In a phase II trial reported in The Lancet Oncology, Garcia-Aguilar et al found that adding neoadjuvant mFOLFOX6 (modified fluorouracil [5-FU], leucovorin, oxaliplatin) after chemoradiation improved the pathologic complete response rate in patients with locally advanced rectal cancer undergoing total mesorectal excision. The strategy may increase patient eligibility for less-invasive treatment.
In the study, four consecutive groups of patients with stage II or III locally advanced rectal cancer were enrolled between March 2004 and November 2012 at 17 sites in the United States and Canada. All patients received neoadjuvant chemoradiation consisting of 5-FU 225 mg/m²/d by continuous infusion throughout radiotherapy and 45.0 Gy in 25 fractions on 5 days per week for 5 weeks followed by a minimum boost of 5.4 Gy. Patients in group 1 had total mesorectal excision at 6 to 8 weeks after chemoradiation. Patients in groups 2 to 4 received two, four, and six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision.
Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 or 400 mg/m² according to investigator discretion, oxaliplatin 85 mg/m² via 2-hour infusion, bolus 5-FU 400 mg/m² on day 1, and a 46-hour infusion of 5-FU 2,400 mg/m². The primary endpoint was the proportion of patients achieving pathologic complete response.
Pathologic Complete Response
Among 259 evaluable patients, pathologic complete response was observed in 11 (18%) of 60 patients in group 1, 17 (25%) of 67 in group 2, 20 (30%) of 67 in group 3, and 25 (38%) of 65 in group 4 (P = .0036 for trend). On multivariate analysis, the study group was independently associated with pathologic complete response (P = .048), with the odds ratio for group 4 vs group 1 being 3.49 (P = .011); odds ratios were 1.58 (P = .63) and 1.95 (P = .79) for groups 2 and 3 vs 1.
Grade 3/4 adverse events associated with neoadjuvant mFOLFOX6 occurred in 3%/1% of group 2 patients, 18%/0% of group 3 patients, and 28%/8% of group 4 patients. The most common grade ≥ 3 adverse events associated with mFOLFOX6 were neutropenia (five group 3 and six group 4 patients) and lymphopenia (three group 3 and four group 4 patients). A total of 25 patients had grade ≥ 3 surgery-related complications, including 10 in group 1, 5 in group 2, 3 in group 3, and 7 in group 4, with the most common being pelvic abscesses (seven patients) and anastomotic leaks (seven patients).
The investigators concluded: “Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to increase the proportion of patients eligible for less invasive treatment strategies; this strategy is being tested in phase 3 clinical trials.”
Julio Garcia-Aguilar, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author of The Lancet Oncology article.
The study was funded by the National Cancer Institute. For full disclosures of the study authors, visit www.thelancet.com.
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