Ann. Cancer Res. Ther. Vol. 30, No. 1, pp. 38-44, 2022

Original papers

Longitudinal efficacy and safety of capecitabine and cyclophosphamide
as early-line treatment in patients with metastatic breast cancer:
A prospective cohort study by the Kyushu Breast Cancer Study Group, Japan.
Kohjiro Mashino1), Maki Tanaka2), Miki Yamaguchi2), Reiki Nishimura3), Yutaka Yamamoto4),
Hiroaki Ueo5), Toshihiro Tanaka6), Kenichiro Koga7), Tomoyuki Yoshiyama8), Shoshu Mitsuyama7),
Kazuo Tamura6), and the Kyushu Breast Cancer Study Group
Department of Breast Surgery, Oita Prefectural Hospital, Oita, Japan
Department of Breast Surgery, JCHO Kurume General Hospital, Kurume, Japan3)
Department of Breast Oncology, Kumamoto Shinto General Hospital, Kumamoto, Japan
4)
Department of Breast and Endocrine Surgery, Kumamoto University Hospital, Kumamoto, Japan
5)
Department of Surgery, Ueo Breast Cancer Hospital, Oita, Japan
6)
Division of Oncology, Hematology, and Infectious Diseases, Department of Internal Medicine, Fukuoka University,
Fukuoka, Japan
7)
Department of Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan
8)
Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
1)

2)

Abstract
Introduction: Oral combination chemotherapy using capecitabine and cyclophosphamide (XC) has demonstrated synergistic antitumor activity in preclinical studies. We investigated the efficacy and safety of early-linen XC therapy use in patientswith metastatic breast cancer (MBC).
Methods: In this prospective cohort study conducted at 10 site in Kyushu, Japan, patients with human epidermal growth
factor receptor 2 (HER2)-negative MBC, regardless of the history of previous treatment, were enrolled. XC therapy was administered at the recommended dose on a three-week schedule for at least six courses unless disease progression and unacceptable toxicities occurred. The primary endpoint was response rate (RR), and the secondary endpoints were progressionfree survival (PFS), overall survival (OS), and adverse events.
Results: Of the 83 patients enrolled, 71 (median age, 60 years [range, 34–86 years]) fulfilled the inclusion criteria and wereanalyzed. A total of 45 (63%) patients did not previously receive chemotherapy for metastatic disease, 10 (14%) received one
chemotherapy regimen. The median number of cycles of XC was eight (range, 1–45), and the RR was 28%. Median PFS was
7.6 months (95% confidence interval [CI]: 5.7–9.5 months), and median OS was 26.4 months (95% CI: 13.9–38.9 months).
The most frequent grade 3–4 adverse events were leukopenia (n = 20) and neutropenia (n = 15).
Conclusions: In clinical practice, XC therapy exhibited efficacy and manageable tolerability in Japanese women with MBC
in early-line use. (ID: UMIN000044444)
Keywords: capecitabine, cyclophosphamide, metastatic breast cancer, prospective cohort study(Received February 28, 2022; Accepted April 4, 2022)

Introduction
Metastatic breast cancer (MBC) remains incurable;
as such, the goals of therapy are to prolong survival, alleviate symptoms, and optimize quality of life (QoL).
Anthracycline- or taxane-containing regimens haveoften been chosen as a first-line therapy for human epidermal growth factor receptor 2 (HER2)-negative MBC.
Corresponding author: Kohjiro Mashino, MD, PhD., Department of Breast Surgery,
Oita Prefectural Hospital, 2-8-1, Bunyo, Oita City, Oita 870-8511, Japan. E-mail: kmashino@oitapref-hosp.jp

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Annals of Cancer Research and Therapy Vol. 30 No. 1, 2022

Current guidelines suggest the use of an agent for firstline therapy to optimize the treatment length and QoL1).
However, with the long-term use of these drugs, virtually
all patients experience adverse events including peripheral neuropathy, hair loss, and cardiotoxicity. Based onthese guidelines, agents with reduced toxicity—but withcomparable efficacy to that of anthracyclines and taxanes—could be a therapeutic option as a first-line therapy
in such patients. In fact, a recent clinical study conductedin Japan demonstrated that the oral 5-fluorouracil (5-FU)
derivative S-1 is non-inferior to taxane in terms of overall survival (OS) and QoL as first-line chemotherapy forpatients of MBC2).

