State of the Art: Colorectal Liver Metastases

●● Adjuvant treatment post-R0 resection The efficacy of pure adjuvant chemotherapy in stage 4 disease is debatable. Certainly, the benefit of adjuvant chemotherapy in stage 4 disease appears to be less than that observed with adjuvant chemotherapy in stage 3 disease. Data from a meta-analysis showed that fluorouracil (FU) afforded a bor derline significant benefit in terms of recurrence-free survival compared with surgery alone [1], while folinic acid (leucovorin), 5-fluorouracil (5-FU), irinotecan (FOLFIRI) produced a numerically better recurrence-free survival than FU, but this difference was not statistically significant [2]. Importantly, folinic acid (leucovorin), 5-FU, oxaliplatin (FOLFOX) has not been studied in this setting, although it is the regimen that is most commonly employed in clinical practice around the world. ● ● Neoadjuvant chemotherapy of resectable metastases ‘Neoadjuvant chemotherapy’ of resectable metastases has only been investigated as a ‘perioperative strategy’ (i.e., as part of a strategy in which chemotherapy is continued after surgery). A systematic review of 23 neoadjuvant chemotherapy trials for resectable colorectal liver metastases reported a median response rate of 64% (leading to a 93% R0 resection rate) and a median disease-free survival of 21 months [3]. The European Organisation for Research and Treatment of Cancer (EORTC) conducted the only randomized controlled Phase III study comparing perioperative chemotherapy (six cycles of FOLFOX before and six cycles after surgery) versus surgery alone. This study found that the absolute increase in the rate of progression-free survival at 3 years was only 7.3% (from 28.1% [95.66% CI: 21.3–35.5] to 35.4% [95.66% CI: 28.1–42.7]; HR: 0.79 [95.66% CI: 0.62–1.02]; p = 0.058) [4], with a non-significant difference in overall survival at 5 years of follow-up (HR: 0.88; 95% CI: 0.68–1.14; p = 0.339) [5]. Last year, the New EPOC study investigated the addition of adjunct cetuximab to FOLFOX perioperative chemotherapy in K-RAS-wild-type patients [6]. This study unexpectedly found that the addition of the cetuximab had a detrimental effect on survival compared with FOLFOX alone in the neoadjuvant setting (14.8 vs 24.2 months; HR: 1.5; 95% CI: 1.0–2.2; p < 0.048).