What is the FLOT chemotherapy regimen and how does it work?

FLOT is a combination chemotherapy regimen that includes fluorouracil, leucovorin, oxaliplatin, and docetaxel. It is primarily used to treat cancers of the stomach and esophagus. It is typically administered in 14-day cycles, 4 cycles before surgery (neoadjuvant) and 4 after surgery (adjuvant), to improve surgical outcomes and reduce cancer recurrence.

What Does FLOT Stand For?

FLOT is an acronym for the four medications in the chemotherapy regimen:

• F – Fluorouracil (5FU): An antimetabolite that disrupts DNA/RNA synthesis, preventing cancer cells from dividing and growing.
• L – Leucovorin (folinic acid): Enhances the effect of 5-FU by stabilizing its binding to the target protein.
• O – Oxaliplatin: A platinum-based drug that causes DNA cross-linking and cell death.
• T – Docetaxel: A taxane class drug that disrupts cell division by affecting microtubules.

Because these drugs target rapidly dividing cells, they are particularly effective against cancer cells, which grow and divide more quickly than most normal cells.

When Is FLOT Chemotherapy Used?

FLOT chemotherapy is primarily used to treat cancers of the stomach, esophagus (food pipe), and the gastroesophageal junction (the area where the stomach joins the esophagus). It is most commonly recommended for patients with localized or resectable (operable) tumors, where surgery is possible, and the patient is healthy enough to tolerate combination chemotherapy.

FLOT is considered a first-line treatment for resectable gastric and gastroesophageal junction cancer, and may also be used in esophageal cancer treatment based on oncologist recommendations.

Perioperative Setting (Before and After Surgery)

FLOT is typically given both before (neoadjuvant) and after (adjuvant) surgery. This approach is called perioperative chemotherapy. The cycles before surgery help shrink the tumor, making it easier to remove, while the cycles after surgery aim to destroy any remaining cancer cells and reduce the risk of recurrence.

This regimen is now considered a standard of care for patients with resectable gastric, gastroesophageal junction, and esophageal adenocarcinoma, based on clinical trial data showing improved survival compared to older regimens.

Locally Advanced Disease

FLOT is especially used for locally advanced, non-metastatic cancers, where the tumor has not spread to distant organs but may be large or involve nearby structures.

Metastatic Gastric Cancer

There is emerging evidence that FLOT can also be used in the first-line treatment of metastatic (stage IV) gastric cancer, although its primary and most established role remains in the perioperative setting for resectable disease.

How Is FLOT Administered?

FLOT chemotherapy is given intravenously, typically through a cannula, central line, PICC line, or portacath. It is usually given in cycles, with each cycle lasting 14 days (2 weeks). Most patients have a total of 8 cycles, with surgery to remove the cancer after cycle 4. Each cycle typically consists of the following steps:

Steroid premedication: You usually take dexamethasone (a steroid) tablets for 3 days, starting the day before chemotherapy begins, to help prevent side effects.

Day 1 (at the hospital or chemotherapy unit):

• Docetaxel: IV infusion over 1 hour.
• Oxaliplatin: IV infusion over 2 hours (sometimes longer to reduce side effects).
• Leucovorin (folinic acid): IV infusion over 2 hours.
• Fluorouracil (5FU): Continuous IV infusion over 24 hours, delivered through a portable pump connected to a central line, PICC line, or portacath; this allows you to go home with the pump, which is disconnected after the infusion is complete.
• Continue to take dexamethasone tablets.

Day 2:

• Fluorouracil drip is removed.
• Continue to take dexamethasone tablets.

Days 3 to 14:

• No treatment, allowing your body to recover.

Supportive medications: Antiemetics like ondansetron are given to prevent nausea, and growth factors such as filgrastim may be administered after chemotherapy to support white blood cell counts.

Cycle repetition: After the 24-hour infusion of 5FU, there is a break. The next cycle begins on day 15.

Your healthcare provider may provide different instructions than the example cycle above. Treatment duration and dosing may be adjusted based on patient tolerance.

How Effective Is FLOT Chemotherapy?

The FLOT chemotherapy regimen’s effectiveness has been evaluated in several large clinical trials and real-world studies, often in comparison to older regimens or chemoradiotherapy. It has proven effective even in high-risk patients with locally advanced disease.

