Although there are no randomized 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.
The evidence supporting this protocol is provided by a phase III, multicentre, international, open label, randomised trial (RAPIDO) involving 912 patients comparing short-course radiation therapy followed by clinician's choice of CAPOX/FOLFOX4 with standard of care chemoradiation therapy prior to total mesorectal excision (TME) in treatment-naive patients with high risk (tumour stage T4a or T4b, extramural vascular invasion, nodal stage N2, involved mesorectal fascia, or enlarged lateral lymph nodes) locally advanced rectal adenocarcinoma.r
Between June 2011 and June 2016, 912 patients were randomised in a 1:1 ratio. 462 patients were randomised to short-course radiation therapy followed by clinician's choice of CAPOX (capecitabine 1000 mg/m2 BD on days 1-14 and oxaliplatin 130mg/m2 on day 1, every 21 days for 6 cycles) or FOLFOX4 (oxaliplatin 85 mg/m2 on day 1, folinic acid 200 mg/m2 on days 1 and 2, bolus fluorouracil 400 mg/m2 and infusional fluorouracil 600 mg/m2 on days 1 and 2, every 14 days for 9 cycles) followed by TME. 450 patients were randomised to the standard of care chemoradiation (capecitabine 825 mg/m2 BD on days with radiation therapy) followed by TME. Patients in the standard of care group could proceed to adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4 based on local guidelines.r
The majority of patients in the experimental arm received CAPOX (99%).r Therefore, the applicability of evidence to neoadjuvant FOLFOX needs to be assumed. However given CAPOX is considered interchangeable with FOLFOX in most instancesr, its use in this setting is not unreasonable.
The primary end point was disease-related treatment failure which was changed from disease-free survival during recruitment as the endpoint was inappropriate for a neoadjuvant trial where patients are not disease free at randomisation. Secondary endpoints were completion rate of neoadjuvant treatment, R0 resection rate, pathological complete response rate, surgical complications within 30 days, overall survival (OS), and safety.r
This protocol has adopted the modified FOLFOX6 regimen in place of FOLFOX4 used in the trial. This is based on overall better tolerance with modified FOLFOX6 with similar efficacy.
Efficacy
After a median follow up of 4.6 years, the median 3-year probability of disease-related treatment failure was 23.7% in the experimental group vs 30.4% in the standard of care group (HR=0.75; CI 95% 0.60 to 0.95; p=0.019) with distant metastasis being the major cause of treatment failures (20.0% vs 26.8% in the experimental group and the standard of care group respectively; HR=0.69; CI 95% 0.54 to 0.90; p=0.0048). The median 3-year probability of locoregional failure was 8.3% vs 6.0% respectively (HR=1.42; CI 95% 0.91 to 2.21; p=0.12). No significant difference in 3-year OS was demonstrated between experimental and the standard of care groups (89.1% vs 88.8% HR=0.92; CI 95% 0.67 to1·25; p=0.59). Quality of life data was collected but has not yet been published.r
Kaplan-Meier curves of cumulative probability of disease-related treatment failure (A), distant metastases (B), and locoregional failure (C)r
© Lancet Oncol 2021
Kaplan-Meier curve of overall survivalr
© Lancet Oncol 2021
Toxicity
Grade ≥3 toxicities were seen in 48% of patients in the experimental arm and 25% of patients in the standard of care arm. 34% of patients in the standard of care arm had a grade ≥3 toxicity during adjuvant chemotherapy phase. Serious adverse events (SAE) occurred in 38% vs. 34% of patients in the experimental and standard of care groups, respectively. The most common SAE in both groups was diarrhoea. There were 4 treatment-related deaths (5% of all deaths) in both groups. 15% vs. 9% of patients in the experimental and standard of care groups respectively, stopped preoperative chemotherapy prematurely.r
Treatment-related adverse eventsr
@ Lancet Oncol 2021