The goals of the current treatment for patients with MBC are to prolong survival and improve or maintain an adequate QOL and HRQOL (1–4). Thus, less-toxic treatments should be chosen as long as the treatment can control the disease progression (9). Compared to intravenous chemotherapy for patients with MBC, the use of oral chemotherapy affords a better QOL (4,6). S-1 chemotherapy, which is often used in Japan, is composed of oral fluorouracil derivatives. In the SELECT BC trials, S-1 was shown to be noninferior to taxane with respect to OS and better than taxane with regard to HRQOL as a first-line treatment for patients with MBC (4). In addition, 5-FU demonstrated a synergistic antitumor effect in combination with CPA in experimental studies and in a phase II trial (14,19–22), but it also had a significantly higher rate of toxicity (21,22).
The present study’s ORR and CBR were 33.3% and 66.7%, respectively, with 9.5 months as the median PFS of and 20.2 months as median OS. The treatment was well tolerated. The most common toxicity was leukopenia, which was observed in 19.4% of cases. Previous phase II studies using standard metronomic chemotherapy revealed that leukopenia was observed in 51% or 31% (12,13) and thrombocytopenia was observed in 5% and 8% (12,13), which is considered to be same to the toxicity of this study. These results strongly suggest that sequential S-1 and CPA therapy is an effective treatment option for MBC, with a manageable toxicity profile. In the SELECT BC trial, the median time to failure (TTF) was 8.0 months in the group administered S-1 as the first-line chemotherapy (4). Regarding capecitabine+CPA combination treatment, two phase II studies have already reported this regimen's efficacy (15,16). The ORRs of 35.6% and 30.3% in those studies are consistent with our present study. The median PFS in those studies were 6.6 months and 5.2 months, respectively (15,16).
There is no meaningful biomarker for the efficacy of S-1/CPA. We conducted the comparison of the data obtained in certain subgroups of patients in order to find out patients with better chances of having a good clinical response. We divided the patients into two groups based on a) metastatic de-novo versus metastatic recurrent; b) with no prior chemotherapy versus those with one or more of them; c) with visceral metastasis versus non-visceral metastasis; d) luminal type versus triple negative breast cancer. There were no significant differences between patients with and without prior chemotherapy, visceral metastasis or subtype, however, the PFS was significantly shorter in patients with metastatic de-novo than that in patients with metastatic recurrent, suggesting that this therapy may show superior effect in patients with metastatic recurrent. The mechanism is unknown, however, all patients with metastatic de-novo were luminal type. Further study should be done to evaluate how metastatic de-novo breast cancer influence the anti-tumor effect of S-1/CPA in large number of patients.
All-grade leukopenia was observed in 19.4% of our present series, and one patient was unable to continue the therapy. In the SELECT BC trial, all-grade leukopenia was observed in 43% of the S-1 group (4). Of our 36 patients with MBC, grade 3 leukopenia was observed in 13.9%, as one of the most common adverse events in this regimen. Adverse events such as hair loss, peripheral neuropathy, gastrointestinal toxicity and edema — which are commonly observed in patients with taxane or anthracycline regimens (23) — were not observed in our study. The benefit of avoiding hair loss is of particular concern from the patients' perspective (24). Approximately 10%–20% of patients who received S-1 developed lacrimal drainage obstruction or stenosis (25,26). In the present trial, only one (2.8%) patient developed lacrimal drainage obstruction. In light of these results, we suggest that this sequential S-1 and CPA therapy is a feasible and tolerable regimen in terms of both efficacy and safety.
This study has potential limitations, the major one being the small number of cases (n=36) and the inclusion of a single center. However, this is the first prospective clinical trial to evaluate the efficacy of sequential therapy with S-1 and CPA for metastatic breast cancer. Additional research is needed to explore the efficacy of this therapy in larger numbers of patients to confirm the effects and safety profile of sequential therapy with S-1 and CPA.