Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial

Abstract

Summary Background Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. Methods We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II–III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m2 per day by continuous infusion throughout radiotherapy, and 45.0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5.4 Gy). Patients in group 1 had total mesorectal excision 6–8 weeks after chemoradiation. Patients in groups 2–4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m2 or 400 mg/m2, according to the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. Findings Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10–30) of 60 patients in group 1, 17 (25%, 16–37) of 67 in group 2, 20 (30%, 19–42) of 67 in group 3, and 25 (38%, 27–51) of 65 in group 4 achieved a pathological complete response (p=0.0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3.49, 95% CI 1.39–8.75; p=0.011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). Interpretation Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to in...

Neoadjuvant Treatment Strategies for Locally Advanced Rectal Cancer

“…A non-randomised trial examining 4 sequential study groups in the USA and Canada, recruited between 2004 and 2012 [58]. Group 1 had LCPCRT followed by 12 TME 6-8 weeks later.…”

Complete Clinical Response in Rectal Adenocarcinoma: Review of Treatment Options

“…Patients with pCR have better long term outcomes, with lower LR rates and improved disease free survival (DFS) and overall survival (OS) compared to patients with residual tumor cells [6,7]. The rates of pCR appear to increase with a longer interval between nCRT and TME [8,9], as well as with the addition of an intensified mFOLFOX regimen prior to resection [10,11]. The delay in surgery does not appear to affect clinical outcomes [12,13].…”

Surgical outcomes of post chemoradiotherapy unresectable locally advanced rectal cancers improve with interim chemotherapy, is FOLFIRINOX better than CAPOX?

“…The addition of chemotherapy to pre-operative radiotherapy (RT) has improved local control and DFS rates but has not significantly affected the distant metastatic rates and OS. Methods to reduce distant failure include the use of neo-adjuvant chemotherapy (NACT) pre or post chemo-radiotherapy (CRT) prior to surgery and early studies support these strategies in terms of increased pathological complete response (pCR) rates and R0 resection rates (2,3).…”

“…There is some evidence supporting that additional NACT after pre-operative CRT and delaying surgery can lead to improvement in pathological complete response rates (2,3). Limited experience with NACT prior to CRT in MRI defined high-risk disease has shown good response rates and improvement in R0 resection rates suggesting that NACT is a feasible option (16).…”