What is FOLFIRINOX regimen​ and how is it used?

FOLFIRINOX is a four-drug chemotherapy regimen that contains folinic acid (leucovorin), fluorouracil (5-FU), irinotecan, and oxaliplatin. It is primarily used to treat advanced pancreatic cancer, including metastatic and locally advanced (inoperable) cases. It is considered a first-line treatment for patients with good performance status due to its higher toxicity compared to other regimens, and improves survival compared to gemcitabine.

What Does FOLFIRINOX Stand For?

FOLFIRINOX is an acronym that stands for the four medications it contains:

• FOL – Folinic acid (leucovorin): Enhances the effectiveness of 5-FU by helping it attach better to its target protein.
• F – Fluorouracil (5-FU): An antimetabolite that disrupts DNA synthesis, preventing cancer cell division and ultimately leading to cell death and slowed tumor growth.
• IRIN – Irinotecan: Inhibits a protein called topoisomerase I, blocking DNA replication and causing cancer cell death.
• OX – Oxaliplatin: A platinum-based agent that causes DNA crosslinking and damage.

These medications work together to kill cancer cells.

When Is FOLFIRINOX Used?

The FOLFIRINOX chemotherapy regimen is primarily used for the treatment of advanced pancreatic cancer, especially in the following situations:

• Metastatic Pancreatic Cancer: FOLFIRINOX is commonly given to patients whose pancreatic cancer has spread to other parts of the body (metastatic disease). It is often considered the first-line treatment for these patients, particularly if they are in good general health.
• Locally Advanced Pancreatic Cancer: The regimen may also be used for patients with locally advanced pancreatic cancer that cannot be removed surgically (inoperable), but has not yet spread to distant organs. In some cases, it is used in hopes of shrinking the tumor enough to make surgical removal possible.
• Neoadjuvant Therapy: FOLFIRINOX can be administered before surgery (as neoadjuvant therapy) to try to shrink the tumor, potentially allowing for surgical resection in patients who were previously considered inoperable.
• Other Cancers: While its main use is in pancreatic cancer, FOLFIRINOX (sometimes called FOLFOXIRI) may also be used to treat certain cases of bowel cancer and, less commonly, other types of cancer, depending on the specific clinical scenario and at the discretion of the oncology team.

FOLFIRINOX is generally reserved for patients who are relatively fit (Eastern Cooperative Oncology Group, or ECOG, performance status 0–1), as it is associated with a higher risk of side effects compared to other chemotherapy regimens. Modified versions of FOLFIRINOX may be used to reduce toxicity while preserving efficacy. This includes reduced dosages of individual drugs in the regimen, or removal of certain drugs. Other adjustments include changes in infusion timing or use of other supportive medications.

How Is FOLFIRINOX Given?

All medications in the FOLFIRINOX chemotherapy regimen are administered intravenously (IV), typically through a cannula, central line, PICC line, or portacath. Your 5-FU infusion may be given through a portable pump that you can wear at home.

The regimen is usually given in 2-week cycles, with each cycle involving the following sequence:

The total number of cycles depends on your response and side effects, but some patients receive up to 12 cycles over 6 months.

Additionally, hydration and certain medications may be required to manage side effects. Common medications given with FOLFIRINOX include:

• Ondansetron (an antinausea medication)
• Dexamethasone (a steroid)
• Pegfilgrastim (a growth factor)
• Atropine (an anticholinergic medication)
• Loperamide (an antidiarrheal medication)

Monitoring includes blood counts, liver function, and performance status.

How Effective Is FOLFIRINOX?

FOLFIRINOX has become a standard of care for patients with advanced pancreatic cancer, particularly those with good performance status. Its effectiveness has been demonstrated in several key clinical trials and real-world studies.

Survival Outcomes

• Median Overall Survival (OS): In the pivotal PRODIGE trial, patients with metastatic pancreatic cancer treated with FOLFIRINOX had a median OS of 11.1 months, compared to 6.8 months for those treated with gemcitabine alone. Other studies report median OS ranging from 9.8 to 13.6 months, depending on patient selection and treatment duration. One phase 3 study of patients with locally advanced pancreatic carcinoma not suitable for surgery demonstrated a median OS of 15.7 months in the FOLFIRINOX group.
• Progression-Free Survival (PFS): Median PFS was significantly improved with FOLFIRINOX (6.4 to 8.8 months) compared to gemcitabine (3.3 months).
• Long-Term Survival: Five-year overall survival rates in the adjuvant (post-surgery) setting were 43% for modified FOLFIRINOX versus 31% for gemcitabine, indicating a substantial long-term benefit.

Response Rates

• Objective Response Rate (ORR): FOLFIRINOX achieves higher response rates than gemcitabine. In the main trial, the ORR was 31.6% for FOLFIRINOX versus 9.4% for gemcitabine. Some real-world and modified regimens have reported disease control rates as high as 88.2%, with partial and complete responses in 53% of patients.

What Are the Side Effects of FOLFIRINOX?

FOLFIRINOX is associated with a range of side effects, some of which can be severe. The side effects result from the combined toxicities of its component drugs. Not all patients will experience every side effect, and their severity can vary.