Capecitabine is an oral active agent that is converted
to 5-FU in a three-step enzymatic process and delivered
selectively to the neoplastic tissue3). After gastrointestinal absorption, capecitabine is hydrolyzed in the liver;deaminated by cytidine deaminase, an enzyme locatedprincipally in the hepatic and neoplastic tissue; and catalyzed by thymidine phosphorylase. Because thymidine
phosphorylase activity is higher in neoplastic tissues
than in normal tissues, 5-FU is preferentially generated
in the neoplastic tissues. Previous clinical studies haveshown that capecitabine monotherapy is an active firstline therapy for patients with anthracycline- and taxanerefractory MBC4, 5).
In xenograft and mammary tumor models, the administration of taxanes or cyclophosphamide was shown
to upregulate the levels of thymidine phosphorylase inneoplastic tissues, and combination therapy using theseagents with capecitabine demonstrated synergistic antitumor effects without significantly potentiating toxicity6, 7). In humans, the efficacy of the combination of
capecitabine and docetaxel was clinically demonstrated
in a phase III study, which showed that the aforementioned therapy resulted in significantly superior time toprogression and OS, with a manageable toxicity profile
compared with that of docetaxel monotherapy8)oncologists are frequently faced with the challenge of treating
patients whose disease has progressed during or following anthracycline therapy or who are ineligible for further anthracycline therapy. Many of these women remain
candidates for cytotoxic chemotherapy, and several treatment options exist. Until recently, the taxanes, docetaxel
in particular, were widely regarded as the most effective
therapy for these patients, based on a survival advantage observed with docetaxel. However, a recent phase
III study demonstrated that the addition of capecitabine
to docetaxel results in superior overall survival (with a
3-month improvement in median survival.
Oral administration of antineoplastic agents is convenient, leading to enabling outpatient therapy much easily,
which is believed to improve QoL compared to hospitalbased therapy, especially in patients with advanced cancers. Both capecitabine and cyclophosphamide are active
therapeutic agents for breast cancer and can be administered orally. Harvey et al. demonstrated the efficacy andfeasibility of combined capecitabine and cyclophosphamide (XC) therapy in a randomized study in comparison
with the capecitabine monotherapy 9). We conducted
phase I study of the combination therapy in patients with
MBC, and the recommended dose of these agents was established10). The excellent antitumor effects and favorable
toxicity profiles of XC therapy were revealed in a prospective phase II study11). This study was undertaken toprospectively evaluate the clinical efficacy of XC therapy
as well as its adverse reactions in clinical practice.

