Background
Metastatic breast cancer (MBC) is not yet curable. The current treatment strategies for patients with MBC simply prolong survival and improve or maintain the patient’s quality of life (QOL) [
1‐
4]. There is an increasing demand for effective regimens that have less adverse effects for MBC patients. Taxane- or anthracycline-based regimens are established cytotoxic agents for patients with MBC, but the administration of taxane or anthracycline can cause serious adverse events (including myelosuppression, hair loss, nausea, edema, and peripheral neuropathy) that may affect patients’ health-related quality of life (HRQOL) [
4,
5]. Less-toxic treatments that do not reduce the HRQOL are needed for the management of MBC.
Orally administered drugs are generally more convenient to use than intravenous drugs [
4,
6]. The oral fluorouracil derivatives S-1 is widely used in Japan [
3,
4,
7‐
10]. S-1 is a combination of tegafur (a prodrug of 5-fluorouracil), gimeracil (an inhibitor of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in the catabolism of 5-fluorouracil), and potassium oxonate (an inhibitor of orotate phosphoribosyltransferase, which suppresses the gastrointestinal toxicity of 5-fluorouracil) in the molar ratio of 1.0: 0.4: 1.0 [
2,
3]. S-1 treatment resulted in an overall response rate of 41.7% in a phase II trials of patient with breast cancer in Japan [
8].
A recent randomized phase III study (the SELECT BC trial) indicated that as a first-line treatment for MBC, S-1 is noninferior to taxane with respect to overall survival [
4]. We also reported that the combination of S-1 and trastuzumab was tolerable and had excellent efficacy with good response and disease control for HER2-positive metastatic breast cancer [
3]. Regarding adverse events, S-1 has shown low incidences of myelosuppression, nausea, vomiting, alopecia, and peripheral neuropathy [
2,
3]. Thus, S-1 was demonstrated to have high efficacy for MBC with a low incidence of adverse events [
4,
8].
Cyclophosphamide (CPA) is one of the oldest drugs used in oncology; it was the first available drug in oral formulations for the management of MBC [
11‐
13]. CPA is typically used as a component of combination regimens such as AC (doxorubicin and CPA) and fluoropyrimidine-based combination regimens including CMF (CPA, methotrexate, and 5-fluorouracil [5-FU]) [
14]. The use of oral agents can make a significant contribution to a patient’s QOL. Several studies reported that oral combination regimens of CPA plus UFT (tegafur/uracil) or capecitabine is effective with well-tolerated toxicities in patients with MBC [
15‐
17]. However, no data evaluating the efficacy of S-1 plus CPA therapy for MBC is available in the existing literature. We thus conducted a phase I study of sequential S-1 and CPA therapy to determine the dose-limiting toxicities (DLTs) and recommended doses (RDs) in patients with MBC [
18], and we reported that sequential therapy with S-1 and CPA could be safely and effectively used for the treatment of MBC; the RDs determined for this regimen were 80 mg/m
2/day for S-1 and 100 mg/m
2/day for CPA [
18]. We then performed a phase II trial to verify the clinical efficacy of sequential S-1 and CPA for MBC, and we report the results as follows.
Discussion
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.
Conclusions
The combination of sequential therapy with S-1 and CPA was tolerable and had efficacy with good disease control in this study. Sequential therapy with S-1 and CPA may be a feasible new treatment option for patients with MBC. Further study is warranted to explore the efficacy of sequential therapy with S-1 and CPA, especially considering this is a small, open-label, single center trial with no formal hypothesis testing.
Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit
http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (
http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.