019.01.005
14. Yamazaki, K., et. al. 2016. Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).. Annals of oncology : official journal of the European Society for Medical Oncology, 27 8, 1539-46 . https://doi.org/10.1093/annonc/mdw206
15. Zhang, X., et. al. 2022. FOLFIRI (folinic acid, fluorouracil, and irinotecan) increases not efficacy but toxicity compared with single-agent irinotecan as a second-line treatment in metastatic colorectal cancer patients: a randomized clinical trial. Therapeutic advances in medical oncology, 14, 17588359211068737. https://doi.org/10.1177/17588359211068737

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