FOLFIRI combines folinic acid, fluorouracil and irinotecan every two weeks, with a portable pump for 46 hours. It is one of the two backbone regimens for metastatic bowel cancer, matched FOLFOX for survival in the GERCOR trial, and with cetuximab reached a median of 28.7 months in FIRE-3.
About This Department
Medical Oncology
Three drugs, every two weeks, with a small pump that goes home with you. FOLFIRI is one of the two backbones of bowel cancer treatment.
A treatment plan for bowel cancer that has spread, or that has come back, names FOLFIRI, sometimes with cetuximab, panitumumab or bevacizumab after it. Its name abbreviates its three drugs. Folinic acid, fluorouracil and irinotecan are given on one day every two weeks, and the fluorouracil keeps running for 46 hours from a small pump carried home in a bag. In the French GERCOR trial, first-line FOLFIRI shrank the cancer in 56 percent of patients. Starting with FOLFIRI or with its partner regimen FOLFOX made no difference to survival, which was 21.5 and 20.6 months, so the choice turns on side effects and on what comes next. Adding cetuximab in cancers without a RAS mutation took median survival to 28.7 months in the German FIRE-3 trial. This page explains how a cycle runs, which cancers it treats, the two gene tests that make it safer, how to handle its main side effect, and how a treatment given every two weeks fits with a visit to Istanbul.
56%
Tumors shrinking on first-line FOLFIRI, GERCOR trial
21.5 vs 20.6 mo
Median survival, FOLFIRI first or FOLFOX first, no real difference
28.7 months
Median survival with FOLFIRI and cetuximab in RAS wild-type disease, FIRE-3
Free
Review of your pathology, gene tests and scans
Free consultation
The review of your file is free and commits you to nothing. Send the pathology report, the RAS, BRAF and microsatellite results if they have been done, the latest CT or MRI, every treatment given so far with dates, and the most recent blood tests. A medical oncologist tells you whether FOLFIRI is the right regimen now, which antibody should go with it, and whether surgery on the metastases could follow, and a coordinator writes to you in your own language.
FOLFIRI Chemotherapy combines three drugs, and the name comes from their initials.
FOL, folinic acid
Also called leucovorin. It leaves the cancer alone. What it does is make fluorouracil stick to its target for longer, which strengthens its effect.
F, fluorouracil
Often written 5-FU. Bowel cancer treatment has used it since the 1950s, longer than any other drug. It blocks the building of DNA in dividing cells, and it works best given slowly over two days.
IRI, irinotecan
A topoisomerase I inhibitor. It stops cancer cells from unwinding and repairing their DNA as they divide, and it causes most of the side effects of the regimen.
FOLFIRI and FOLFOX differ by one drug. FOLFOX uses oxaliplatin in place of irinotecan. The two work equally well in trials, and most patients with advanced bowel cancer receive one and then the other.
The two-week cycle
A cycle takes fourteen days, and only the first three involve any treatment. Day 1 happens in the oncology day unit. Days 2 and 3 happen at home with the pump.
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One FOLFIRI cycle
When
What
How long
Day 1, morning
Blood tests and a visit with the oncologist, who checks the count and asks about the last cycle
One to two hours
Day 1
Anti-sickness medicine, then irinotecan and folinic acid into the vein, run side by side
Ninety minutes to two hours
Day 1
A short push of fluorouracil
A few minutes
Day 1 to day 3
Fluorouracil by continuous infusion from a portable pump
46 hours, at home
Day 3
The pump is disconnected at the clinic, or at home by a nurse
Fifteen minutes
Days 4 to 14
Recovery. The next cycle starts on day 15
Eleven days
Twelve cycles make six months. For advanced disease nobody fixes the count in advance, and treatment continues while it works and is tolerated, often with breaks or a lighter maintenance schedule once the cancer is under control.
The port and the pump
Most patients receiving FOLFIRI have a port, a small chamber placed under the skin of the upper chest with a thin tube running into a large vein. It spares the arm veins, which fluorouracil irritates over months, and makes every cycle a single needle into the port.
Placing the port. A short procedure under local anesthetic, done once before the first cycle or on the same day.
Connecting the pump. A balloon or electronic pump the size of a water bottle is attached to the port needle at the end of day 1, and it rides in a small bag or a belt pouch.
Two days at home. Showering is done with the pump and the needle covered. Sleeping is normal. The pump empties itself.
Disconnecting. On day 3 the needle comes out and the port is flushed. Nothing shows under the skin between cycles except a small bump.
For a patient in Istanbul
Patients who come for their first cycles stay near the hospital for the 46 hours, and the pump is disconnected here before they fly. A pump running on a plane is avoided, since a disconnection or a leak far from a clinic creates a problem nobody needs.
Which cancers
Bowel cancer accounts for most FOLFIRI treatment. Elsewhere in the digestive tract it serves as a later option, after the first regimen has stopped working and the patient remains well enough for three drugs.