Methods
Patients
Female patients with histologically-confirmed HER2negative MBC including those with unresectable advanced disease, aged ≥20 years, with no history of combination chemotherapy with 5’-deoxy-5-fluorocytidine
and cyclophosphamide other than perioperative chemotherapy which was given before at least 12 months
since the last administration, with Eastern Cooperative
Oncology Group performance status (ECOG-PS) 0
to 3, with measurable lesion(s) based on the Response
Evaluation Criteria in Solid Tumors (RECIST) version
1.1, with at least 3 months of life expectancy, and withadequate bone marrow, liver, renal, and lung function
were included in the study. Premenopausal women withhypersensitivity to pyrimidine fluoride drugs or cyclophosphamide, systemic infection, uncontrolled pleural
effusion or ascites, pericardial effusion, symptomaticbrain tumor, serious complications, active concomitantmalignancy, or history of organ transplantation and those
who are pregnant including those with possible pregnancy were excluded. Patients who were considered to beineligible by the investigator were also excluded.
Study design
This prospective, single-arm, multicenter cohort study
was conducted at 10 sites in Japan. The study protocol
and all amendments were approved by the local ethics committees or at the institutional review board ateach participating study site. This trial was conductedin accordance with the Japanese Guidelines for ClinicalResearch of the Ministry of Health, Labor and Welfare,and the Declaration of Helsinki as well as other regulatory requirements. All participants provided written
informed consent before enrolled into the study. This
investigator-initiated clinical trial was supported by nonprofit organization the Clinical Hematology-Oncology
Treatment Study Group (CHOT-SG).
The doses of capecitabine and cyclophosphamide
were determined according to an earlier phase I trial10). A
capecitabine dose of 1,657 mg/m2/day and a cyclophosphamide dose of 65 mg/m2/day were given orally twice
daily from days 1 to 14 and one week rest. The treatment
was continued for at least six cycles at a every three-weekcycle or until disease progression or toxicity or significant complications as described below. Treatment beyond
six cycles was permitted at the discretion of the treating
physician.
The therapy was withheld if significant toxicity occurred, and the treatment was resumed once the toxicity
had resolved as dose adjustment was taken place. The
treatment modification measures were as follows. The
next cycle of treatment was initiated if the following con-

XC therapy as early-line treatment in patients with MBC

39

ditions were met: neutrophil count ≥1.5×109/L, platelet
count ≥75×109/L, hemoglobin ≥8 g/dL, serum creatinine≤1.5 times the upper limit of normal, serum total bilirubin ≤1.5 times the upper limit of normal, and aspartate
aminotransferase (AST) and/or alanine aminotransferase (ALT) levels ≤2.5 times the upper limit of normal.
The treatment was interrupted if patients developed anadverse event classified as grade 2, 3, or 4 according to
the National Cancer Institute Common Toxicity Criteria.
Treatment was interrupted at the first occurrence ofgrade 2 toxicity and then resumed at the original doseonce the toxicity has resolved to grade 0–1. If the same
grade 2 toxicity subsequently occurred, then treatment
was discontinued and the dose was reduced by 25%. If
grade 3 or 4 toxicity occurred, then treatment was interrupted, and the dose was reduced by 25% or 50%, respectively. At the third appearance of grade 2 toxicity or
the second appearance of grade 3 toxicity, the treatment
was interrupted until the toxicity resolved to grade 0–1,
and treatment was continued at 50% of the original dose.
Treatment was discontinued at the third occurrence ofgrade 3 toxicity or the second appearance of grade 4 toxicity, and the patient was withdrawn from the study. The
treatment was maintained as long as treatment response
was persisted and toxicity was acceptable.
Study assessments
Tumor size was measured according to the RECIST
guideline at baseline, and tumor response was assessed
after every two cycles of XC. Hematological and nonhematological toxicities were evaluated according to the
National Cancer Institute Common Toxicity Criteria, version 3.0.
The primary aim of the present study was to objectively determine the RR, i.e., complete response (CR)+ partial response (PR). Secondary objectives were toestimate the progression-free survival (PFS) and OS andto determine the safety of this regimen. The PFS and OS
were calculated and compared using the Kaplan-Meiermethod and log-rank test. PFS was defined as the interval from the time of assignment to this study until progression of the disease or death from any cause. OS was
measured from the time of inclusion into this study until
death from any cause. Survivors who did not experiencedisease progression were censored at the last date of contact. All eligible patients who received at least one doseof XC were included in the intention-to-treat analysis ofefficacy and safety.
Statistical analysis
The threshold response rate was set to 25% in consideration of the response rate of capecitabine alone in thefirst-line therapeutic effect on MBC, and the expected
response rate was set to 40% in consideration of the response rate of taxane-based monotherapy8, 9).

