Although there are no RCTs which provide a comparison between FOLFOX regimens, the FOLFOX6 (modified) regimen is widely accepted and is currently used as the control arm in most clinical trials (link todiscussion on FOLFOX protocols).
Due to the lack of conclusive evidence to identify the optimum dose of calcium folinate (Leucovorin®), it is the consensus of the eviQ reference committee to adopt flat dosing of calcium folinate (Leucovorin®) as a 50 mg IV bolus when used with bolus 5FU across all colorectal and upper gastrointestinal protocols. A discussion regarding the effect ofdosing on outcome can be foundin thecalcium folinate (Leucovorin®) dosedocument.
The evidence supporting the use of FOLFOX6 in the adjuvant setting is based on a Phase III multicentre international randomised trial (MOSAIC) involving 2,246 patients comparing oxaliplatin + 5FU/LV with infusional 5FU/LV (FOLFOX4) alone in patients with Stage II and III colon cancer.rAlthough FOLFOX4 (oxaliplatin dose 85 mg/m2) was used in the MOSAIC trial, more recent adjuvant studies have used a modified FOLFOX6 regimen (oxaliplatin dose remains at 85 mg/m2 rather than 100 mg/m2 as per unmodified FOLFOX6). The justification for using modified FOLFOX6 is that this regimen is considered to be as effective as FOLFOX4 but avoids the need for day 3 administration of bolus fluorouracil. There are no RCTS which provide a head to head comparison of mFOLFOX4 with mFOLFOX6 in the adjuvant setting.
The International Duration Evaluation of Adjuvant Chemotherapy(IDEA) Collaboration in 2020 published analysed datafrom 6 phase III randomised trials to determineif a 3 month course of oxaliplatin-based adjuvant treatment(FOLFOX4/mFOLFOX6 or XELOX) is non-inferior to the current standard 6 month treatment for stage IIIcolon cancer. For patients being treated with FOLFOX, 3 months therapy was inferior to 6 months therapy particularly for high-risk patients (T4 or N2), non-inferiority was not demonstrated for low-risk patients (T1-3N1). However, for patients planned to receive 12 cycles of FOLFOX, whereoxaliplatin is ceased due to neuropathy after at least 6 cycles, outcomes were not found to be inferior for these patients that stopped oxaliplatin early. These patients usually continue 5FU/LV to complete the full 12 cycles (6 months). Non-oxaliplatin based adjuvant therapy was not examined in this study and monotherapy is recommended to be given for 6 months.r
Efficacy
In the MOISAICtrial published 2009, disease free survival (DFS) at 5 years was significantly increased in the intention to treat (ITT) population (HR 0.80, 95% CI 0.68 to 0.93, p=0.003) and in the sub-group of patients with Stage III disease (0.78, 95% CI 0.65 to 0.93, p = 0.005) in the oxaliplatin-containing arm. The overall survival (OS) at 6 years was 78.5% in the oxaliplatin containing arm and 76% in the infusional 5FU/LV alone arm (HR 0.84, 95% CI 0.71 to 1.0, p = 0.46). Therewas no evidence of a benefit of this regimen in the subgroup of patients with Stage II disease.r
In the IDEA analysis, patients received adjuvant chemotherapy (ACT), 39%CAPOX and the remainder received FOLFOX. In the overallpopulation, the 5-year OSwas 82.4% with 3 months of therapy and 82.8% with 6 months of therapy, with an estimated OS HR of 1.02 (95% CI 0.95 to 1.11). The absolute difference in 5-year OS rate was -0.4% (95% CI -2.1–1.3%).Five-year OS rate in 3 compared to 6 months treatment in CAPOX was 82·1% versus 81·2% with an estimated HR of 0·96 (95% CI, 0·85-1·08; NI FDRadj p, 0·033) and in FOLFOX was 82·6% and 83·8%, estimated HR of 1·07 (95% CI, 0·97-1·18; NI FDRadj p, 0·34).CAPOXhad considerably less toxicity, especially neuro toxicity.r
Kaplan-Meier curves IDEACollaboration- 5 year DFS, 3 months versus 6 months ACTr
© Lancet Oncol 2020
Kaplan-Meier curvesIDEA Collaboration- combined 5 year OS for 3 versus 6 months ACTr
© Lancet Oncol 2020
Kaplan-Meier curvesIDEA Collaboration- 5 year OS 3 months versus 6 months by type of ACTr
© Lancet Oncol 2020
Overall survivalr
©J Clin Oncol2009
Toxicity
| Toxicityr | FL plus Oxaliplatin n=1108 | Fluorouracil n=1111 | ||
|---|---|---|---|---|
| Grade 3 (%) | Grade 4 (%) | Grade 3 (%) | Grade 4 (%) | |
| Paresthesia | 12 | 12 | <1 | n/a |
| Neutropenia | 29 | 12 | 4 | 1 |
| Nausea | 5 | <1 | 1 | <1 |
| Diarrhoea | 8 | 2 | 5 | 1 |
| Vomiting | 5 | <1 | 1 | <1 |
Peripheral sensory neuropathy was the most common dose-limiting toxicity with oxaliplatin and the incidence of grade 3 and 4 toxicities were higher in the oxaliplatin-treated arm. Grade 3 sensory neuropathy occurred during treatment in 12.5% of patients treated with the oxaliplatin regimen compared to 0.2% in the infusional 5FU/LV arm. Adverse events resulted in the withdrawal from treatment of 160 patients (14.4%) in the oxaliplatin and 61 patients (5.5%) in the 5FU arm.r
The proportion of patients experiencing neuropathy at various time pointsr
© J Clin Oncol2009
Grade 0 represents no change; 1 mild paresthesia, 2 mild or moderate objective sensory loss, moderate paresthesia (interferes with function but not ADLs), grade 3 severe objective sensory loss or paresthesia (usually pain, ADLs impaired).
