Hepatocellular carcinoma (HCC) is a major challenge for oncologists, being the fifth most common cancer in men and the seventh in women, representing the third most frequent cause of cancer death worldwide [1]. Treatment strategies for HCC depend on both tumour stage and liver disease status.

In patients with advanced HCC, or where surgical or locoregional treatment is contraindicated because of underlying cirrhosis or patient characteristics, medical therapy becomes the only strategy [2]. Sorafenib, a multikinase inhibitor, was the first molecular targeted therapy to demonstrate a survival benefit [3], and the only globally approved frontline treatment for advanced HCC. The efficacy of sorafenib has been demonstrated in two randomized, double-blinded, placebo-controlled phase III clinical trials: the Sorafenib HCC Assessment Randomized Protocol (SHARP) [3] and the Asia-Pacific [4] trials. Sorafenib is considered moderately effective in HCC treatment, with a less than 3-month increase in overall survival (OS) in comparison with placebo [3]. Cases of complete response (CR) to sorafenib have been reported in the literature [5], but no data on the duration of the CR are available.

Capecitabine is an oral fluoropyrimidine carbamate that acts as a 5-fluorouracil (5-FU) pro-drug to mimic the continuous infusion of 5-FU. It is globally approved for the treatments of colon, gastric, and breast cancer.

Capecitabine administration according to a standard (or reduced standard) schedule has been evaluated in the postoperative adjuvant setting after curative HCC resection [6], in advanced disease [7], and in recurrent HCC after liver transplantation [8]. In a small randomized controlled trial among patients with HCC, 30 controls treated with best supportive care (BSC) were compared with 30 subjects who received 2 weeks of capecitabine at 1000 mg/m², twice a day, followed by 1 week without treatment for a total of 4–6 cycles [6]. The data showed that adjuvant therapy with capecitabine was well tolerated, postponed and reduced the risk of HCC recurrence, and was likely to improve postoperative survival.

In a single-centre phase II, open-label trial, 52 patients with advanced HCC who had not received previous systemic treatment were randomly assigned to receive either sorafenib (at a dose of 400 mg twice daily) or capecitabine to a modified standard schedule (1000 mg/m² twice daily on days 1–14) [7]. Median OS was 7.05 months in the sorafenib group and 5.07 months in the capecitabine group. Thus, capecitabine at the modified dosing schedule was found to be inferior to sorafenib with respect to OS [7]. However, when capecitabine was administered according to a metronomic schedule, varying results were reported [9, 10].

Metronomic therapy is defined as the continuous administration of a lower dose of cytotoxic drug, without treatment pauses [11]. While standard chemotherapy exerts an antiproliferative effect, metronomic chemotherapy functions to inhibit angiogenesis by directly disrupting endothelial cell proliferation, up-regulating antiangiogenic factors such as thrombospondin-1 (TSP-1) and angiostatin, and down-regulating of angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (b-FGF), and hypoxia-inducible factor-1 (HIF-1) [12]. Metronomic chemotherapy also inhibits vascular development by reducing the number and viability of circulating endothelial progenitor cells from bone marrow [13]. In addition, metronomic chemotherapy stimulates the immune response by reducing regulatory T cells and promoting dendritic cell maturation [14, 15]. Low-dose regimens of chemotherapy can also induce senescence in tumours through an antiproliferative response [16]. The use of metronomic treatment is becoming more frequent for the treatment of various cancers, owing to its antiangiogenic properties and tolerability. However, the effects of metronomic chemotherapy appear to vary according to solid tumour type.

Metronomic chemotherapy has been evaluated only to a limited extent for the treatment of advanced HCC. Hsu et al. [17] conducted a phase II study to evaluate the efficacy and safety sorafenib (400 mg twice daily) in combination with metronomic tegafur/uracil (UFT) (125 mg/m² based on tegafur twice daily) in 53 patients with HCC and a Child–Pugh class A score. Median progression-free survival was 3.7 months, and median survival was 7.4 months. The use of metronomic chemotherapy and sorafenib was shown to augment antitumor efficacy without a high incidence of severe side effects.

Metronomic capecitabine for advanced HCC, in first line treatment, has been evaluated in a phase II study, and was shown to be well tolerated and associated with an OS of 14.47 months, further emphasized by a propensity analysis comparing treated subjects with matched controls [9]. Sustained CR to capecitabine was also reported [18]. In the present case report, we describe three cases of sustained CR following treatment with metronomic capecitabine in patients with advanced HCC. Informed consent to the treatment was obtained from the patients.

The efficacy of metronomic capecitabine in advanced HCC has been evaluated both as frontline and post-sorafenib treatment in retrospective analysis [10, 12] and in a phase II prospective trial [9]. In the first retrospective study, the outcome of 26 patients treated with metronomic capecitabine after sorafenib failure was reported, with a median OS of 8 months [10]. Another retrospective case–control study reported a median OS of 12 months in patients treated with capecitabine versus 9 months in patients who received only BSC [21]. Furthermore, a large multicentre retrospective analysis compared patients treated with metronomic capecitabine or BSC after sorafenib discontinuation and found that the median survival was approximately 10 months in patients treated with metronomic capecitabine and less than 5 months in those receiving BSC. This benefit was confirmed in patients matched in a propensity analysis [22].

In 2013, our group published a phase II study on metronomic capecitabine in patients with advanced HCC. Metronomic capecitabine (500 mg twice daily continuously without breaks) was administered to 59 patients naïve to systemic therapy and 31 patients who were intolerant to sorafenib or following sorafenib failure. Median PFS and OS were 6.03 and 14.47 months, respectively, in the first-line group, and 3.24 and 9.77 months in the second-line group. Additionally, we recorded two cases of CR and one of partial response in sorafenib-naïve patients [9].

Other sustained (but incomplete) tumour responses have been observed in three cases of unresectable HCC treated with metronomic capecitabine [21, 23].

The difference between the absolute number of CR cases linked to sorafenib (51 cases of CR following a PubMed search with the string “HCC OR hepatocellular carcinoma AND sorafenib AND complete AND response”) and to metronomic capecitabine is likely attributable to the limited use of metronomic capecitabine for HCC, in contrast with the sorafenib, the standard treatment. No data on the duration of sorafenib-related CR are available in the literature, reinforcing the rationale for exploring the efficacy of metronomic capecitabine

Moreover, important positive aspects of metronomic capecitabine treatment include its approximately 100-fold lower cost than sorafenib, which is expected to further decrease in the near future following patent expiration. Savings to national health systems associated with the use of metronomic capecitabine are therefore likely to be significant compared with sorafenib treatment.

To identify a biomarker predictive of treatment response and, subsequently, patients with advanced HCC who are more likely to benefit from therapy at an optimal dose, it is necessary to explore the molecular determinants of susceptibility to a given treatment strategy. Variation in lactate dehydrogenase serum level during sorafenib treatment is an example of such a biomarker [24].

Further studies are needed to understand the phenomenon of the long-term response to metronomic capecitabine observed in this case report. We can speculate that tumours showing a dramatic response to treatment are more likely to display a specific molecular pattern, preventing drug resistance. The use of next-generation sequencing techniques may help to clarify the determinants of there markable responses observed in the cases reported here.

The outcomes of the three cases of CR described here suggest that metronomic capecitabine represents a viable treatment option in patients with HCC and may be highly effective in a subgroup of “super respondent” patients, with a rare but possible CR. CR linked to sorafenib and metronomic capecitabine suggests that a specific subset of HCC maybe particularly responsive to antiangiogenic treatment.