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Annals of Cancer Research and Therapy Vol. 30 No. 1, 2022

The required sample size was estimated based on a
threshold RR of 25% and an expected RR of 40%, 80%
power, and an alpha value of 0.1 (one-sided) using thebinomial test. Given 10% of ineligible patients, the target
sample size was determined to be at least 70 patients.
We used the Kaplan–Meier method to estimate survival
curves to calculate 95% CIs for survival rates. Statisticalanalyses were performed using BellCurve version 3.20
(Social Survey Research Information Co., Ltd, Tokyo,
Japan) for Excel (Microsoft Corporation, Redmond, WA,USA).
Results
Patients
A total of 83 patients were enrolled in this study between November 2009 and February 2012. Of them, 12
were excluded because they did not meet the inclusion
criteria; thus, 71 patients were eligible for this study. The
demographic and baseline characteristics of the patientsare summarized in Table 1. The median age was 60 years(range, 34–86 years), and all patients had an ECOG-PS of
0 or 1. A total of 55 (77%) patients had estrogen receptor(ER)-positive MBC, 41 (58%) had progesterone receptorpositive MBC, and 11 (16%) did not have both receptors.

Table1 Patient demographics and baseline characteristics
Characteristics
Eligible patients
Age, years
Median (Range)
≤49
50–64
≥65
ER status
positive
negative
PR status
positive
negative
Metastatic sites
Visceral metastases
Liver
Lung
Soft tissue
Bone
OthersNumber of metastatic sites
1
2≥3
Prior adjuvant chemothrapy
Anthracyclin or/and Taxane containing
FU containing
OthersPrior chemotherapy for metastatic disease01≥2

No. of patients (%)
71 (100)
60 (34–86)
12 (17)35 (49)24 (34)55 (77)16 (23)41 (58)30 (42)52 (73)38 (54)27 (38)30 (42)43 (61)13 (18)13 (18)25 (35)33 (46)44 (62)28 (39)9 (13)2 (3)
45 (63)10 (14)16 (23)

Table2 Response to the treatment by the number of prior regimens, by the ER status, and by the patients’ age.
Over allClinicalNumberof patients response (%) Benefit (%)
Prior chemotherapy
for MBC
ER status
Age

CR

PR

Best responseSD≥SD<
6months
6months

PD

NA

0

45

16 (36)27 (60)3 (7)13 (29)11 (24)7 (16)

7 (16)

4 (9)

1

10

1 (10)

7 (70)0 (0)1 (10)

6 (60)

1 (10)

2 (20)

0 (0)

2≤

16

3 (19)

9 (56)0 (0)3 (19)

6 (38)

3 (19)

2 (13)

2 (13)
6 (11)

positive55

13 (24)34 (62)2 (4)

11 (20)21 (38)8 (15)

7 (13)

negative16

7 (44)

9 (56)1 (6)

6 (38)

2 (13)

3 (19)

4 (25)

0 (0)

≤64

47

16 (34)29 (62)3 (6)13 (28)13 (28)6 (13)

7 (15)

5 (10)

65≤

24

4 (17)

14 (58)0 (0)4 (17)

10 (41)5 (21)

4 (16)1 (4)71

20 (28)43 (61)3 (4)

17 (24)23 (32)

11 (15)

11 (15)

6 (8)

Total

Table3 Clinical benefit rate of the treatment by the metastatic site.
Metastatic site of CR, PR or SD (IR/SD)≥6months /number of assessable patients (%)
Metastatic site

Prior chemothrapy
for MBC

Liver

Bone

0
1or2
Total

9/18 (50)
15/19 (79)24/37 (65)21/25 (84)
15/17 (88)36/42 (86)

N.A: not assessable.

