FOLFOX (modified FOLFOX6)

Oxaliplatin, leucovorin and infusional fluorouracil every 14 days for adjuvant and metastatic colorectal cancer

For clinicians and students · Regimen tutorial · Colorectal cancer · 10 min read · last reviewed September 30, 2026

Overview

FOLFOX combines folinic acid (leucovorin), fluorouracil and oxaliplatin. "Modified FOLFOX6" (mFOLFOX6) is the version most centres use today. It gives a single 2-hour oxaliplatin infusion, a fluorouracil bolus, and a 46-hour fluorouracil infusion through an ambulatory pump, every 14 days. Leucovorin modulates fluorouracil by stabilizing its binding to thymidylate synthase. Oxaliplatin forms platinum–DNA adducts. The regimen is the backbone of adjuvant colon cancer therapy and one of the two standard first-line chemotherapy doublets for metastatic colorectal cancer.

Indications

Eligibility in the BC Cancer protocols includes ECOG ≤ 2 and adequate marrow, renal and liver function. Congenital long QT syndrome is an exclusion. The cautions are prior pelvic radiotherapy, recent MI or uncontrolled cardiac disease, baseline diarrhea (> 3 loose stools/day without an ostomy), and symptomatic peripheral neuropathy.

Regimen

Source: BC Cancer GIAJFFOX and GIFOLFOX (identical drug doses).

Cycle length: 14 days (the schedule may be modified ± 3 days per GIAJFFOX).

Number of cycles:

• Adjuvant, high-risk stage III (any T4 and/or N2): 12 cycles.
• Adjuvant, low-risk stage III (T1–3 N1): 6 cycles. BC Cancer calls 3 months of mFOLFOX6 "a recommended option due to the significantly lower risk of neurotoxicity", and allows up to 12 cycles if the oncologist judges the benefit worth the risk.
• Metastatic: repeat every 14 days until progression or unacceptable toxicity.

Variants across sources.

• Leucovorin dose. eviQ (ID 637) gives leucovorin 50 mg flat IV bolus rather than 400 mg/m². The eviQ reference committee also reduced oxaliplatin from the original FOLFOX6 trial dose of 100 mg/m² to 85 mg/m². Levoleucovorin (the l-isomer) is dosed at half the racemic dose. Check which product and dose your pharmacy stocks.
• Adjuvant duration. The eviQ adjuvant protocol lists 12 cycles and notes that in the IDEA meta-analysis, 3 months of FOLFOX was not shown to be non-inferior even in low-risk patients. Non-inferiority for 3 months in low-risk disease was shown with CAPOX. Many centres therefore prefer 3 months of CAPOX, rather than 3 months of FOLFOX, when a short course is chosen.
• Fluorouracil bolus. In the metastatic setting BC Cancer allows the bolus to be omitted. Leucovorin may then be omitted, or given as 20 mg/m² IV push.

Premedication and supportive care

• Antiemetics. The regimen is moderately emetogenic (BC Cancer SCNAUSEA; eviQ "MODERATE"). A typical approach is a 5-HT3 antagonist plus dexamethasone on day 1, with or without an NK1 antagonist according to local guidance. BC Cancer notes that a single 8 mg dose of ondansetron is lower risk for QT prolongation than repeated or higher doses. This matters because oxaliplatin can prolong QT.
• Cold avoidance. Counsel the patient to avoid cold drinks and cold air, especially for 3–5 days after each oxaliplatin dose. Do not use ice chips (oral cryotherapy) with oxaliplatin, because they can precipitate pharyngolaryngeal dysesthesia. This is the opposite of bolus-5-FU regimens.
• Hypersensitivity premedication (only after a grade 1–2 reaction), per BC Cancer:
• dexamethasone 20 mg IV 45 minutes before oxaliplatin; then
• diphenhydramine 50 mg IV plus famotidine 20 mg IV 30 minutes before.
• Also consider slowing the oxaliplatin infusion to 4–6 hours.
• Growth factor. Neither BC Cancer nor eviQ builds routine primary G-CSF prophylaxis into mFOLFOX6. Consider it on a case-by-case basis, for example after febrile neutropenia when dose maintenance matters, following local febrile neutropenia risk policy.
• Line care. Patients with PICC lines need a weekly site assessment for infection or thrombosis.

Key toxicities

Oxaliplatin neurotoxicity: know the two syndromes

1. Acute neurotoxicity. Cold-triggered paresthesias and dysesthesias of the hands, feet and perioral area begin during the infusion or within hours to days, then resolve. They are very common. Pharyngolaryngeal dysesthesia feels like difficulty breathing or swallowing, but oxygen saturation is normal and there is no stridor or bronchospasm. BC Cancer's protocol has a side-by-side table separating it from platinum hypersensitivity:

1. Cumulative sensory neuropathy. This is dose-dependent, "stocking-glove" in distribution, and can cause functional loss such as buttons, writing and gait. It may keep worsening for weeks after the drug stops (coasting). It drives dose reduction and early discontinuation. Grade it by function (BC Cancer definitions):

• Grade 2 interferes with function but not ADLs.
• Grade 3 comes with pain or interferes with ADLs.
• Grade 4 is disabling.

