Impact of adjuvant mFOLFOX6 on imaging diagnosis after hepatectomy for colorectal liver metastasis: A supplemental analysis of JCOG0603.

120 Background: Recent studies have reported that relapse-free survival is not a reliable surrogate endpoint for overall survival (OS) in studies of resected colorectal liver metastasis (CRLM). We hypothesized that the divergence between disease-free survival (DFS) and OS observed in the JCOG0603 trial may be partly due to overestimation of DFS as a result of difficulties in diagnosing liver recurrence, and these diagnostic challenges might be related to drug-induced liver injuries, such as sinusoidal obstruction syndrome (SOS) or steatohepatitis, following adjuvant mFOLFOX6. In this post hoc supplemental analysis, a central review committee (CRC) re-evaluated the imaging diagnoses, aiming to clarify the divergence between DFS and OS, and the impact of drug-induced liver injury on the diagnosis of liver recurrence. Methods: Diagnostic imaging data from all enrolled patients, covering the period from the diagnosis of primary liver metastases to the data cut-off (Nov. 26, 2019), were reviewed by the CRC. The primary outcome was diagnostic delay for recurrence, defined as the difference in DFS between the prospective review (chronological review from hepatectomy) and the retrospective re-review with knowledge of recurrence (reverse chronological review from recurrence). Secondary outcomes included CT findings of drug-induced liver injury, post-oxaliplatin heterogeneity of liver parenchyma (POHL; 6-grade score), and fatty liver (FL; 5-grade score). Results: The CRC reviewed imaging data from all 300 randomized patients. In the prospective review, the prevalence of POHL (≥4) at the time of DFS events was slightly higher in the chemotherapy (CTX) arm than the surgery-alone (S-alone) arm, but not significantly (4.7% vs 8.6%). FL (≥3) showed no significant difference between CTX (12.1%) and S-alone (9.9%). Serum CEA levels at liver recurrence were slightly higher in the S-alone arm but not significantly (8.2 ng/mL vs 4.5 ng/mL). Median liver recurrence size was not notably different between CTX (1.6 cm) and S-alone (1.7 cm). DFS remained better in the CTX arm than in the S-alone arm after the prospective review (HR 0.783, 95% CI 0.577-1.062) and the retrospective re-review (HR 0.846, 95% CI: 0.622-1.150), although not significantly different. However, diagnostic delay was greater in the CTX arm, resulting in a larger overestimation of 1-year DFS (Table). Conclusions: A larger overestimation of DFS was observed in the CTX arm during the early follow-up period. However, drug-induced liver injury after adjuvant mFOLFOX6 did not have a significant impact on the imaging diagnosis of liver recurrence. Clinical trial information: jRCTs031180285 . Prospective review Retrospective re-review Overestimation 1-y DFS S-alone arm 58.2% 54.9% 3.3% CTX arm 75.9% 63.2% 12.7% 3-y DFS S-alone arm 41.1% 42.6% -1.5% CTX arm 50.6% 49.5% 1.1% 5-y DFS S-alone arm 40.2% 42.6% -2.4% CTX arm 48.5% 48.4% 0.1%