Lung (visceral) Lung (pleural)
11/16 (69)
10/11 (91)
21/27 (78)Lung or liver metastasis was present in 27 (38%) and38 (54%) patients, respectively. Among the 71 patientstreated in this study, 44 (62%) had previously undergone
adjuvant chemotherapy. A total of 45 (63%) patients did
not previously receive chemotherapy for metastatic disease, 10 (14%) received one chemotherapy regimen, and
15 (21%) received two chemotherapy regimens.
The median number of XC therapy cycles was eight(range, 1–45). The reasons of discontinuing the treatment
beyond 6 cycles are progression of disease (32%), severe
diarrhea (1%), bone marrow suppression (1%), severe
weight loss (1%), infection (1%), and pulmonary embolism (1%).
Efficacy analysis
The best responses to the treatment protocol are summarized in Table 2. Objective CR and PR were observedin 20 of the 71 patients in the intention-to-treat population, resulting in an overall RR of 28%. Thirty-four (48%)
additional women had stable disease (SD), and 23 had
SD for ≥ 6 months, corresponding to a clinical benefit
response (CBR [CR +PR + SD ≥ 6 months]) rate of 61%.
For patients without prior chemotherapy for metastatic
lesions, the response rate was 36% and CBR was 60%.
Table 2 summarizes the efficacy by treatment line, ER
expression, and age. Over all RR in the first line therapy
is 36%, while that of beyond the second line therapy is19%. The analysis of ER expression revealed that theoverall RR was 24% in the ER-positive group and 44% in
the ER-negative group, respectively. Over all RR of thetreatment in the elderly aged 65 and over was 17%, andthat in the aged 64 and under was 34%. CBR was 58%

4/5 (80)
N.A
4/5 (80)

Skin

Lymph node

2/3 (67)
1/2 (50)
3/5 (60)

14/22 (64)
5/6 (83)
19/28 (68)

ContralateralbreastN.A
1/1 (100)
1/1 (100)and 62%, respectively.
Table 3 shows the CBR rates according to the metastatic site. The clinical benefits to receiving this treatment were observed in 65% of patients with liver, 68%of those with lymph node, and 78% of those with lungmetastases.
The median duration of follow-up was 16.1 months.
Median PFS based on the Kaplan-Meier estimate was 7.6
months (95% CI: 5.7–9.5 months [range, 1–23 months]),
and median OS was 26.4 months (95% CI: 13.9–38.9
months [range, 1–60 months]).
Safety analysis
The different adverse events of this treatment are summarized in Table 4. Of the 71 patients, grade 3 leukopenia was observed in 20 (28%), neutropenia was observedin 14 (19%), anemia was observed in two (3%), andthrombocytopenia was observed in two (3%) patients.
One patient died of pulmonary embolism after receiving one cycle of treatment. This patient had a large tumor burden, with metastases to the liver, lung, skin, andlymph nodes, which were resistant to endocrine therapy.
There were grade 1/2 non-hematological toxicities. The
ALT and AST levels increased to grade 3 in two (3%)
patients and one (1%) patient, respectively. Hand-footsyndrome was observed in 24 (34%) patients, although
grade 3 was observed in only one (1%) patient. Twentyfour (34%) patients were discontinued before 6 cycles oftreatment. Fifteen (21%) patients were discontinued due
to disease progression. Two patients were discontinued
due to changes in their own intentions, and the other two
were discontinued due to the protocol regulations. Other

XC therapy as early-line treatment in patients with MBC

41

Table4 Treatment-related adverse events.
number of patients (percent) N=71
Adverseevent (AE)Any grade

Grade1

Grade2

Grade3

Grade4

Grade5

Leukopenia

49 (85)

11 (15)29 (41)20 (28)0

0

Neutropenia

50 (70)17 (24)18 (25)14 (19)1 (1)0Anemia44 (62)33 (46)

9 (5)

2 (3)

0

0

Thrombocytopenia

33 (46)29 (41)

2 (3)

2 (3)

0

0

AST elevation

33 (46)28 (39)

4 (6)

1 (1)

0

0

Fatigue30 (42)23 (32)

6 (8)

1 (1)

0

0

Hand-foot syndrome

24 (34)16 (23)7 (10)

1 (1)

0

0

Nausea23 (32)16 (23)7 (10)000

Cr elevation

17 (24)14 (20)

3 (4)

0

0

0

ALT elevation

15 (21)

12 (17)

