Breast Cancer

, Volume 17, Issue 4, pp 233–240

Phase II study of 4-weekly capecitabine monotherapy in advanced/metastatic breast cancer

Authors

    • Tokyo Medical University
    • Sinjyuku Breast Center Kusama Clinic
  • Tadashi Nomizu
    • Hoshi General Hospital
  • Kenjiro Aogi
    • National Hospital Shikoku Cancer Center
  • Masataka Yoshimoto
    • Cancer Institute Hospital
    • International University of Health and Welfare, Mita Hospital
  • Noboru Horikoshi
    • Japanese Foundation for Cancer Research
    • Juntendo University School of Medicine
  • Toshio Tabei
    • Saitama Prefectural Cancer Center
  • Shinzaburo Noguchi
    • Osaka University
  • Shigeto Miura
    • Aichi Prefecture Cancer Center
    • Kamiiida Daiichi General Hospital
  • Norio Yoshimura
    • Kyoto Prefectural University
  • Morihiko Kimura
    • Gunma Prefecture Cancer Center
    • Ohta General Hospital
  • Kazushige Toyama
    • Shizuoka Prefecture General Hospital
    • Shizuoka Health Management Center
  • Eisei Shin
    • National Osaka Hospital
    • Iseikai Hospital
Original Article

DOI: 10.1007/s12282-009-0137-5

Cite this article as:
Kusama, M., Nomizu, T., Aogi, K. et al. Breast Cancer (2010) 17: 233. doi:10.1007/s12282-009-0137-5
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Abstract

Background

A multicenter, phase II study was conducted to evaluate the efficacy and safety of the Japanese intermittent 4-week regimen of capecitabine in patients with advanced/metastatic breast cancer.

Methods

Fifty patients who had received no more than one prior chemotherapy regimen for advanced/metastatic disease were enrolled from 23 centers and received at least two 4-weekly cycles of capecitabine (828 mg/m2 orally twice daily for 3 weeks followed by a 1-week rest period).

Results

The overall response rate assessed by the Independent Review Committee (standard population, n = 46) was 28.3% (95% confidence interval 16.0–43.5%), including complete responses in 6.5%. Stable disease was observed in 20 patients and maintained for more than 6 months in 10 patients. The median duration of response in 13 evaluable responders was 5.3 months. Among evaluable patients (n = 47), median time to disease progression was 5.1 months. Median overall survival was 20.2 months. The most common treatment-related adverse events (all grades) were hand–foot syndrome (66%), nausea (26%), stomatitis (22%) and diarrhea (20%). Grade 3/4 treatment-related adverse events were seen in 23 patients (46%). The most common grade 3/4 adverse events were lymphocytopenia (22%), hand–foot syndrome (18%) and hyperbilirubinemia (10%).

Conclusions

Although the target overall response rate was not reached, the Japanese intermittent 4-week regimen of capecitabine was shown to be an effective and well-tolerated first- or second-line therapy for advanced/metastatic breast cancer.

Keywords

CapecitabineBreast cancerAdvancedMetastaticEfficacySafetyFour-week (Japanese) regimen

Introduction

Breast cancer is the most common form of malignancy afflicting women in Japan and is the second most common cause of cancer death in this population. Despite improvements in screening, control of locoregional disease and adjuvant therapy, recurrent metastatic breast cancer remains distressingly common. Anthracyclines and taxanes are widely used in the adjuvant and first-line settings. In patients whose disease progresses following treatment with these agents, the oral fluoropyrimidine capecitabine is an established treatment option. Capecitabine delivers 5-fluorouracil (5-FU) preferentially to the tumor site [1] by exploiting the significantly higher concentrations of thymidine phosphorylase in tumors compared with adjacent normal tissue [2]. The internationally approved intermittent capecitabine regimen (1,250 mg/m2 twice daily for 2 weeks followed by a 1-week rest period) has demonstrated consistently high single-agent activity and a favorable safety profile, including minimal myelosuppression and alopecia, in taxane- and anthracycline-pretreated metastatic breast cancer [36]. The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated advanced breast cancer [7]. In patients with advanced gastric cancer, the internationally approved schedule is either an intermittent regimen of capecitabine 1,000 mg/m2 twice daily or a continuous regimen (without drug-free period) of capecitabine 625 mg/m2 twice daily in combination with platinum-based therapy [8, 9]. A continuous regimen showed very similar efficacy and tolerability to a 3-weekly intermittent regimen in patients receiving first-line capecitabine for advanced breast cancer in a randomized, phase III trial [10]. In rectal cancer, a weekday regimen is often used in combination with radiotherapy [11].