Survival Outcomes

• Esophageal Cancer: The recent phase 3 ESOPEC trial demonstrated that patients with resectable esophageal adenocarcinoma who received perioperative FLOT chemotherapy had a median overall survival rate of 57% compared to 51% for those treated with the CROSS chemoradiotherapy regimen. Progression-free survival at 3 years was 52% in the FLOT group and 35.0% in the CROSS group.
• Gastric and Gastroesophageal Junction Cancer: In a small real-world Italian study, FLOT led to a median disease-free survival of 30 months, compared to 22.2 months for other regimens for resectable gastric cancer. Another study found a median overall survival of 50 months for FLOT-treated patients versus 35 months for those on the ECF/ECX regimen.

Tumor Response and Pathological Outcomes

• FLOT has shown higher rates of complete tumor regression compared to older regimens such as ECF/ECX (14% vs. 9% in one small study).
• In the ESOPEC trial, complete disappearance of the tumor (complete response) was observed in 35 of 191 FLOT patients, compared to 24 of 180 in the CROSS group.

What Are the Side Effects of FLOT Chemotherapy?

FLOT chemotherapy can cause a range of side effects, affecting various organs and body systems. The severity and type of side effects can vary from person to person.

Common Side Effects

• Increased risk of infection: Due to lowered white blood cell counts, patients are more susceptible to infections, which can sometimes be life-threatening. Signs include fever, chills, cough, and feeling generally unwell.
• Anemia and breathlessness: A drop in red blood cells can cause fatigue, breathlessness, and pallor.
• Bruising and bleeding: Reduced platelets can lead to easy bruising, bleeding gums, nosebleeds, or small red spots on the skin (petechiae).
• Nausea, vomiting, diarrhea, constipation: These are frequent gastrointestinal side effects.
• Fatigue: Feeling unusually tired or weak is common.
• Hair loss (alopecia): Many patients experience thinning or loss of hair.
• Mouth and throat problems: Soreness, ulcers, and increased risk of mouth or throat infections can occur.
• Hand-foot syndrome: Soreness, redness, and peeling of the palms and soles.
• Peripheral neuropathy: Numbness, tingling, or pain in the hands and feet, often due to oxaliplatin.
• Weight gain or swelling
• Mood changes: Depression, anxiety, sleep problems, and other mood changes are common due to dexamethasone.
• Nail changes
• Taste changes
• Pain at the infusion site

Serious Side Effects

• Liver and kidney changes
• Heart problems: 5FU can rarely cause chest pain, heart attacks, or heart failure.
• Severe allergic reactions: This may occur during the infusion, and cause itching, breathing difficulties, chills, and fever.
• Neurologic effects: Rarely, confusion, speech or movement difficulties, or a condition called posterior reversible encephalopathy syndrome (PRES).
• Hearing problems: Some patients may experience hearing loss or ringing in the ears.

To reduce the risk of side effects, your healthcare team will administer premedications (e.g., antihistamine, corticosteroid). You also may receive a medication known as a granulocyte-colony stimulating factor (G-CSF) to help boost your white blood cell count to reduce the risk of infection. Make sure to wash your hands often and avoid people who are sick. Dose adjustments may be required to help manage side effects.

Important Considerations During Treatment

FLOT chemotherapy requires careful monitoring and management to optimize outcomes and minimize risks. Key considerations include:

• Organ function evaluation: Your healthcare team will monitor your kidney function, liver enzymes, cardiac history, and blood counts during treatment through blood tests.
• Neurological assessments: Regular evaluation for peripheral neuropathy (tingling, numbness), which may require oxaliplatin dose reduction or discontinuation.
• Infusion monitoring: Observe closely for hypersensitivity reactions during oxaliplatin/docetaxel administration, especially in early cycles.
• Infusion pump education: Patients with 5FU pumps require education on disconnection and spill management.
• Education on emergency symptoms: Seek immediate help for PRES (headache, confusion, seizures), cardiac symptoms (chest pain), or signs of infection like fever or cough.
• Hydration: Drink plenty of water (unless fluid restricted) to reduce bladder irritation and kidney toxicity.
• Avoid pregnancy and breastfeeding: FLOT chemotherapy can cause harm to babies.

Summary

FLOT chemotherapy contains a combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel. It is highly effective for resectable gastroesophageal and gastric adenocarcinomas, offering superior survival and tumor response rates compared to both chemoradiotherapy (CROSS) and older chemotherapy regimens (ECF/ECX). The benefits are most pronounced when patients complete the full perioperative regimen. Side effects are common, but they are generally manageable with medications and lifestyle changes.