1 (1)

2 (3)

0

0

Stomatitis

11 (15)

11 (15)

0

0

0

0

Vomitting

9 (13)

5 (7)

4 (6)

0

0

0

Alopecia

7 (10)

6 (8)

1 (1)

/

/

/

Diarrhea

6 (8)

4 (6)

2 (3)

0

0

0

BUN elevation

2 (3)

2 (3)

0

0

0

0

Thromboembolic event

1 (1)

/

0

0

0

1 (1)

Maximum grade any AE

69

13 (18)30 (42)24 (34)

1 (1)

1 (1)

cases were discontinued due to adverse events such as
infection, myelosuppression, and weight loss.
Discussion
Previous studies investigating combined XC therapy
in patients with MBC have reported positive primary
RR, PFS, and OS results compared with the historical reports describing capecitabine as monotherapy9, 12, 13). Our
study group previously reported the efficacy and toxicity
of XC combination chemotherapy in patients who previously had the anthracycline therapy11). In this prospective
cohort study, we aimed to reveal how XC therapy wasused in clinical practice, and to investigate its efficacy
and safety. Thus, this prospective observational study did
not specify the timing of administration or disease state,
but virtually all of the registered cases were upfront formetastatic breast cancer. For patients without prior chemotherapy for metastatic lesions, response rates werecomparable to our previous study.
After completing this study, we found that the XC regimen was preferably used in three specific patient groups,
the first of which was older adults. We compared the effects of treatment and the frequency of adverse events inpatients aged 65 years or older with those aged 64 years
or younger. More than 80% of the patients enrolled in thepresent cohort study were aged >50 years; in particular,
34% were over 65 years. The clinical benefit rate in thesepatients was 58%, which was comparable to that of theyounger group (Table 2). Same is true for PFS and OS

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Annals of Cancer Research and Therapy Vol. 30 No. 1, 2022

(Fig. 1). It is important to minimize the side effects inolder patients with decreased activity of daily living andmultiple comorbidities. They may not be able to tolerate strong intravenous anticancer drugs that can possibly
induce severe adverse events. In the present study, theincidence of grade ≥ 3 adverse events was 36%, most ofwhich showed controllable leukopenia and neutropenia
except for 2 patients who experienced grade3 anemia
and elevated liver enzymes (Table 4). One patient died of
pulmonary embolism after completing one cycle of treatment. It is thought that advanced cancer was most likely
cause of this thromboembolic event. Although hand-footsyndrome is one of the most frequent and troublesome
adverse events for capecitabine, but grade ≥3 was recorded in only 1 patient.
The second potential candidate for XC therapy is patients with non-life-threatening bone or lung metastases.
We investigated the therapeutic effects according to thesite of metastasis based on CBR (Table 3). More than
80% of patients with bone or lung metastases can achieveclinical benefits; even in 65% of patients with liver metastases, an increase in tumor size can be controlled for ≥6months. Although the XC regimen is unlikely to obtainCR, this study showed XC can control tumor progression
to some extent. Moreover, this regimen can also play animportant role in postponing the onset of symptoms orin mitigating the severity of symptoms associated withtumor progression.
The third candidate for XC therapy is those who had
not receive 5-FU prior to this study. In the current prac-

(a)

PFS

(b)

≦64 years old (n=47 ; event=22 )Median months (95% CI) 8.9 (6.7,
11.0)

1.00

65 years old ≦ (n=24 ; event=12 )Median months (95% CI) 17.9 (0.7, 35.2)

0.80

0.60

0.60

0.40

0.40
0.20

0.20

P=0.747

P=0.342

0.00

0

0.5

1

1.5

2

2.5

No. of patients at risk:
0

0.25

0.5

0.75

1

1.25

1.5

1.75

2

≦64y.o

47

37

21

14

8

5

3

0

0

24

22

0.00

0

1

2

3

4

5

6

No. of patients at risk:

years

65y.o≦≦64 years old (n=47 ; event=21 )Median months (95% CI) 29.9 (11.7, 48..1)