In Japan, a less dose-intensive, 4-weekly intermittent capecitabine monotherapy regimen (828 mg/m2 administered twice daily for 3 weeks followed by a 1-week rest period) was identified in a phase I study [12]. This schedule was shown to have good tolerability and very promising efficacy in a pilot phase II study [13]. When administered as second-line treatment in 23 patients with advanced/recurrent breast cancer, the overall response rate was 46% [95% confidence interval (CI) 24.4–67.8%], including one complete response (CR 4.5%), and the median time to disease progression (TTP) was 6.4 months (95% CI 4.1–15.1). The results of this small, single-arm study compare favorably with data for the internationally approved intermittent capecitabine regimen in anthracycline- and taxane-pretreated metastatic breast cancer [36], providing the justification for evaluating the Japanese regimen in a larger study.

The present phase II study was designed to determine the efficacy and safety profile of the Japanese intermittent 4-week regimen of capecitabine in patients with advanced/metastatic breast cancer. We aimed to investigate whether this alternative regimen might provide similar efficacy and safety to the more widely used 3-weekly regimen.

Patients and methods

Study design

This multicenter, single-arm, phase II study was conducted in 23 centers in Japan in accordance with Good Clinical Practice for Trials on Drugs, announced on 2 October 1989 by the Pharmaceutical Affairs Bureau (notification no. 874), and with the Declaration of Helsinki. The study protocol was approved by the institutional review board or ethics committee of each center. All patients gave written informed consent prior to enrollment.

Eligibility

Patients with histologically or cytologically confirmed breast cancer who had received no more than one prior chemotherapy regimen for metastatic disease were eligible. Previous taxane-based chemotherapy was not permitted. Patients were required to have at least one measurable indicator lesion that had not been irradiated. Indicator lesions had to measure ≥10 mm (X-ray, ultrasound or direct measurement) or ≥20 mm (computed tomography or magnetic resonance imaging) in one dimension. Ascites and pleural effusions were not considered measurable. Other eligibility criteria included Eastern Co-operative Oncology Group performance status 0–2, age ≥20 years and life expectancy of at least 3 months.

Patients were not eligible if they were pregnant or lactating, were hypersensitive to 5-FU, had previously experienced a severe reaction to fluoropyrimidines, had a history of other cancer within the previous 5 years, had received other experimental drugs or radiotherapy within 4 weeks before enrollment, or had not fully recovered from recent major surgery. Patients were also excluded if they had organ allografts, central nervous system involvement, neurologic or psychiatric disorders that could interfere with treatment compliance, significant cardiac disease or a myocardial infarction within the previous 12 months, serious uncontrolled infections, or malabsorption syndrome or lack of physical integrity of the upper gastrointestinal tract. Other exclusion criteria were significant abnormalities in hemoglobin (<9.0 × 109/l), leukocytes (<4.0 × 109/l), platelets (<100 × 109/l), serum creatinine or serum bilirubin (>1.5 times the upper limit of normal [ULN]), or alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (>2.5 times the ULN). However, up to five times the ULNs for ALT, AST and alkaline phosphatase were allowed for patients with liver metastases.

