Although there are no randomised controlled trials 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 to discussion 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 fluorouracil across all colorectal and upper gastrointestinal protocols. A discussion regarding the effect of dosing on outcome can be found in the calcium folinate (Leucovorin®) dose document.
A search of the literature did not find strong evidence to support the use of FOLFOX in the adjuvant treatment of rectal cancer. The expert reference committee supported publication of the protocol on the basis of the information summarised below. The committee was most strongly influenced by the multicentre, randomised, phase II controlled ADORE study, involving 321 patients comparing fluorouracil and leucovorin (every 4 weeks for 4 cycles) with FOLFOX (every 2 weeks for 8 cycles) in patients with postoperative ypTNM stage II or III rectal cancer after fluoropyrimidine-based pre-operative chemoradiation therapy (CRT) and total mesorectal excision (TME). The primary endpoint was disease-free survival (DFS).r
Source |
Study & year published |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Hong et al 2019r |
Yes |
Yes |
- |
Rodel et al 2012r |
Yes |
No |
Preoperative CRT with FL (fluorouracil 1g/m2 on d1-5 and d29-33) followed with adjuvant FL (fluorouracil 500 mg/m2 on d1-5, q4w for 4 cycles) versus preoperative CRT with FOLFOX (fluorouracil 250 mg/m2 on d1-14 and d22-35, oxaliplatin 50 mg/m2 on
d1, 8, 22, 29) followed with adjuvant FOLFOX (oxaliplatin 100 mg/m2 on d1, fluorouracil 2400 mg/m2 on d1-2, leucovorin 400 mg/m2 on d1, q2w for 8 cycles) |
Observational studies |
Martín-Aragón et al 2018r |
Yes |
No |
Adjuvant FOLFOX4 in patients with pathological evidence of residual disease after CRT and TME
|
Guidelines |
Date published/revised |
Supports use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
V.1 2021 |
Yes |
Yes |
Recommends FOLFOX and CAPOX as preferred options or only options for higher risk patients |
CCO |
March 2019 |
Yes |
No doses stated |
- |
ESMO |
2018 |
Yes |
No doses stated |
Supports use in stage III and high-risk yp stage II |
BCCA |
October 2012 |
Yes |
Yes |
Supports use in patients with resected stage III (node positive) rectal cancer |
Efficacy
A summary of the evidence supporting the effect of this protocol is below:
Study |
Outcome |
|
DFS (%, 95% CI) |
6 year OS rate (%, 95% CI) |
Pathological complete response (%) |
Hong et alr
(n=321; all yp stage II or III, median follow-up duration: 74.1 months) |
Intent to treat: 68 (61.0-75.4)
stratified HR: 0.63 (0.43-0.93); p=0.018
|
Intent to treat: 78.1 (71.7- 84.5)
stratified HR = 0.73 (0.45-1.19); p=0.21
|
- |
yp stage III: 63.2 (53.8-72.6)
stratified HR: 0.59 (0.38-0.92); p=0.019
|
yp stage III: 74.2
stratified HR: 0.72 (0.41-1.25); p=0.24
|
yp stage II: 77.8 (67.1-88.5)
stratified HR: 0.64 (0.30-1.36); p=0.25
|
yp stage II: 85.7
stratified HR: 0.83 (0.33-2.10); p=0.69
|
Rodel et alr
(n=613, 591 had surgery, 426 received adjuvant FOLFOX) |
- |
- |
17
odds ratio: 1.40 (1.02–1.92); p=0.038
|
Toxicity
A summary of the toxicities associated with this protocol are included in the table below. The most clinically significant toxicities for this treatment are haematological toxicities, diarrhoea, vomiting, nausea and sensory neuropathy.r
Treatment-related adverse eventsr
© J Clin Oncol