Histopathologic Regression and Survival in RAS Wildtype Metastatic Colorectal Cancer Under First-Line Treatment – Subgroup Analysis of the VOLFI Trial (AIO-KRK-0109)

Aim: The VOLFI trial demonstrated an improved objective response rate through the addition of panitumumab to FOLFOXIRI in untreated all-RAS-wildtype mCRCs compared to FOLFOXIRI alone. In this subgroup analysis, we focused on histopathological response as a predictive marker for PFS. Additionally, we analyzed chemotherapy induced steatosis hepatitis (CASH) in both treatment arms. Methods: Histopathological response, CASH, sinusoidal obstructive syndrome, ballooning, steatosis, cholestasis, fibrosis and inflammation were determined in 14 resected liver metastasis. PFS was estimated using Kaplan-Meier method, the logrank test was used for the statistical comparison. The trial is registered with Clinical Trials. gov, NCT01328171. Results: Tissue of 14/18 resected pts. was evaluable. Median age was 57.5 yrs. (32–67), 7 male and 7 females. All primary tumors were located in the left colon. Molecular analysis detected one BRAF V600E mutation and one MSI-H tumor. Median treatment duration until resection were 7 cycles (3 – 12) panitumumab/mFOLFOXIRI and 9.5 cycles (7 - 11) FOLFOXIRI. 7 pts. achieved very good histopathological response corresponding to ≤20% vital tumor cells (panitumumab/ mFOLFOXIRI vs. FOLFOXIRI 2/5) and 7 pts. showed vital tumor cells >20% (panitumumab/mFOLFOXIRI vs. FOLFOXIRI 2/5). A very good histopathological response (residual tumor cells in proportion to the total tumor area ≤20%) showed a trend to an improved PFS in comparison to >20% (median PFS 12.40; 95% CI 6.43-51.22 vs. PFS 9.88; 95% CI 6.17-15.26 months). The severity of CASH was not increased by the addition of panitumumab or longer duration of chemotherapy. Discussion: In this analysis histopathological response seems to correlate with a better PFS after secondary metastasis resection. By analysis of liver toxicity, no relevant difference of CASH were detectable regarding panitumumab/mFOLFOXIRI vs. FOLFOXIRI or the duration of chemotherapy.