Dosage and dose modifications

Patients were instructed to take capecitabine 828 mg/m2 orally twice daily (after breakfast and evening meal) for 3 weeks followed by a 1-week rest period for at least two cycles, except in cases of disease progression, request from the patient/family and/or intolerable adverse events. Patients with a response or stable disease (SD) after two cycles of treatment were able to continue capecitabine at the investigator’s discretion. During the study, other anticancer drugs, such as immunotherapy, hormonal therapy and systemic steroids, were prohibited.

In the event of any drug-related adverse events (excluding alopecia, malaise, taste disturbance, uncontrolled anorexia, nausea, vomiting, lymphocytopenia and hyperbilirubinemia <2 mg/dl) of grade 3 intensity according to the National Cancer Institute of Canada Common Toxicity Criteria (NCIC-CTC), or if the investigator judged continuation of treatment unfeasible, treatment could be delayed for up to 4 weeks until the patient recovered. If the investigator considered that continuation of treatment at the same dose would be intolerable, the dose could be reduced to approximately 75% of the initial dose. Treatment was permanently discontinued in patients who developed drug-related grade 4 adverse events or who could not tolerate the reduced dose.

Study assessments

Before enrollment, baseline demographic characteristics, signs, and symptoms were recorded. Laboratory tests, electrocardiograms and imaging studies of all lesions were also performed.

Tumor responses were evaluated by the investigator according to the General Rules for Clinical and Pathological Recording of Breast Cancer (12th edition) [14]. Disappearance of all known disease at all involved sites was considered a CR. Partial response (PR) was defined as residual disease with a decrease ≥50% in the sum of products of the lesions. Progressive disease (PD) was defined as the appearance of a new lesion or an increase of 25% in the sum of products of the lesions. SD was defined as no change in target lesions or a change not corresponding to CR, PR or PD. To ensure consistency in evaluation, successive tumor measurements and response evaluations for a given patient were conducted by the same investigator. To enable comparison with studies in the literature using the World Health Organization (WHO) criteria response categories, minor response (MR) and no change (NC) were grouped together with SD. An Independent Review Committee (IRC) comprising independent oncologists was responsible for reviewing investigator assessments of tumor response. Survival follow-up was performed during the study and at the time of data cutoff.

During the first two cycles, laboratory examinations were performed every 2 weeks. Safety evaluations (including assessment of laboratory parameters and clinical adverse events) were conducted at least monthly during therapy and until 4 weeks after the end of therapy, unless other therapy had been assigned. Clinical adverse events were graded 1–4 according to the NCIC-CTC grading system (revised May 1991). Hand–foot syndrome (HFS) was graded 1–3, as defined in previous capecitabine trials.

Statistical analysis

All patients who received at least one dose of capecitabine were included in the intent-to-treat (ITT) population, which was used for safety analyses. Efficacy analyses were conducted using the standard population, which included all patients in the ITT population who were evaluable for efficacy.

For the analysis of efficacy, the rate of best response achieved from the start of study treatment to PD was reported with 95% Pearson–Clopper CIs. The goal of this study was to demonstrate a target objective response rate of 40% based on results of the pilot phase II study in patients with advanced and/or metastatic breast cancer [13]. To test achievement of the target response rate in the study population with measurable disease, a binomial test based on the exact binomial distribution was performed at the 2.5% alpha level (one-sided), testing the null hypothesis that the best response rate was 20%.

Secondary endpoints were duration of response, TTP and overall survival, according to WHO criteria. TTP was defined as the interval between first study treatment and the first sign of progression. Time-related endpoints were analyzed by the Kaplan–Meier method.

