Neoadjuvant chemotherapy does not appear to significantly improve disease-free survival in patients with locally advanced colon cancer

1. When compared to upfront surgery, neoadjuvant chemotherapy using mFOLFOX or CAPOX did not appear to significantly improve 3-year disease-free survival.

2. When compared to upfront surgery, neoadjuvant chemotherapy using mFOLFOX or CAPOX did appear to be associated with significant pathological downstaging.

Evidence Rating Level: 1 (Excellent)

Study Rundown: In this phase 3, randomized, multicenter trial, 744 patients, with radiologically staged, locally advanced colon adenocarcinoma were randomly assigned to either the experimental, or standard of care group. Patients in the experimental group received 3 months of neoadjuvant chemotherapy with mFOLFOX or CAPOX, followed by surgery, then 3 months of adjuvant chemotherapy. The standard of care group received immediate surgery; those with pathological stage II and III disease received adjuvant fluoropyrdimidine-based chemotherapy. The primary endpoint was disease-free survival at 3 years. Secondary endpoints were R0 resection, pathological complete response (pCR), pathological TNM staging, tumor regression grade (TRG), overall survival (OS), surgical morbidity / mortality, and chemotherapy adverse events. Neoadjuvant chemotherapy with mFOLFOX or CAPOX did not improve disease-free survival when compared to upfront surgery. Neoadjuvant chemotherapy did appear to increase the chances of pathological downstaging and resulted in a 7% pCR rate. Chemotherapy toxicity, as well as surgical morbidity and mortality, were similar amongst both groups, suggesting neoadjuvant chemotherapy may be safe / feasible. Although promising, the OPTICAL trial relied on radiological staging with CT which has its own limitations; furthermore, only 58% of patients in the experimental group completed neoadjuvant chemotherapy, as planned. Further data, with improved pre-operative staging and improved patient compliance is needed to understand potential benefits moving forward.

Click to read the study in JCO

Relevant Reading: Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial

In-Depth [randomized-controlled trial]: This trial was investigator-initiated and enrolled 744 patients, from 28 Chinese hospitals, between the ages of 18-75, with biopsy proven colon adenocarcinoma. Eligible patients were clinically staged cT4 of cT3, N0-2; patients with non-operable colon cancer, those with recurrent or metastatic disease or those presenting with obstruction, perforation, or significant bleeding, were excluded from the study. Patient characteristics / baseline data were similar between the experimental and standard of care groups; of the 371 eligible patients assigned to the experimental group, 340 went on to receive neoadjuvant chemotherapy (NAC), consisting of either 6 cycles of mFOLFOX6 or 4 cycles of CAPOX. Three-year disease-free survival rates were 82.1% (95% CI, 78.2 to 86.1) in the experimental group and 77.5% (95% CI, 73.3 to 81.9) in the standard of care group (stratified HR, 0.74 [95% CI, 0.54 to 1.03]; log-rank P = 0.07). Three-year overall survival rates were 95.1% (95% CI, 92.8 to 97.4) in the experimental group and 89.6% (95% CI, 86.4 to 92.9) in the standard of care group (stratified HR, 0.42 [95% CI, 0.24 to 0.76]; log-rank P = 0.005). The most common grade 3-4 adverse events related to NAC were neutropenia and anemia. The most common grade 3-4 adverse event related to adjuvant chemotherapy, in both the experimental and standard of care groups, was neutropenia. Surgical approach, intraoperative / postoperative complications, median operating time, and length of postoperative hospital stay were similar amongst both groups. Findings from this study suggest that NAC may be safe in patients with locally advanced colon cancer, but further studies are needed to evaluate the potential impact on disease-free survival.

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