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 of dosing on outcome can be found in the calcium folinate (Leucovorin®) dose document.
The evidence supporting this protocol is based on the FLOT4-AIO study, a randomised phase II/III study comparing perioperative chemotherapy with FLOT versus ECF/ECX.r
Between August 2010 and February 2015, this study randomised 716 patients to either FLOT (n=356) versus ECF/ECX (n=360). Patients were eligible if they had histologically confirmed gastric or gastroesophageal junction adenocarcinoma, with clinical stage cT2-4, or positive nodal stage (cN+), or both.
Patients randomised to FLOT received 4 neoadjuvant and 4 adjuvant 2-weekly cycles of 5FU at 2600 mg/m2, leucovorin 200 mg/m2, oxaliplatin 85 mg/m2 and docetaxel 50 mg/m2. Patients randomised to ECF/ECX received 3 neoadjuvant and 3 adjuvant 3-weekly cycles of epirubicin 50 mg/m2 and cisplatin 60 mg/m2 on day 1, plus either 200 mg/m2 5-FU as a continuous infusion or 1250 mg/m2 of capecitabine orally on days 1 to 21.
The majority of patients (56% in each group) had gastro-oesophageal adenocarcinoma and 44% had gastric adenocarcinoma. Of all patients randomised, 162 (46%) in the FLOT group and 132 (37%) in the ECF/ECX group completed all allocated cycles. 121 (34%) in the FLOT group and 77 (21%) patients in the ECF/ECX group received G-CSF at any time-point.
The primary end point was overall survival (OS), and the secondary end points were progression-free survival (PFS), complete resection rate, surgical morbidity and mortality, and chemotherapy-related toxicity.
After a median follow up of 43 months, the median OS was 50 months in the FLOT group, compared with 35 months in the ECF/ECX group (HR=0.77, 95% CI 0.63-0.94; p=0.01). The estimated overall survival at 5 years was 45% versus 36% favouring the FLOT regimen. There was no detected interaction between anatomical location and treatment effect (HR 0.76 for gastroesophageal adenocarcinoma versus 0.77 for gastric, test for heterogeneity p=0.9).
Patients treated with FLOT had longer PFS of 30 months, compared with 18 months in ECF/ECX, HR=0.75 (95% CI 0.62-0.91), p=0.004. In the FLOT group, more patients proceeded to tumor surgery (94% vs 87%, p=0.001), and the R0 resection rate was higher (85% vs 78%, p=0.02). There was comparable surgical morbidity and mortality, with 50% of patients in both groups experiencing a post-operative complication.r
Kaplan-Meier curve for overall survivalr
© The Lancet 2019
There were more grade 3 or 4 infections, neutropenia, diarrhoea and neuropathy in the FLOT group, but more grade 3 or 4 nausea, vomiting, thromboembolic events and anaemia in the ECF/ECX group. Overall, the rate of treatment-related serious adverse events (27% vs 27%) and hospitalisations (25% vs 26%) were comparable. 90% of patients treated with FLOT and 91% treated with ECF/ECX completed their neoadjuvant chemotherapy, whilst 46% in the FLOT group and 37% in the ECF/ECX group completed their adjuvant/post-operative chemotherapy. Quality of life data was not captured.r
© The Lancet 2019