Results

Patient population

Between December 1998 and September 2000, 50 patients with measurable disease were enrolled and received at least one cycle of capecitabine therapy. Three patients were subsequently found to be ineligible because they had received more than one prior chemotherapy regimen for metastatic disease. One patient was withdrawn during the first 4 weeks of the study. Consequently, the investigators assessed efficacy in all enrolled patients (ITT population, n = 50), and the IRC assessed efficacy in only the eligible patients (standard population, n = 46). Table 1 summarizes the baseline demographics of the ITT population. All patients were female, and all had undergone surgery.
Table 1

Baseline patient characteristics (intent-to-treat population, n = 50)

Parameter

No. of patients

%

Median age, years (range)

52.5 (35–75)

ECOG performance status

 0

47

94

 1

3

6

 2

0

0

No. of prior chemotherapy regimens for metastatic disease

 0

27

54

 1

20

40

 2

3

6

Prior therapy

 Alkylating agent

27

54

 Anthracycline

18

36

 Fluoropyrimidine

37

74

 Hormonal

38

76

Metastatic sites

 Lymph nodes

23

46

 Lung

20

40

 Bone

15

30

 Skin and subcutaneous

15

30

 Liver

10

20

 Primary

3

6

 Other

2

4

ECOG Eastern Cooperative Oncology Group

Efficacy

The overall response rate according to the IRC assessment (standard population, n = 46) was 28.3% (95% CI 16.0–43.5%), including CRs in 6.5% (Table 2). Stable disease was observed in 20 patients and was maintained for more than 6 months in 10 of these patients. The result of the binomial test corresponded to the lower limit of the 95% CI of the response rate, which was more than 20%. The response rate was 23.5% in patients previously treated with anthracyclines and 24.3% in patients previously treated with fluoropyrimidine-containing therapy.
Table 2

Summary of overall tumor response rates (intent-to-treat and standard populations)

 

No. of patients

%

Investigator (ITT population)

n = 50

 Overall response (complete or partial response)

17

34.0

  Complete response

3

6.0

  Partial response

14

28.0

 Stable disease

19

38.0

 Progressive disease

13

26.0

 Not evaluablea

1

2.0

Independent Review Committee (standard population)

n = 46

 Overall response (complete or partial response)

13

28.3

  Complete response

3

6.5

  Partial response

10

21.7

 Stable disease

20

43.5

 Progressive disease

13

28.3

ITT intent-to-treat

aPatient withdrew during the first 4 weeks of the study

The median duration of response in the 13 responding patients in the standard population was 5.3 months (range 2.8–16.4). The median TTP was 5.1 months (95% CI 2.9–6.4, Fig. 1). The median overall survival was 20.2 months (95% CI 19.2–not reached, Fig. 2).
https://static-content.springer.com/image/art%3A10.1007%2Fs12282-009-0137-5/MediaObjects/12282_2009_137_Fig1_HTML.gif
Fig. 1

Time to disease progression

https://static-content.springer.com/image/art%3A10.1007%2Fs12282-009-0137-5/MediaObjects/12282_2009_137_Fig2_HTML.gif
Fig. 2

Overall survival

Safety

Patients received a median of five cycles (range 1–18). All patients experienced at least one treatment-related adverse event during the course of the study. The most common treatment-related clinical adverse events were HFS (66%), nausea (26%), stomatitis (22%) and diarrhea (20%) (Table 3). Significant hair loss was not reported. The majority of treatment-related adverse events were mild (grade 1) or moderate (grade 2) in intensity. Grade 3/4 treatment-related adverse events were seen in 23 patients. The only treatment-related grade 3/4 adverse events occurring in at least 10% of patients were lymphocytopenia (22%), HFS (18%) and hyperbilirubinemia (10%). The majority of these adverse events occurred during the first two cycles. There were no cases of infection due to lymphocytopenia.
Table 3

Summary of frequently reported treatment-related adverse events (≥10% of patients) (n = 50, ITT population)

 

No. of patients (%)

Grade 1

Grade 2

Grade 3

Grade 4

Total

Hand–foot syndrome

17 (34)

7 (14)

9 (18)

33 (66)

Nausea

11 (22)

2 (4)

13 (26)

Stomatitis

9 (18)

2 (4)

11 (22)

Diarrhea

9 (18)

1 (2)

10 (20)

