Evidence
FOLFOX has been used extensively for the treatment of colorectal cancer. 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 5-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, open-label, randomised trial (ABC-06) involving 162 patients comparing modified FOLFOX6 plus active symptom control (ASC) or ASC alone in locally advanced and metastatic biliary and gallbladder cancer after failure of first line cisplatin and gemcitabine chemotherapy.r
Between March 2014 and January 2018, 162 patients were randomised 1:1 to receive either ASC (e.g biliary drainage, analgesia, antibiotics, steroids, antiemetics, palliative treatment, blood products transfusion etc. as per requirements of individual patients) with modified FOLFOX6 chemotherapy (oxaliplatin 85 mg/m2, calcium folinate 350 mg, 5-fluorouracil 400 mg/m2 bolus and 2400 mg/m2 continuous infusion over 46 hours every 14 days for up to 12 cycles) or ASC alone. Participants needed to have histologically or cytologically confirmed advanced biliary tract cancer with disease progression after first-line cisplatin and gemcitabine chemotherapy. The primary tumour was either intrahepatic cholangiocarcinoma (44%), extrahepatic cholangiocarcinoma (28%), gallbladder cancer (21%) or ampullary cancer (7%).r
The primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS), radiological response, adverse events, quality of life and health economics.r
Efficacy
After a median follow-up of 21.7 months, the median OS was 6.2 months (95% CI 5.4 to 7.6) in the ASC + FOLFOX arm versus 5.3 months (95% CI 4.1 to 5.8) in the ASC arm (HR=0.69; 95% CI 0.50 to 0.97; p=0.031). The effect of FOLFOX chemotherapy on OS was reasonably consistent across subgroups, including by platinum sensitivity (platinum-sensitive HR=0.81, platinum-resistant HR=0.63) and primary tumour (intrahepatic cholangiocarcinoma HR=0.64, extrahepatic cholangiocarcinoma HR=0.84, gallbladder cancer HR=0.56, ampullary cancer HR=0.71). Quality of life and health economic data were collected but have not yet been published.r
Outcomer |
ASC + FOLFOX
n = 81
|
ASC
n = 81
|
Median OS (months) |
6.2 (95% CI 5.4 to 7.6) |
5.3 (95% CI 4.1 to 5.8) |
Median PFS (months) |
4.0 (95% CI 3.2 to 5.0) |
NR |
6-month OS rate (%) |
50.6 (95% CI 39.3 to 60.9) |
35.5 (95% CI 25.2 to 46.0) |
12-month OS rate (%) |
25.9 (95% CI 17.0 to 35.8) |
11.4 (95% CI 5.6 to 19.5) |
3-month PFS rate (%) |
66.7 (95% CI 55.3 to 75.8) |
NR |
6-month PFS rate (%) |
32.1 (95% CI 22.3–42.3) |
NR |
12-month PFS rate (%) |
8.6 (95% CI 3.8–16.0) |
NR |
Overall response rate (%) |
5 (complete: 1, partial: 4) |
NR |
Disease control rate (%) |
33 (complete: 1, partial: 4, stable: 28) |
NR |
NR = not reported
Kaplan-Meier curve for overall survivalr
© Lancet Oncol 2021
Subgroup analysis of overall survivalr
© Lancet Oncol 2021
Toxicity
Grade ≥ 3 toxicities were seen in 69% of patients in the ASC + FOLFOX arm and 52% of patients in the ASC alone arm. The most common chemotherapy-related grade ≥ 3 toxicities were neutropenia (12%), fatigue or lethargy (11%) and infection (10%). There were 3 chemotherapy-related deaths (infection, febrile neutropenia and acute kidney injury) in the ASC + FOLFOX group.r
Grade ≥ 3 adverse eventsr
Toxicity |
ASC + FOLFOX (%)
n = 81
|
ASC (%)
n = 81
|
Any grade 3 to 5 toxicity |
69 |
52 |
Fatigue |
19 |
7 |
Neutrophil count decreased |
12 |
1 |
Infection |
19 |
6 |
Biliary event (obstruction, infection) |
20 |
21 |
Anorexia |
1 |
7 |
Nausea |
1 |
1 |
Vomiting |
4 |
5 |
Thromboembolic events |
0 |
5 |
Constipation |
2 |
1 |
Diarrhoea |
2 |
2 |
Anaemia |
2 |
1 |
Catheter-related infection |
2 |
0 |
Allergic reaction |
1 |
0 |
Neuropathy |
1 |
0 |
Febrile neutropenia |
2 |
0 |
Myocardial infarction |
1 |
0 |
Acute kidney injury |
4 |
0 |