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Where FOLFIRI is used
Cancer
When
Usually combined with
Bowel cancer, metastatic
First line, as an alternative to FOLFOX
Cetuximab or panitumumab if RAS wild-type and left-sided, bevacizumab otherwise
Bowel cancer, metastatic
Second line, after FOLFOX has stopped working
Bevacizumab, aflibercept or ramucirumab, or an anti-EGFR antibody if not used before
Bowel cancer, liver metastases that might become removable
To shrink them before surgery
An antibody chosen by RAS status
Stomach and esophageal cancer
Second or later line
Ramucirumab in some regimens
Pancreatic cancer
After gemcitabine, in some centers
Alone
After surgery for early bowel cancer, FOLFIRI has no place. Trials showed irinotecan added nothing there. FOLFOX or capecitabine with oxaliplatin is the standard for that setting.
FOLFIRI or FOLFOX first
The GERCOR trial, published in the Journal of Clinical Oncology in 2004, gave 220 patients with untreated metastatic bowel cancer either FOLFIRI followed by FOLFOX, or the reverse, and found four things.
Survival was the same. 21.5 months starting with FOLFIRI, 20.6 months starting with FOLFOX.
First-line results were the same. Tumor shrinkage in 56 against 54 percent, and 8.5 against 8.0 months before the cancer grew.
Second-line results favored FOLFOX slightly. Given after FOLFIRI, FOLFOX shrank tumors in 15 percent. FOLFIRI given after FOLFOX, in 4 percent.
The side effects differed. FOLFIRI caused more mouth sores, nausea, vomiting and hair loss. FOLFOX caused more low white cell counts and nerve damage.
How the first regimen is chosen
Oxaliplatin damages the nerves of the hands and feet, building with each dose, and the damage can last for years. A pianist, a surgeon, a patient with diabetic nerve damage, or anyone who works with their hands may do better starting with FOLFIRI. A patient who would find hair loss hard to bear may prefer FOLFOX. Both routes lead to the same place.
Adding an antibody
A targeted antibody joins FOLFIRI in nearly every plan, and the gene tests on the tumor decide which.
1
RAS and BRAF first
A tumor with a mutation in KRAS or NRAS ignores cetuximab and panitumumab, and giving them does harm. The test is done on the original biopsy or the operation specimen before the first cycle.
2
Cetuximab or panitumumab
For RAS wild-type tumors, especially those that began on the left side of the bowel. In CRYSTAL, 1,198 patients received FOLFIRI with or without cetuximab, and the benefit was confined to tumors without a KRAS mutation. Skin rash like severe acne is expected, and it tends to mean the drug is working.
3
Bevacizumab
For RAS-mutant tumors, right-sided tumors, and as a second choice in others. It cuts off the blood supply the tumor recruits, and blood pressure and urine protein are checked each cycle. Surgery waits six weeks after the last dose.
FIRE-3, Lancet Oncology 2014
592 patients with KRAS wild-type metastatic bowel cancer received FOLFIRI with cetuximab or with bevacizumab. Tumor shrinkage and time without progression were similar, 62 against 58 percent and 10.0 against 10.3 months. Median survival was 28.7 months with cetuximab against 25.0 with bevacizumab. Severe skin reactions occurred in 26 percent with cetuximab against 2 percent.
Two gene tests before the first dose
Two of these tests look at the patient and one at the tumor. Together they decide the dose, and sometimes the whole plan.
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Tests that make FOLFIRI safer
Test
What it finds
What changes
DPD deficiency, DPYD gene
A shortfall in the enzyme that breaks down fluorouracil. Present in a few percent of people
The fluorouracil dose is reduced, or the drug avoided, since a normal dose can be fatal
UGT1A1*28
A slow version of the enzyme that clears irinotecan, common in people with Gilbert syndrome
The irinotecan dose starts lower, because diarrhea and low white counts are more severe
Microsatellite instability, MSI or dMMR
A tumor with faulty DNA repair, in about 5 percent of metastatic bowel cancers
Immunotherapy replaces chemotherapy as the first treatment, with far better results
Two blood tests about the patient, one test on the tumor. All three should be in the file before the first FOLFIRI cycle, and the review checks that they are.
Diarrhea, the side effect to know
Irinotecan causes diarrhea in two distinct ways, at two different times, and each has its own treatment. Telling them apart keeps a manageable problem from turning dangerous.
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The two kinds of diarrhea with irinotecan
Early
Late
When
During or within 24 hours of the infusion
From the second day onward, peaking around day 5 to 7
With it
Sweating, cramps, watery eyes, a runny nose, slow pulse
Watery stools, sometimes many a day
Cause
A reaction of the nerves of the gut to irinotecan
Direct damage to the bowel lining
Treatment
An injection of atropine, given in the day unit, and before later cycles as prevention
Loperamide at home, by the rule below, and hospital fluids if it does not settle
The loperamide rule
At the first loose stool after day 1, take two loperamide capsules. Then one every two hours, two every four hours at night, until twelve hours have passed with no loose stool. Drink at least two liters a day. If diarrhea lasts more than 24 hours on this plan, or comes with fever, dizziness or blood, go to hospital the same day, because irinotecan diarrhea with a low white count is an emergency.
Other side effects
The remaining effects will sound familiar from other chemotherapy, and most prove milder than patients fear.