Fluoropyrimidine toxicities

• Diarrhea, mucositis/stomatitis, hand-foot syndrome (less than with capecitabine), and neutropenia.
• DPD deficiency. Reduced dihydropyrimidine dehydrogenase activity can cause severe or fatal stomatitis, diarrhea, neutropenia and neurotoxicity. BC Cancer estimates it affects about 3% of the population. Testing policy varies by jurisdiction:
• BC Cancer lists a baseline DPYD test (not needed if previously tested, or if fluorouracil/capecitabine was tolerated before). Doses follow the DPYD Activity Score table: activity score 2.0 → no reduction; 1.0–1.5 → reduce by 50% and titrate; 0.5 → not recommended (if unavoidable, reduce by at least 75% with early therapeutic drug monitoring); 0 → do not use.
• The eviQ adjuvant FOLFOX protocol notes that DPD testing is available in Australia but not reimbursed, and asks for investigation of severe unexplained toxicity.
• European and US regulatory positions have also shifted towards pre-treatment testing.
• Follow your own institution's policy.
• Cardiotoxicity. Coronary vasospasm, angina and arrhythmia are rare. BC Cancer advises stopping treatment and arranging urgent cardiac assessment. Rechallenge with fluorouracil or capecitabine is generally not recommended. Record the reaction in the allergy profile.

Other oxaliplatin effects

• Hypersensitivity reactions, which become more likely after multiple cycles.
• QT prolongation.
• Pulmonary fibrosis (rare).
• Hepatic sinusoidal obstruction (veno-occlusive disease, rare).
• Hemolytic uremic syndrome (rare).
• Irritant on extravasation.

Interactions: fluorouracil can raise the INR on warfarin and raise phenytoin/fosphenytoin levels.

Monitoring

Per BC Cancer GIAJFFOX / GIFOLFOX:

• Baseline:
• CBC and differential, creatinine, ALT, alkaline phosphatase, total bilirubin, albumin, sodium, potassium.
• DPYD test.
• If clinically indicated: CEA, CA 19-9, GGT, ECG.
• Before each cycle: CBC and differential, creatinine, total bilirubin, ALT. Assess neuropathy grade (functional history) and diarrhea/stomatitis grade at every visit.
• Warfarin: check INR weekly during fluorouracil therapy until the warfarin dose is stable, then before each cycle, then weekly for one month after fluorouracil stops.
• ECG and electrolytes: in patients with cardiac disease, QT-prolonging co-medications or electrolyte abnormalities. Correct electrolytes before treatment.

Dose-modification principles

BC Cancer uses dose levels. Summary of GIAJFFOX:

Leucovorin is not dose-reduced. For further reductions, use 20% below the previous level or consider stopping.

• Day-1 thresholds. Hold if ANC < 1.2 × 10⁹/L or platelets < 75 × 10⁹/L. Recheck weekly, up to 4 times. Resume at the dose level matching the worst count, and discontinue if counts have not recovered by 4 weeks.
• Neutropenia or thrombocytopenia.
• Grade 3 neutropenia → oxaliplatin down one level.
• Grade 4 neutropenia → oxaliplatin down one level, omit the fluorouracil push, and reduce the infusion by one level.
• Grade 3 thrombocytopenia → oxaliplatin down one level; grade 4 → down two levels.
• Neuropathy (oxaliplatin only).
• Grade 2 persisting to the next cycle → reduce one level.
• Grade 3 → reduce one level; if it persists to the next cycle, discontinue.
• Grade 4 → discontinue.
• Pharyngolaryngeal dysesthesia → no dose change, but prolong the infusion.
• Patients who recover well from grade 3 (not grade 4) neuropathy may be rechallenged one level lower.
• Diarrhea and stomatitis. Hold for grade ≥ 2 on day 1. Grade 3 → reduce fluorouracil one level. Grade 4 → reduce oxaliplatin and fluorouracil one level.

The eviQ reductions are percentage-based and differ in detail. Apply your own institution's protocol table, not a remembered one.

Key trials and evidence

• MOSAIC (André, NEJM 2004). Adding oxaliplatin to infusional 5-FU/LV (FOLFOX4) improved disease-free survival in resected stage II–III colon cancer. It established oxaliplatin-based adjuvant therapy.
• IDEA (Grothey, NEJM 2018). A pooled analysis of six trials comparing 3 vs 6 months of adjuvant FOLFOX or CAPOX in stage III disease. Non-inferiority of 3 months was not shown overall. For low-risk (T1–3 N1) disease, 3 months of CAPOX was sufficient, with far less neurotoxicity. The regimen-specific findings underpin current duration choices.
• GERCOR (Tournigand, JCO 2004). FOLFIRI→FOLFOX6 and FOLFOX6→FOLFIRI gave similar survival in metastatic disease, so the first-line doublet can be chosen by toxicity profile.

Clinical pearls

• "Not in saline." Oxaliplatin precipitates or degrades in chloride-containing solutions. Keep NS off the line. This is a common pharmacy and nursing catch.
• Know the difference at the bedside. A patient who "can't breathe" during oxaliplatin, with normal SpO₂, no wheeze and a cold-drink history, most likely has pharyngolaryngeal dysesthesia rather than anaphylaxis. Check saturation first.
• Ask functional questions. "Can you do up buttons?", "Are you dropping things?", "Can you feel the floor?" separate grade 2 from grade 3 neuropathy better than "any tingling?".
• Stop oxaliplatin, not the plan. In the metastatic setting, stop-and-go strategies (oxaliplatin holiday with fluoropyrimidine maintenance) preserve function. In adjuvant therapy, stopping oxaliplatin for neuropathy after at least 6 cycles and completing 5-FU/LV is common practice (noted in eviQ ID 637).
• Pump logistics. Confirm the patient knows what to do if the 46-hour pump leaks or disconnects, and who to call. Spill kits and disconnection appointments are part of the regimen.
• Warfarin patients need a plan before cycle 1. Many switch to a low-molecular-weight heparin or a direct oral anticoagulant where appropriate.

Educational material for health professionals and students. Not a prescribing order; it does not replace your institution's approved protocol, pharmacy verification or clinical judgement.

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