Anorexia

7 (14)

2 (4)

9 (18)

Body weight loss

6 (12)

6 (12)

Red blood cell decrease

24 (48)

2 (4)

26 (52)

Leukopenia

16 (32)

8 (16)

1 (2)

25 (50)

Lymphocytopenia

3 (6)

11 (22)

9 (18)

2 (4)

25 (50)

Granulocyte decrease

10 (20)

8 (16)

1 (2)

19 (38)

Bilirubin elevation

1 (2)

11 (22)

5 (10)

17 (34)

AST elevation

13 (26)

1 (2)

14 (28)

ALT elevation

11 (22)

1 (2)

12 (24)

Alkaline phosphatase elevation

10 (20)

1 (2)

11 (22)

Hyperglycemia

7 (14)

2 (4)

9 (18)

LDH elevation

8 (16)

8 (16)

Urinary sediment

5 (10)

2 (4)

7 (14)

Prothrombin time prolongation

5 (10)

1 (2)

6 (12)

Urinary protein

6 (12)

6 (12)

ALT alanine aminotransferase, AST aspartate aminotransferase, LDH lactate dehydrogenase

Ten patients developed treatment-related adverse events requiring temporary interruption of treatment with or without dose reduction. The most common treatment-related adverse events leading to treatment interruption were HFS (n = 7) and leukopenia (n = 3). A total of five patients required dose reduction as a result of HFS (n = 4) and leukopenia, granulocytopenia and lymphocytopenia (n = 1). Treatment was discontinued in three patients (6%) due to HFS (n = 2) and calf cramps (patient decision) (n = 1). No treatment-related deaths were reported during the study.

Discussion

In this study, the Japanese 4-week capecitabine regimen demonstrated high activity, including an IRC-assessed overall response rate (standard population, n = 46) of 28.3% (95% CI 16.0–43.5%). Median TTP was 5.1 months, and median overall survival was 20.2 months. While the overall response rate did not reach the 40% target response rate specified in the study protocol, the null hypothesis of a response rate <20% was disproved. In addition, the disease control rate of 72% and median overall survival of 20.2 months demonstrate considerable activity. These data are similar to the 20–22% response rate, 60–66% disease control rate and 22-month median overall survival recently reported by Stockler et al. from their randomized, phase III trial comparing capecitabine monotherapy with a reference arm of classical oral cyclophosphamide, methotrexate and 5-FU (CMF) as first-line therapy in 323 women with advanced/metastatic breast cancer [10]. Approximately half of the patients in our study received capecitabine as second-line therapy and one-third had been previously treated with an anthracycline. Therefore, the efficacy findings with the less dose-intensive Japanese regimen are compelling. Since this study was conducted, results of a retrospective study in Japan have been published, demonstrating that the low dose intensity intermittent capecitabine monotherapy regimen achieved a high disease control rate with minimal toxicity in heavily pretreated metastatic breast cancer [15].

The activity of capecitabine after fluoropyrimidine exposure merits mention. In our study, 74% of patients had received prior treatment with a 5-FU-containing regimen. The response rate in these patients was 24%, similar to that seen in the overall population, suggesting that capecitabine is a valid treatment option in patients whose disease has progressed during or following 5-FU-based therapy. This observation is consistent with results of preclinical studies, which show that capecitabine has anti-tumor activity in cell lines that are resistant to 5-FU [16, 17]. 5′-DFUR, an intermediate metabolite of capecitabine, showed activity in most but not all the 5-FU-resistant cell lines in which capecitabine was active [17]. In contrast, UFT (an oral fluoropyrimidine combining tegafur and uracil) showed no anti-tumor activity in the majority of 5-FU-resistant cell lines. Susceptibility of xenograft models to capecitabine correlates with the ratio of tumoral thymidine phosphorylase to dihydropyrimidine dehydrogenase [17, 18], but such a correlation is not seen with UFT [17]. Therefore, it is possible that the activity of capecitabine in 5-FU-resistant tumors may relate to generation of 5-FU preferentially in tumor tissue, where thymidine phosphorylase concentrations are significantly higher than in non-tumor tissue [18]. Of note, in the clinical setting others have reported activity of capecitabine in patients previously exposed to 5-FU [18]. These prelinical and clinical findings are relevant to current and future clinical practice, as recent data have shown that the addition of capecitabine to adjuvant anthracycline- and taxane-containing regimens significantly improves recurrence-free survival [19]. Our data provide an indication that re-exposure to capecitabine may be effective.