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Other effects of FOLFIRI
Effect
How common
What helps
Low white cell count
Common, lowest around days 7 to 10
A blood count before each cycle. Growth factor injections when it keeps falling
Nausea and vomiting
Common in the first days
Two or three anti-sickness drugs before each cycle
Hair thinning or loss
Common with irinotecan
Grows back after treatment
Mouth sores
Frequent with fluorouracil
Mouthwash, soft food, and a lower dose if severe
Tiredness
Builds over months
Rest, activity, and treatment breaks
Hand-foot soreness
Sometimes, from fluorouracil
Moisturizer, and a dose change if it blisters
Fever above 38 degrees in the ten days after a cycle means the emergency department, the same day. A low white count can turn an ordinary infection into a serious one within hours.
Days in Istanbul
First cycle
Five to six days. Consultation, gene tests if missing, a port placed, the first cycle on day 1, and the pump disconnected on day 3 before you fly.
Two cycles here
Around two and a half weeks, for patients who want the first cycle and its recovery watched, then the second given before going home.
Later cycles
Every two weeks at home, by an oncologist on the protocol we write. A scan every two to three months is sent back for review.
Why most cycles happen at home
A cycle every fourteen days, for six months or longer, cannot sensibly be given by air. The first cycle here sets the doses from your gene tests and your first blood counts. Your own oncologist follows the same protocol after that.
What a quote contains
The drugs are not the main cost
Fluorouracil, folinic acid and irinotecan are old, generic and inexpensive. The antibody given with them, cetuximab, panitumumab or bevacizumab, costs many times more than the chemotherapy and decides most of the price of a cycle.
No figure appears on this page. A quote you can compare names the antibody, the dose by body surface area or weight, the number of cycles, whether the port and the pump are included, and whether the gene tests are inside the figure. Packages published by Turkish hospitals and medical travel agencies for chemotherapy cover consultation, a stated number of cycles and the day unit, and leave out later cycles, scans, flights and accommodation. The quote follows the free review.
Coordinator, language, companion
One coordinator, your language
Biruni Hospital assigns one coordinator from the first message, on the same WhatsApp number afterwards. The international patients team works in English, Arabic, French, Russian, Serbian, Romanian and Spanish, with interpreters for other languages, and the interpreter sits in on the first consultation, where the loperamide rule and the fever rule are explained.
A companion is worth bringing for the first cycle. The office books accommodation near the hospital, arranges airport transfers and the car for the pump days, and issues an appointment confirmation and invitation letter for a visa ten days or so before travel. The kitchen prepares halal, vegetarian and diabetic meals, a prayer room is on site, and a female physician is arranged where the rota allows for anyone who asks in the first message.
Cycles at home
What your oncologist receives
Once you get back home, your oncologist receives the protocol with every dose, the gene test results and any dose reductions they led to, the antibody plan, the loperamide and fever rules in writing, and the schedule below.
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Checks during FOLFIRI
Check
How often
Blood count, kidney and liver tests
Before every cycle
Blood pressure and urine protein, on bevacizumab
Before every cycle
Magnesium, on cetuximab or panitumumab
Every few cycles
CT of chest, abdomen and pelvis
Every two to three months
CEA tumor marker
Every cycle or every other
Every scan and CEA result goes to the coordinator. The oncologist here reviews it at no charge and says whether to continue, pause, change the antibody, or ask a liver surgeon whether the metastases can now be removed.
FOLFIRI Chemotherapy FAQ
What does FOLFIRI stand for?
Folinic acid, fluorouracil and irinotecan, given together every two weeks, with the fluorouracil continuing for 46 hours from a portable pump.
Is FOLFIRI better than FOLFOX?
Neither is better. In the GERCOR trial, starting with FOLFIRI gave median survival of 21.5 months and starting with FOLFOX 20.6 months. The side effects differ, and most patients receive both in turn.
How long does FOLFIRI treatment last?
Each cycle lasts two weeks. For advanced disease treatment continues for as long as it works and is tolerated, commonly around six months before a break or a lighter maintenance schedule.
What is the worst side effect of FOLFIRI?
Diarrhea from irinotecan. Early diarrhea during the infusion is treated with atropine. Late diarrhea from day 2 is treated with loperamide by a strict rule, and diarrhea with fever is an emergency.
Is FOLFIRI given with cetuximab?
For bowel cancer without a RAS mutation, frequently. In FIRE-3, FOLFIRI with cetuximab gave median survival of 28.7 months against 25.0 with bevacizumab.
How long do I need to stay in Istanbul?
Five to six days for the first cycle, including the port and the 46 hours of the pump. Later cycles are given at home on our protocol.
Will the staff be able to speak my language?
The international patients team works in English, Arabic, French, Russian, Serbian, Romanian and Spanish and arranges interpreters for other languages.
References
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. Journal of Clinical Oncology. 2004;22(2):229-237.
Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. The New England Journal of Medicine. 2009;360(14):1408-1417.
Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. The Lancet Oncology. 2014;15(10):1065-1075.
Editor's note
Written by the Biruni Hospital medical editorial team. Reviewed by Prof. Dr. Mustafa Teoman YANMAZ, Medical Oncology.
