Capecitabine but not 5-FU worsened hepatosplenomegaly and liver function when used with oxaliplatin and cetuximab as first-line treatment in K-ras wild-type metastatic colorectal cancer

Abstract

Background: MRC COIN study showed that OXA and CAP (CAPOX) have greater toxicities compared with OXA and 5-FU (FOLFOX) when cetuximab (C225) was added for mCRC. Meanwhile, OXA was associated with splenomegaly and hepatic sinusoidal injury. We investigated if CAPOX+C225 worsened hepatosplenomegaly and liver function compared with FOLFOX+C225 in K-rasWT mCRC. Methods: 97 patients with K-ras WT mCRC received either FOLFOX or CAPOX (n=57) or the same regimen+C225 (n=40) as 1st line treatment. CT scan of abdomen was performed at baseline and then after every 3-4 cycles. Liver excluding liver metastases if present, and spleen size at baseline and after treatment were contoured in Eclipse Treatment Planning System. Changes in liver and spleen size after treatment in all patients and subgroups (1) use of C225 and (2) CAPOX vs. FOLFOX +/- C225 were compared. Logistic regression was done for any predictors of hepatosplenomegaly and impaired liver function in all patients and subgroups. Results: 25, 32, 15 and 25 patients received FOLFOX, CAPOX, FOLFOX+C225 and CAPOX+C225 respectively.All patients had hepato- (p=0.014) and splenomegaly (p=0.000) after treatment. C225 did not further worsen hepato- (p=0.430) and splenomegaly (p=0.614). Cumulative dose of CAP was predictive of hepato- (p=0.003) and splenomegaly (p=0.008) even after adjusted for cumulative dose of OXA (p=0.021). For subgroup analysis, hepato- (p=0.040) and splenomegaly (p=0.041) were noted when CAPOX+C225 was compared with FOLFOX+C225, but not seen when CAPOX was compared with FOLFOX (p=0.270 and p=0.287 respectively). When comparing CAPOX+C225 with FOLFOX+C225, use of CAP was predictor of both hepato- (p=0.043) and splenomegaly (p=0.007). Dose intensity of CAP (p=0.036) and cumulative dose of OXA (p=0.044) are predictors of ≥grade 1 impaired liver function. However when comparing CAPOX with FOLFOX, no predictor was found for any complication. Conclusions: CAP further worsened hepatosplenomegaly and liver function when combined with OXA and C225 but not with OXA alone, suggesting that CAP and C225 together may add toxicity to liver and spleen.