The safety profile of capecitabine in this study is consistent with previously reported studies evaluating the international regimen of capecitabine monotherapy. Adverse events were predictable, manageable and reversible. The 18% incidence of grade 3 HFS is within the range typically reported with 3-weekly capecitabine. However, diarrhea, the other characteristic side effect of capecitabine, was observed in only ten patients (20%), and there were no grade 3 or 4 cases. The planned dose intensity in the present study was lower than with the registered international intermittent regimen, and this more appropriate dose intensity is probably a major factor in the reduced incidence of diarrhea.

Grade 3/4 treatment-related adverse events were seen in 23 patients (46%). The use of topical emollients for HFS and, if necessary, treatment interruption with or without dose adjustment, allowed the continuation of treatment in most patients. The most frequently reported grade 3/4 treatment-related toxicity was lymphocytopenia (22%), but severe neutropenia, leukopenia, anemia and infection due to lymphocytopenia were not seen. Lymphocytopenia is rarely reported in breast cancer studies evaluating the internationally approved 3-weekly regimen, but has been observed in studies of alternative capecitabine schedules in a range of tumor types [11, 13, 20]. The biological basis of this side effect is not understood.

Our results widen the clinical experience with the Japanese intermittent 4-week regimen of capecitabine (828 mg/m2 twice daily for 3 weeks, followed by a 1-week rest period) and provide further evidence that this regimen is effective and well tolerated in patients with metastatic breast cancer. Although confirmation of this efficacy in larger, randomized studies is required, the flexibility of capecitabine scheduling, together with its high single-agent activity and good tolerability, make it an attractive agent both alone and in combination with other chemotherapeutic and/or biologic agents. As well as widespread use of a 4-weekly regimen in Japan, this regimen may be relevant in other countries when capecitabine is combined with agents that are administered using a 2- or 4-week schedule. Lastly, the international 3-week dose and schedule of capecitabine were recently approved in Japan for advanced metastatic breast cancer, after a phase II study indicated that the 3-weekly regimen is as effective and well tolerated as the 4-weekly regimen in Japanese patients [21].

Acknowledgments

This study was sponsored by Nippon Roche K.K. In addition to the authors, the following investigators took part in this trial: Dr. Yoshiaki Narita (Teine Keijinkai Hospital, Hokkaido, Japan); Dr. Tosei Ohmura (Sapporo Medical University, Hokkaido, Japan); Dr. Yoshiro Hayakawa (Iwate Medical University, Iwate, Japan); Dr. Masahasu Takahashi (Ota-Nishinouchi General Hospital, Fukushima, Japan); Dr. Tsuneo Imai (Nagoya University, Aichi, Japan); Dr. Takayoshi Naruse (Aichi Medical University, Aichi, Japan); Dr. Hideo Inaji (Osaka Adult Disease Center, Osaka, Japan); Dr. Ken Morimoto (Osaka City University, Osaka, Japan); Dr. Yutaka Konishi (Kobe Citizens Hospital, Hyogo, Japan); Dr. Yuichi Takatsuka (Kansai Rosai Hospital, Hyogo, Japan); Dr. Akihiko Osaki (Hiroshima University, Hiroshima, Japan); and Dr. Reiki Nishimura (Kumamoto Citizens Hospital, Kumamoto, Japan).

Copyright information

© The Japanese Breast Cancer Society 2009