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 provided by a phase II/III multicentre randomised trial (PRODIGE5/ACCORD17) involving 267 patients comparing FOLFOX chemoradiation therapy versus cisplatin-fluorouracil chemoradiation therapy in patients with localised oesophageal cancer.r
Between October 2004 and August 2011, 134 patients were randomised to receive 6 cycles of FOLFOX (three concomitant to radiation therapy) of oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, bolus fluorouracil 400 mg/m2, and infusional fluorouracil 1600 mg/m2 (FOLFOX) over 46 hours and 133 patients were randomised to receive 4 cycles of cisplatin-fluorouracil (two concomitant to radiation therapy) of cisplatin 75 mg/m2 on day 1 and fluorouracil 1000 mg/m2 per day for 4 days. Both groups received 50 Gy radiation therapy in 25 fractions.r
The primary end point was progression free survival (PFS) and secondary end points were overall survival, endoscopic complete responses, time to treatment failure, occurrence of grade 3 or 4 toxicities, and quality of life between the two treatment groups.r
The statistical considerations of the trial were designed to demonstrate a 20% improvement in progression-free survival at 3 years from 30% in the cisplatin-fluorouracil group to 50% in the FOLFOX group. This study was not a non-inferiority trial, and did not meet its primary endpoint of a significant improvement in progression-free survival. However it may be considered in patients where a cisplatin based regimen is contraindicated.
After a median follow up period of 25.3 months, an intention to treatment analysis demonstrated similar median and 3 year progression free survival. Median progression-free survival in the FOLFOX group was 9.7 months (95% CI 8.1–14.5) compared with 9.4 months (8.1–10.6) in the cisplatin-fluorouracil group (HR 0.93, 95% CI 0.70–1.24; p=0.64). There was no difference in progression-free survival at 3 years (18.2% [95% CI 10.6–27.4] in the FOLFOX group versus 17.4% [95% CI 9.9–26.8] in the cisplatin-fluorouracil group.r
Median overall survival was similar between the two groups: median overall survival in the FOLFOX group was 20.2 months (95% CI 14.7–25.6), compared with 17.5 months (95% CI 13.9–19.4) in the cisplatin-fluorouracil group (HR 0.94, 95% CI 0.68–1.29; p=0.70). Overall survival at 3 years was 19.9% (95% CI 10.8–31.0) in the FOLFOX group and 26.9% (95% CI 16.9–37.8) in the cisplatin-fluorouracil group.r
Kaplan-Meier curves for (A) progression-free survival and (B) overall survivalr
© Lancet Oncology 2014
Health related quality of life (HRQOL) data was collected, but despite high baseline compliance, at the 6-month follow-up the questionnaire compliance had reduced to 41%. Both treatment arms displayed lower physical, social functioning, increased fatigue and dyspnea during therapy; these returned to baseline at the 6 month follow-up. Dysphagia improved in the fluorouracil-cisplatin compared to the FOLFOX group. During follow-up, HRQOL scores revealed no significant differences between the two groups.r
No significant differences were recorded in the occurrences of the most frequent grade 3 or 4 adverse events (neutropenia, leucopenia, dysphagia, and asthenia) between the treatment groups.r
Paraesthesia and sensory neuropathy were higher in the FOLFOX group compared to the cisplatin-fluorouracil group. In the FOLFOX group 47% of patients sustained paraesthesias compared to 2% receiving cisplatin-fluorouracil. Additionally 18% of patients receiving FOLFOX sustained neuropathy compared to 1% in the cisplatin-fluorouracil group.r
Six patients died in the cisplatin-fluorouracil group, 5 from neutropenic sepsis and one from cardiac ischaemia. One patient died in the FOLFOX group from lung disease and poor nutrition in the context of progressive disease. There was no significant difference in deaths between the two groups (p=0.066).r
© Lancet Oncology 2014