Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial

Abstract

PURPOSE Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. PATIENTS AND METHODS In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis. RESULTS Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. CONCLUSION DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.

Current Surgical Management Strategies for Colorectal Cancer Liver Metastases

“…Both synchronous and metachronous CRLM have traditionally been treated with perioperative chemotherapy, but the benefits of this management strategy have recently come under scrutiny. Results from two randomized controlled trials that evaluated the effectiveness of surgery alone versus surgery with perioperative chemotherapy in patients with synchronous and metachronous CRLM suggest that while perioperative chemotherapy may improve progression-free survival (PFS) or disease-free survival (DFS), there does not seem to be a benefit in OS [ 18 , 19 ]. These findings are also clinically significant as treatment with FOLFOX (folinic acid, fluorouracil, and oxaliplatin), the chemotherapy strategy used in each of these studies, places patients at risk for chemotherapy-related toxicities and adverse events.…”

“…A total of 300 patients were randomly assigned to either hepatectomy alone or hepatectomy followed by mFOLFOX6. The trial was notably terminated early at the third interim analysis per protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy (49.8% vs. 38.7% at 5 years, p = 0.006) [ 19 ]. Just over 75% of enrolled patients had primary colon cancer, about 45% had metachronous disease, and approximately 90% had 1–3 liver metastases [ 19 ].…”

“…The trial was notably terminated early at the third interim analysis per protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy (49.8% vs. 38.7% at 5 years, p = 0.006) [ 19 ]. Just over 75% of enrolled patients had primary colon cancer, about 45% had metachronous disease, and approximately 90% had 1–3 liver metastases [ 19 ]. No difference in postoperative complications or 5-year OS (hepatectomy alone 83.1% vs. 71.2%, p = 0.42) was observed between the two cohorts [ 19 ].…”

“…The treatment of resectable CRLM traditionally began with chemotherapy and included liver resection as a later option depending on response to systemic treatment. For select patients with resectable CRLM, however, a surgery-first approach may be advantageous [ 17 ], and we have recently seen the benefit of perioperative chemotherapy come into question [ 18 , 19 ]. Additionally, there are numerous locoregional therapies for which all patients with CRLM, including those with extrahepatic disease, should be considered [ 20 , 21 ].…”

Prognostic and Therapeutic Implications of Tumor Biology in Colorectal Liver Metastases

“…For example, the value of GAME score in guiding the decision of whether to offer perioperative chemotherapy has been tested in the past; future studies can evaluate the use of other prognostic scores that include biomarkers (e.g., e-CRS and m-CRS) for this purpose [ 16 ]. This may be particularly important in light of a recent prospective study from Japan on the lack of benefit from adjuvant chemotherapy in patients with “low risk” disease [ 17 ]. Optimizing follow-up strategies for patients with distinct biologies is another unanswered question.…”