1.00

65 years old ≦ (n=24 ; event=9 )Median months (95% CI) 6.2 (3.9,
8.5)

0.80

OS

10

6

3

2

2

1

0

years

0

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

5.5

≦64y.o

47

44

29

22

17

16

13

11

5

4

0

0

65y.o≦

24

19

14

9

9

7

4

3

2

2

2

0

Fig 1. Kaplan-Meier Estimates of Progression-free Survival and Overall Survival by age at the treatment
A solid line is shown for patients over 65, while a dotted line for patients under 65. Dot marks indicate censored patientsat the last time when the patient were confirmed to be alive with no event. Panel (a) shows the Kaplan-Meier estimatesof progression-free survival and Panel (b) shows that of overall survival.

tice, anthracycline and taxanes are used as a perioperative chemotherapy, but 5-FU or alkylating agents are notoften included in an adjuvant therapy. Thus, XC combination appears to be suitable regimen for recurrent disease.
Indeed, 62% of the patients had received adjuvant chemotherapy, of which 39% received anthracyclines, 28%
received taxanes, and only 13% received 5-FU (Table 1).
In this cohort study, 43 (63%) patients were chemonaïve for metastatic sites, and all patients, except for
one, received a second-line treatment. The objective RR,
which was the primary endpoint of this study, was 28.1%.
The chemo-naïve group had an objective RR of 36%,
while the second-line and beyond group had an objective RR of 16% (Table 2). Other studies reported that XC
therapy gave rise to the objective RR with no previous
chemotherapy was 30%–36%11-13), and second-line chemotherapy for MBC 13%–35%14), which were comparable to our result. For chemotherapy-naïve patients, themedian PFS and OS in the present study was 8.5 months,
and 35.6 months, respectively, while PFS of 11.3 months
and OS of 26.7 months for paclitaxel and bevacizumab
combination in the E2100 trial15). Although PFS might
be shorten compared with that of E2100 trial, OS wascomparable indicating that the XC combination does notseem to interfere subsequent therapy.
The discrepancy between the OS and PFS results may
be explained by the fact that XC is a mild and durable
regimen that can be administered for a longer period oftime with a gradual effect and tolerable adverse events.
Indeed, 60% of the patients were able to continue treatment for longer than 6 months due to good tolerance to
XC. It is interesting to notice that there were 7 and 1 patients who reached PR and CR beyond 6 months of treatment, respectively.

This study was planned as a cohort study examining
the effects of XC treatment in clinical practice. Therefore,
there was not much intervention in case selection andfollow-up methods on the protocol. This is considered tobe the reasons why the response rate was lower than thatof the phase II study we conducted earlier.
In conclusion, XC combination is a useful regimen asa front-line therapy for MBC unless the patient has a lifethreatening disease. It has tolerable adverse events which
are acceptable to the patients, and long-term treatment ispossible.
Support information:
This work was supported by non-profit organization of theClinical Hematology-Oncology Treatment Study Group (CHOTSG) for conducting the study.
Ethical approval:
Informed consent was obtained from all individual participants
included in this study. All procedures performed were in accordance with the ethical standards of the institutional and/or national
research committee and with 1964 Helsinki declaration and its later amendments, Good Clinical Practice guidelines, and other local
regulatory requirements. This study complies with the current lawsof Japan. The study protocol and its amendments were approved by
the institutional review board at each study institute. This study has
been registered with the University Hospital Medical Information
Network Center (ID: UMIN000044444).
Conflict of interest:
KM, MY, RN, YY, and SM received honoraria from Chugai. Allremaining authors have no conflicts of interest to declare.
Acknowledgement:
The authors all thank Ms. Yukimi Itoh, Noriko Ikoma andEtsuko Kumagawa for collecting and cleaning the clinical data andextensive secretarial work. The authors also would like to thank thepatients who took part in the trial and their families, as well as thestaff who assisted with the study at each site.