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Common Side Effects

• Increased Risk of Infection: Due to a drop in white blood cells (neutropenia), patients are more susceptible to infections, which can sometimes be life-threatening. Symptoms include fever, chills, muscle aches, cough, and general malaise.
• Tiredness: Fatigue is very common and often worsens toward the end of treatment and can persist for weeks afterward.
• Anemia: A reduction in red blood cells can cause breathlessness and looking pale.
• Bruising and Bleeding: A decrease in platelets increases the risk of bruising, bleeding gums, nosebleeds, and tiny red spots on the skin (petechiae).
• Nausea and Vomiting: These are frequent side effects, but anti-sickness medications are usually provided.
• Diarrhea: Can be severe and may require medication or adjustments to the regimen.
• Loss of Appetite and Weight Loss: Many patients experience reduced appetite and weight loss.
• Hair Loss or Thinning: This can occur but is usually temporary.
• Mouth Sores and Ulcers: Painful sores in the mouth are common, especially due to the oxaliplatin component.
• Sore, Red, Peeling Hands and Feet (Palmar-Plantar Syndrome): Skin changes on the hands and feet may occur.
• Changes in Taste or Smell: Foods may taste bland, metallic, or different.
• Eye Problems: Sore, red, or itchy eyes and blurred vision can occur.
• Peripheral Neuropathy: Numbness or tingling in the fingers and toes, often triggered or worsened by cold, can develop and may persist after treatment ends.
• Sensitivity to Cold: Some patients experience pain or difficulty swallowing or breathing when exposed to cold air or drinks.
• Nail Changes: Nails often become brittle.
• Tinnitus: Some patients experience ringing in the ears.
• Amenorrhea: Some women may temporarily stop having periods.

Serious Side Effects

• Allergic Reactions: These can occur during infusion, causing rash, itching, swelling, breathing difficulties, or fever. Severe reactions require immediate medical attention.
• Liver Function Changes: Mild changes in liver enzymes are common; rarely, jaundice or abdominal swelling may occur.
• Irinotecan Reaction (Acute Cholinergic Syndrome): This can cause diarrhea, tummy cramps, sweating, increased saliva, dizziness, and vision problems within 24 hours of treatment. It is usually managed with atropine.
• Lung Toxicity: Symptoms may include difficulty breathing and chest pain.
• Heart Problems: Symptoms may include chest pain and abnormal heartbeat.

Important Considerations During Treatment

Patients with good performance status (ECOG 0–1), adequate organ function, and without significant comorbidities are good candidates for FOLFIRINOX chemotherapy due to its high toxicity profile. Elderly patients, those with poor performance status, or with organ dysfunction (especially liver or kidney) may not be suitable candidates and may require dose adjustments or alternative regimens.

Other key considerations during FOLFIRINOX treatment include:

Genetic Testing

• DPD enzyme testing: A baseline blood test for dihydropyrimidine dehydrogenase (DPD) may be done before administering 5FU. A low DPD level increases your risk of side effects, and may necessitate dose reductions or alternative treatments.
• UGT1A1 enzyme testing: A UGT1A1 blood test may be ordered before administering irinotecan. UGT1A1 polymorphisms are one of the risk factors for increased toxicity from irinotecan.

Pre-Treatment and Ongoing Monitoring

• Comprehensive blood tests are required before each cycle: complete blood count (CBC), renal and liver function tests, electrolytes, and, for some patients, INR if on warfarin.
• Blood pressure should be monitored, especially during and after irinotecan administration.
• Routine cardiac monitoring may be recommended, since 5-FU is known to be associated with cardiotoxicity.
• Patients should be reviewed by a healthcare professional before every cycle to assess for toxicity and suitability to proceed.
• Your healthcare provider will monitor for allergic reactions, especially during the infusions of oxaliplatin.
• Tumor response is typically assessed radiologically after every few cycles, along with evaluation of symptom improvement or progression.

Side Effect Management

• Dose reductions or delays may be necessary if patients develop significant toxicities, such as severe low white blood cells, low platelets, diarrhea, or nerve problems.
• Monitor for signs of infection, such as fever, chills, or cough. Wash your hands often and avoid crowds and people who are sick.
• Eat a balanced diet to ensure adequate nutrition during treatment.
• Antinausea medications (e.g., ondansetron) and steroids (e.g., dexamethasone) may be given before chemotherapy to reduce nausea and vomiting.
• Atropine may be administered before irinotecan to prevent acute cholinergic symptoms (e.g., abdominal cramping, diarrhea).
• Loperamide or other antidiarrheals may be given to help with diarrhea.
• Growth factors (e.g., G-CSF) may be considered for patients at high risk of neutropenia.

Harm to Babies and Fertility Preservation

• Medications in FOLFIRINOX chemotherapy can cause harm to babies, so it is not recommended while pregnant or breastfeeding.
• FOLFIRINOX can also affect fertility (ability to have children). It is important to have a discussion with your healthcare provider about fertility preservation if you want to have children in the future.

Summary

FOLFIRINOX is a four-drug intravenous chemotherapy regimen (folinic acid, fluorouracil, irinotecan, and oxaliplatin) primarily used as a first-line treatment for advanced pancreatic cancer (metastatic or locally advanced and inoperable) in patients with good performance status. It has shown improved survival rates compared to gemcitabine.

While effective, FOLFIRINOX carries a higher risk of side effects, including increased infection risk, fatigue, nausea, diarrhea, and peripheral neuropathy, necessitating careful patient selection, monitoring, and potential dose adjustments. The regimen is typically administered in 2-week cycles and may also be used for other cancers like bowel cancer or as neoadjuvant therapy for pancreatic cancer.