A randomized phase II/III trial comparing hepatectomy followed by mFOLFOX6 with hepatectomy alone for liver metastasis from colorectal cancer: JCOG0603 study.

Abstract

4005 Background: The role of adjuvant chemotherapy after hepatectomy is controversial for liver only metastases from colorectal cancer (LM). Current recommendations for oxaliplatin-containing adjuvant regimen (FOLFOX) for LM are based on extrapolation of the results of the EORTC intergroup trial 40983, which showed that perioperative FOLFOX confirmed a progression-free survival benefit but did not affect overall survival (OS) in LM patients. We conducted a randomized controlled trial to determine if adjuvant modified FOLFOX (mFOLFOX) is superior to hepatectomy alone for LM. Methods: Eligible patients aged 20-75 years who had histologically proven colorectal adenocarcinoma with an unlimited number of LM were randomly assigned (1:1) to receive either adjuvant mFOLFOX6 (oxaliplatin 85mg/m2, l-LV 200 mg/m2, 5-FU bolus 400 mg/m2 and 2400mg/m2 over 48 h), for 12 cycles after surgery (CTX arm), or surgery alone (S alone arm). When treatment compliance after 9 courses of CTX was as high as expected in phase II, the registration was continued in phase III. The primary endpoint of phase III was disease-free survival (DFS), and the secondary endpoints were OS, toxicity, and sites of relapse. The planned sample size was 150 patients (pts) per arm, with a one-sided alpha of 5%, and 80% power detecting a 5y-DFS difference of 12% (25% with S alone vs. 37% with CTX). Results: Between Mar. 2007 and Jan. 2019, 300 patients were randomized. 151 pts were allocated to CTX, and 149 pts to S alone. When the third interim analysis of phase III was performed in Dec. 2019, the DSMC recommended the early termination of the trial because a statistically significant difference in terms of DFS but the futility in terms of OS was found. With a median follow-up period of 54 months for disease-free surviving patients, the 3y-DFS was 52.1% (95% CI 43.2 – 60.2) with CTX and 41.5% (33.2 – 49.6) with S alone (hazard ratio 0.63 [0.45 – 0.89], one-sided p = 0.002 < 0.0163 for the one-sided alpha level at the interim analysis). However, the 3y-OS was 86.6% (79.2-91.4) with CTX and 92.2% (86.0 – 95.8) with S alone (hazard ratio 1.35 [0.84 – 2.19]). The 5y-OS was 69.5% (59.6-77.5) with CTX and 83.0% (74.5-88.9) with S alone. Median OS after recurrence was 38.4 months in the CTX arm and 87.6 in the S alone arm. Conclusions: DFS did not correlate with OS for LM. Postoperative chemotherapy with mFOLFOX6 improves DFS but worsens OS over surgery alone due to more deaths after recurrence in the CTX arm. Adjuvant mFOLFOX is not beneficial to patients after hepatectomy for LM. Clinical trial information: UMIN000000653 .

Hepatectomy Followed by Adjuvant Chemotherapy with 3-Month Capecitabine Plus Oxaliplatin for Colorectal Cancer Liver Metastases

“…Previously, recurrence after resection of CLM was often considered to occur in the residual liver, but in this study, all cases of recurrence involved extrahepatic metastasis. This was also observed in JCOG0603, in which 66% of recurrent cases in the adjuvant FOLFOX arm were extrahepatic metastases [6]. The very low recurrence of residual liver metastasis in our study suggests that CAPOX as postoperative adjuvant chemotherapy for CLM may suppress the recurrence of metastasis to residual liver.…”

Limited Liver or Lung Colorectal Cancer Metastases. Systemic Treatment, Surgery, Ablation or SBRT

“…Recently, a Japanese group presented results of the JCOG0603 at ASCO 2020, in which patients with resected liver metastases were randomized to observation or adjuvant chemotherapy with FOLFOX6m × 12 cycles, in a phase III trial. This trial demonstrated a benefit of adjuvant FOLFOX6m for disease-free survival (DFS 1.7 years vs. 4.3 years, HR 0.67 (0.5–0.92)) but no benefit for overall survival (5-year OS 83% vs. 71%, HR 1.25 (0.78–2)) in this subgroup of patients [ 40 ]. Adjuvant treatment with irinotecan in patients with CRC after liver surgery was not shown to be superior to 5FU/LV in a phase III study [ 41 ].…”

“…The role of perioperative chemotherapy with FOLFOX4 was evaluated in the EORTC intergroup trial 40,983 (EPOC). This study clearly demonstrated that perioperative FOL-FOX4 therapy (6 cycles before surgery and 6 cycles after) significantly improved PFS compared to surgery alone in CRC patients with resected liver metastases [46].…”

Adjuvant Therapies in Colon Cancer

“…In the EORTC 40983 trial, perioperative chemotherapy was associated with 7.3% absolute increase in 3-year progression-free survival, however there was no difference in overall survival [29,30]. Another Japanese study also did not show overall survival benefit with adjuvant chemotherapy [31]. Given the established role of adjuvant therapy in stage III colon cancer, despite lack of strong evidence many expert groups support perioperative or postoperative chemotherapy for resectable colorectal cancer metastases.…”