XC therapy as early-line treatment in patients with MBC

43

Author contributions:
KM, MT, RN, YY, SM, and KT designed, conducted, and coordinated the clinical trial. KM performed the mathematical and statistical analyses. KM, MT, MY, RN, YY, and HU enrolled patients
into this trial and collected the majority of the data. KM wrote themanuscript. All authors discussed, read, and approved the manuscript.
Availability of data and material:
Qualified researchers may request access to data by contacting
the corresponding author.

References1)

Gradishar WJ, Anderson BO, Abraham J, et al. Breast Cancer,
Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. J
Natl Compr Canc Netw. 2020;18(4):452-78.
2) Takashima T, Mukai H, Hara F, et al. Taxanes versus S-1 as thefirst-line chemotherapy for metastatic breast cancer (SELECT BC):
An open-label, non-inferiority, randomised phase 3 trial. Lancet
Oncol. 2016;17(1):90-8.
3) Miwa M, Ura M, Nishida M, et al. Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5 fluorouracil
selectively in tumours by enzymes concentrated in human liver andcancer tissue. Eur J Cancer. 1998;34(8):1274-81.
4) Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II
study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J
Cancer. 2004;40(4):536-42.
5) Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patientswith anthracycline- and taxane-pretreated metastatic breast cancer.
Med Oncol. 2004;21(3):223-31.
6) Sawada N, Ishikawa T, Fukase Y, et al. Induction of Thymidine
phosphorylase activity and enhancement of capecitabine efficacy
by taxol / taxotere in human cancer xenografts : Clin Cancer Res.
1998;4(4):1013-9.

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Annals of Cancer Research and Therapy Vol. 30 No. 1, 2022

7) Endo M, Shinbori N, Fukase Y, et al. Induction of thymidine phosphorylase expression and enhancement of efficacy of capecitabineor 5’-deoxy-5-fluorouridine by cyclophosphamide in mammary
tumor models. Int J Cancer. 1999;83(1):127-34.
8) O’Shaughnessy J, Miles D, Vukelja S, et al. Superior survival withcapecitabine plus docetaxel combination therapy in anthracyclinepretreated patients with advanced breast cancer: phase III trial
results. J Clin Oncol. 2002 ;20(12):2812-23.
9) Harvey VJ, Sharples KJ, Isaacs RJ, et al. A randomized phase II
study comparing capecitabine alone with capecitabine and oral cyclophosphamide in patients with advanced breast cancer-cyclox II.
Ann Oncol. 2013;24(7):1828-34.
10) Ohno S, Mitsuyama S, Tamura K, et al. Dosage of capecitabine andcyclophosphamide combination therapy in patients with metastatic
breast cancer. Anticancer Res. 2007;27(2):1009-13.
11) Tanaka M, Takamatsu Y, Anan K, et al. Oral combination chemotherapy with capecitabine and cyclophosphamide in patientswith metastatic breast cancer: A phase II study. Anticancer Drugs.
2010;21(4):453-8.
12) Wang Z, Lu J, Leaw S, et al. An all-oral combination of metronomic cyclophosphamide plus capecitabine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: A phase II
study. Cancer Chemother Pharmacol. 2012;69(2):515-22.
13) Yoshimoto M, Takao S, Hirata M, et al. Metronomic oral combination chemotherapy with capecitabine and cyclophosphamide: Aphase II study in patients with HER2-negative metastatic breast
cancer. Cancer Chemother Pharmacol. 2012;70(2):331-8.
14) Puglisi F, Rea D, Kroes MA, et al. Second-line single-agent chemotherapy in human epidermal growth factor receptor 2-negative
metastatic breast cancer: A systematic review. Cancer Treatment
Reviews. 2016;43:36-49.
15) Gray R, Bhattacharya S, Bowden C, et al. Independent review of
E2100: A phase III trial of bevacizumab plus paclitaxel versus
paclitaxel in women with metastatic breast cancer. J Clin Oncol.
2009;27(30):4966-72.