The multivariate ordered logistic regression analysis performed in this study clarified that significant predictors for the development of HFS included concomitant use of RAS inhibitor, high BSA, and low albumin. PPIs, anticholinergic drugs and celecoxib were not extracted as predictors. The combined use of anticholinergic agents was associated with a decrease in the incidence of capecitabine-induced HFS in univariate analysis, but was not significant in multivariate analysis. ROC curve analysis of factors potentially responsible for the development of HFS Grade ≥ 2 indicated thresholds of BSA ≥ 1.68 m2 and albumin ≤ 3.9 g/dL.
This study determined that the optimal BSA cut-off value for the occurrence of HFS was ≥ 1.68 m2. The dose of capecitabine is determined based on the BSA. These results are therefore consistent with the findings of previous studies that reported the development of HFS as dose-dependent [10, 13, 14]. Clinicians thus need to be alert to the fact that HFS is likely to occur in patients receiving high doses of capecitabine, particularly patients with BSA ≥ 1.68 m2. The predictive model of HFS in patients receiving capecitabine allows the prediction of toxicity risk based on cumulative capecitabine dose . In this study, HFS also tended to develop in a dose-dependent manner, but the actual dose of capecitabine was not significant. In addition, weight loading may contribute to the exacerbation of HFS in the foot.
The present study suggested an albumin cut-off for the occurrence of HFS of ≤ 3.9 g/dL. Previous studies have clarified that skin inflammation is difficult to heal if nutritional status is poor . Our results agree on this point. When administering chemotherapy, good nutritional status is important.
Concomitant use of RAS inhibitor was a significant risk factor for the occurrence of HFS. RAS inhibitors with ACE-Is or type II ARBs protect the vascular endothelium by decreasing the concentration of angiotensin II, which inhibits nitric oxide (NO) production and activity. RAS inhibitors prevent angiogenesis through increased NO production. NO has been suggested to be involved in dermatitis and inflammatory skin diseases caused by various inflammatory stimuli, such as exposure to ultraviolet light . NO has also been reported to be involved in inflammatory skin diseases. NO regulates the expression of various genes involved in differentiation, proliferation, apoptosis, wound healing and angiogenesis [18–21]. On the other hand, NO promotes local accumulation of neutrophils , which not only help protect against infection but also promote local chronic inflammation (tissue damage) and exacerbate symptoms. RAS inhibitors may also dilate peripheral blood vessels and promote the transfer of capecitabine to peripheral tissues. Our results differed from those of previous studies in which ACE-I was a preventive factor for HFS . Further verification is needed on this point.
Development of stomatitis showed a significant correlation with the onset of HFS. The mechanisms of onset for stomatitis and HFS may be similar, and further investigation of this issue is needed.
Several limitations of the present study need to be considered. First, the retrospective nature of our investigation may have decreased the reliability of the data collected. Second, as this study only involved patients treated at a single institute, the cohort size was relatively small. A larger, multicenter study is needed to confirm our findings. Third, potential confounding, selection, and information biases cannot be fully excluded in this study.
In conclusion, we used a statistical approach to identify significant predictors for the development of HFS, including concomitant use of RAS inhibitors, high BSA, and low albumin. However, these preliminary findings need to be confirmed in further studies. Nevertheless, the identification of potential predictors of HFS may assist in the development of strategies that can be used to improve QoL in patients receiving chemotherapy regimens that include capecitabine.