Can metronomic chemotherapy be an alternative to sorafenib in advanced hepatocellular carcinoma?

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Conventional hepatic arterial infusion chemotherapy (HAIC), consisting of 5-fluorouracil (5-FU) and cisplatin delivered via implanted chemoport every 4 weeks, is a form of regional to systemic chemotherapy to treat unresectable or advanced hepatocellular carcinoma (HCC). The idea of localized infusion of cytotoxic agents into liver originated from hepatic metastasis of colorectal cancer [1]. It is interesting that the first application of HAIC to HCC has been done in Western country [2,3], even though that modality is now being used in Japan, Korea and Taiwan. In a Japanese retrospective study of 48 patients with portal vein tumor thrombosis, the objective (complete and partial) response rates were high (48%) and 3-year survival rates were 25% [4]. In a large Japanese cohort, the median survival times of patients who underwent HAIC was 14.0 months, which were significantly higher than in those who did not receive active treatment (5.2 months, P<0.0001) [5]. In contrast with daily, low doses of cisplatin (7 mg/m2 on day 1-5) and 5-FU (170 mg/m2 on day 1-5) in Japanese practice, Korean regimen consisted of higher cisplatin (60 mg/m2 on day 2) and 5-FU (500 mg/m2 on day 1-3) doses repeated every 4 weeks [6,7]. The dictionary meaning of ‘metronome’ is a device that produces regular, metrical ticks or beats; these represent a fixed, regular pulse. In the current issue by Yang et al. [8], 1 cycle of metronomic chemotherapy (MET) was composed of single low doses of cisplatin (15 mg/m2) and 5-FU (50 mg/m2) infused via hepatic arterial infusion chemoport for 3 weeks (1 week break) [8]. The authors aimed to retrospectively compare the efficacy and safety between MET and sorafenib in patients with advanced (BCLC-C) stage. In 54 and 53 patients who received MET and sorafenib treatment, the median overall survival (OS) was 158 and 117 days, respectively (P=0.029). The disease control rate assessed at week 8 tended was higher in MET group than in sroafenib group (53.7% vs. 22.0%; P=0.014). In subgroup of patients with Child-Pugh class B, the median OS was significantly longer in MET group than in sorafenib group (190 vs. 58 days, P<0.001). In terms of safety, although there is no information on the proportion of treatment discontinuation due to adverse events (AEs), MET was more related to hematologic AE including leukopenia and thrombocytopenia, whereas the majority of sorafenib-related toxicity was hand foot skin reaction and AE of gastrointestinal tract. Based on these results, the authors state that MET would be an alternative to sorafenib in HCC patients with BCLC-C stage, particularly if they don’t have preserved liver function.

This article by Yang et al. [8] suggests that MET, a sort of regional cytotoxic chemotherapy, might be a potential option for advanced HCC. The MET seems to have an advantage of lower rates of toxicity such as hepatic decompensation compared with conventional HAIC. In addition, there seems to be no need of hospitalization for drug administration. However, the study has several limitations. Apart from the retrospective nature of data, sample size is not enough to draw the conclusion that MET is comparable to sorafenib. Most importantly, the variables are imbalanced between the two groups. Although there was no significant statistical difference, more patients in sorafenib group had main portal vein tumor thrombosis than in MET group (45.3% vs. 33.3%). The frequency of extrahepatic metastasis, which is an important prognostic factor, was also higher in sorafenib group than in MET group (66.0% vs. 51.9%, P=0.136).

Though the role and positioning of HAIC, including MET, has not yet been established in HCC, a recently published paper reporting the efficacy of sorafenib plus HAIC suggests a possibility of combining systemic therapy and regional cytotoxic chemotherapy to enhance anti-tumor effect. In the Japanese prospective, multicenter trial, a total 108 patients with advanced HCC were randomized to sorafenib group and sorafenib plus HAIC group (infusion of only cisplatin). The median survival times were 8.7 and 10.6 months, respectively (P=0.031). The response rate was 7.3% in sorafenib group and 21.7% in combination group [9].

For HAIC to be widely accepted as a modality for HCC, more scientific evidences should be accumulated. The deterioration of liver function encountered with repeated cycles of HAIC is a major concern. In this regards, lower probability of liver toxicity by MET is obviously a merit, if we can guarantee that the efficacy of MET is similar to conventional HAIC. With few available regimens for patients with sorafenib failure except regorafenib, HAIC including MET also needs to be further evaluated as a second-line modality [10,11].