Recent advances in chemotherapy for colorectal cancer have improved the resection rate and prolonged survival for patients with initially unresectable CRLMs (1, 14–16). Although several advantages of preoperative chemotherapy for CRLMs have been demonstrated, drawbacks have also been recognized (17, 18). Cytotoxic agents cause certain types of hepatic parenchymal injury, such as steatohepatitis or sinusoidal obstruction syndrome (7, 19), but the actual effect of chemotherapy-induced hepatotoxicity on liver regeneration after resection and postoperative complications remains unclear. This study revealed that an increase in splenic volume mediated by preoperative chemotherapy is associated with poor preoperative liver function, which is consistent with the previous report that showed oxaliplatin-based chemotherapy increases splenic volume as a result of sinusoidal injury (9). Furthermore, we clarified that patients with splenic enlargement during chemotherapy had impaired liver regeneration and liver dysfunction after liver resection.
Long-term chemotherapy reportedly fails to improve the response rate, but it increases the incidence of sinusoidal injury, thus leading to postoperative liver failure (20). In the current study, among patients undergoing 9 or more cycles of chemotherapy, splenomegaly in the OX-based group was significantly greater than that in the IRI-based and OX-based + Bmab treated groups, which suggests that long-term oxaliplatin-base chemotherapy favorably causes splenic enlargement. Consistent with previous reports (21, 22), the current study also demonstrated that bevacizumab is likely to inhibit enlargement of the spleen, probably because of a decrease in sinusoidal injury. Patients with splenic enlargement had increased levels of aspartate aminotransferase and alanine aminotransferase and worse ICG-R15 those of which relate to liver injury and deterioration of hepatic function. Taken together, the evidence suggests that changes in splenic volume, which can be easily assessed before hepatectomy without invasive examination, are likely to be a marker of chemotherapy-induced liver damage and a decision-making marker of selecting chemotherapy regimen for conversion surgery.
The influence of preoperative chemotherapy on liver regeneration after liver resection is still controversial. Although some reports showed that preoperative chemotherapy itself does not affect liver regeneration and post-operative course (23–25), few studies have argued the adverse effects of chemotherapy-induced hepatotoxicity on early liver regeneration after liver resection. Current study suggested that splenic enlargement which represents liver injury caused by chemotherapy is related to impaired liver regeneration after hepatectomy. Our results also showed that there was no significant difference in liver regeneration between patients whose SP index was less than 1.2 and patients without preoperative chemotherapy. By measuring splenic volume during preoperative chemotherapy, we may preoperatively select the patients who will suffer chemotherapy-mediated impaired liver regeneration after resection.
Liver regeneration is achieved through multiple signaling pathways by mitogenic growth factors, such as HGF, EGF, and TGF-α, leading eventually to hepatocyte growth and proliferation (26). Sinusoidal endothelial cells play an important role in the release of HGF through VEGFR2 (27). We measured liver volume 7 days after hepatectomy to assess early liver regeneration, which may directly correlate with postoperative liver failure. In the current study, patients with an SP index ≥1.2 had less early liver regeneration after adjusting for imbalances of the FRLV, but there was no correlation between early liver regeneration and ICG-R15 as previously reported (28). Splenic volume is negatively correlated with liver regeneration after major hepatectomy (29). Liver regeneration may be inhibited by splenic upregulation of TGF-β1 and downregulation of HGF (30, 31). These findings suggest that a prolonged duration of OX-based chemotherapy that induces splenomegaly may affect liver regeneration. Furthermore, the sinusoidal obstruction syndrome model induced by monocrotaline resulted in decreased mRNA expression of mitogenic growth factors and impaired hepatic regeneration in rats (32). Sinusoidal obstruction syndrome is likely to inhibit liver hypertrophy after first hepatectomy with portal vein embolization in a two-stage hepatectomy (33). It seems likely that splenic enlargement induced by long-term preoperative chemotherapy influences liver regeneration after resection for CRLMs. Consistent with these findings and based on our multivariate analysis, an SP index of ≥1.2 is a possible candidate marker for predicting impaired liver regeneration.
A previous study showed that sinusoidal injury increased the risk of greater morbidity and longer hospital stay after major hepatectomy (8). An increase in splenic volume has been correlated with major complications after hepatic resection (34). Current study showed that splenic enlargement was associated with a longer operative time and increased blood loss during operation. Furthermore, patients with an SP index ≥1.2 were likely to be at greater risk of postoperative liver failure as defined by hyperbilirubinemia, suggesting that preoperative chemotherapy-induced splenic enlargement may be a caution for the occurrence of postoperative liver failure after major liver resection. The limitation of this study is the number of patients, but the result of the current study may be helpful for considering continuation of chemotherapy or operative risk after conversion surgery to avoid occurrence of liver dysfunction after hepatectomy.