P-0225 a retrospective analysis of preoperative folfox chemotherapy for locally advanced colon cancer patients with pharmacokinetic-guided dose adjustements of 5-FU: preliminary results.
Introduction: Preoperative chemotherapy remains an experimental approach in patients (pts) with locally advanced colon cancer (LACC) that is being actively tested in ongoing randomised trials. We assessed the feasibility and preliminary evidence of activity of incorporating a direct monitoring of 5-FU levels based on pharmacokinetic-(PK) guided dose adjustments.
Methods: Radiologically-staged LACC pts (T4 or T3 with >5mm invasion beyond the muscularis propia), were planned to receive 4 cycles of Oxaliplatin (85mg/m2), Leucovorin (400 mg/m2), bolus 5-FU (400 mg/m2) and infusional 5-FU (initial dose of 2400mg/m2 in 46h and subsequent cycles tailored according to PK monitoring in order to reach a target 5-FU area under the curve (AUC) between 20-30 mg·h·L-1) on a biweekly basis. Surgery was scheduled 4 to 6 weeks after the completion of chemotherapy treatment. All pts were staged at baseline and before surgery. Pathological tumor regression was graded according to the MSKCC classification. Toxicity was reported according to the NCI-CTCAE 4.0.
Results: From March 2011 to August 2013, 19 pts (M/F: 13/6; median age 60) with LACC were evaluated. Median dose of 5-FU was 5000 mg. 78.9% of the pts required a 5-FU dose increase to reach the target AUC. Median 5-FU plasma clearance was 199,58 L/h. Side effects profile included G3 neutropenia (6 pts), G2 diarrhea (5 pts), G2 nausea (3 pts) and G2 asthenia (5 pts). Neoadjuvant treatment was discontinued in 2 pts due to small bowel obstruction requiring surgery. No progressive disease was observed during preoperative chemotherapy. A radiological dowstaging was achieved in 11 pts (58%). All pts underwent surgery (laparoscopy-assisted 50%) with an R0 resection rate of 89.47%. There were no treatment-related deaths. Pathological responses (MSKCC score) included grades 4, 3+ and 3 in 10.5%, 15.78% and 21% of pts, respectively. Median number of harvested nodes was 23 (7-51) with a ypN0 rate of 79%. Median time to hospital discharge was 9 days. After a median follow-up of 15 months (6-35), the 12-month actuarial PFS and OS were 76.5% and 97.4%, respectively.
Conclusion: Preoperative PK-adjusted FOLFOX in LACC pts is safe and well tolerated, achieving major pathological responses in almost 50% the pts and a remarkable R0 resection rate. This strategy may be an alternative in the management of patients with LACC but further research seems warranted. Almost 80% of the patients required a dose increase to achieve target dose levels.