Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers

Abstract

Background: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). Objective: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. Methods: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. Results: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. Conclusions: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients

Adjuvant Chemotherapy for Stage III Colon Cancer

“…However, for these two trials, the baseline pre-therapeutic CT scan selected in 25 to 30% of cases low-risk CC patients theoretically not requiring chemotherapy, underlining the need for improving pre-treatment disease assessment in this setting. Adding anti-EGFR therapy to neo-adjuvant FOLFOX in patients with RAS wild-type tumors did not provide any benefit in both studies [40,41].…”

“…Given the nice results of pre-operative treatments in gastric, esophageal and rectal cancers, neoadjuvant chemotherapy has been explored in colon cancer patients. The PRODIGE 22 phase 2 trial initially showed that neo-adjuvant chemotherapy by FOLFOX (4 cycles) for patients with locally advanced CC (T3/T4 and/or N2 on the initial CT scan evaluation) was well tolerated, with no increase in surgical morbidity and interesting downstaging rates but without significant association with a major histological response (TRG1), compared to patients without neo-adjuvant treatment [40]. The larger phase 3 FOxTROT trial (n = 1050 patients) showed the same results in these situations with three cycles of neo-adjuvant FOLFOX, with no significant difference but a strong tendency to decrease the 2-year recurrence rate, which was the primary endpoint of the study, for patients treated with neo-adjuvant FOLFOX, compared to those treated with upfront surgery (13.6% versus 17.2%, respectively, HR: 0.75, p = 0.08) [41].…”

Neoadjuvant Chemotherapy without Radiation in Colorectal Cancer

“…We found one completed phase III FOxTROT (NCT00647530) and five ongoing (either recruiting or completed) randomized phase III trials-a Chinese trial (NCT02777437), NEOCOL (NCT01918527), the OPTICAL trial (NCT02572141) 56 and a Spanish trial ELECLA (EudraCT: 2016-002970-10). We also found two randomized phase II trials-VOLFI (NCT01328171) 57 and ECKINOXE PRODIGE-22 (NCT01675999) 33,34 in colon cancer.…”

“…Recently, the concepts of early tumor shrinkage and depth of response (DoR) have been derived from post hoc analyses to capture the level of efficacy of treatment. A pilot study, Fluoropyrimidine Oxaliplatin and Targeted Receptor Pre-Operative Therapy (FOxTROT) 32 and the preliminary results of the randomized PRODIGE 22 trial 33,34 partially support the rationale for NACT.…”

Neoadjuvant Chemotherapy for Colon Cancer

“…After the interim analysis, the data monitoring committee recommended stopping the cetuximab arm due to lack of prespecified efficacy by TRG and a severe postoperative morbidity rate of 15% in this arm. Enrollment continued into the two other arms and the results of the trial were published earlier this year [27]. Ultimately, 104 patients were included in the primary endpoint analysis.…”