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Capecitabine maintenance therapy in patients with recurrent or metastatic breast cancer.

Introduction

Breast cancer is the most common malignant tumor in women; its morbidity is increasing year by year, but the mortality rate has been decreasing due to early diagnosis and improvements in therapy. The Early Breast Cancer Trialists' Collaborative Group (EBCTCG) large sample meta-analysis reported that adjuvant chemotherapy could significantly improve the prognosis of breast cancer patients (1), but that the recurrence or metastasis rates were still 20-35% (2). The major goal of recurrent or metastatic breast cancer treatment is to prolong survival time, relieve symptoms and improve quality of life (3). After initial disease control is achieved by various treatments and medications in metastatic breast cancer patients, maintaining progression-free survival and ensuring a relatively high quality of life present a major challenge for clinicians. The present study demonstrates that extending the duration of first-line chemotherapy of advanced breast cancer can improve overall survival and progression-free survival to a certain extent. However, further clinical studies are required to elucidate the role of maintenance therapies, improve suitable medication regimens, and evaluate the duration for medical maintenance therapies (2).

Anthracyclines are effective drugs for treating breast cancer, but they are not suitable as a long-term maintenance treatment because of cardiac toxicity caused by drug accumulation. In addition, in the maintenance paclitaxel 1 (MANTA 1) study, 255 metastatic breast cancer patients who received a first-line anthracycline / paclitaxel combination chemotherapy followed by a paclitaxel maintenance regimen had a median time to progression (MTTP) that was not significantly better than that of the control group [8 months in the sequential paclitaxel maintenance therapy group vs 9 months in the control group (P = 0.817)], and the median overall survival rates were 28 and 29 months (P = 0.547). The study was terminated because no survival advantage of a paclitaxel maintenance medication was demonstrated (4).

The effect of oral vinorelbine as maintenance therapy was investigated in a phase II multicenter clinical trial. After achieving an overall response rate (ORR) of 70% and a clinical benefit rate (CBR) of 83% in 30 patients in response to intravenous first-line chemotherapy with 3-6 cycles of vinorelbine + anthracycline combined chemotherapy regimens, maintenance therapy with sequential oral vinorelbine therapy resulted in an ORR of 38% and CBR of 44%. The MTTP was 8 months (33% of patients were stage IV; 67% had local metastasis). Although this small trial achieved good results, the main side effect of bone marrow suppression resulted in an incidence of grade III-IV leukopenia of 44% during the combined chemotherapy and 18% in maintenance therapy (5), thereby not really making it the best choice for a long-term maintenance therapy when safety is considered.

Capecitabine is a novel oral fluoropyrimidine carbamate that is inactive and absorbed quickly by the mucous membrane of the small intestine. After conversion into 5'-deoxy-5-fluorouridine, it is transformed into cytotoxic 5-fluorouracil (5-FU) by thymidine phosphorylase (TP). 5-FU reduces DNA synthesis via inhibiting thymidylate synthase, and by blocking nucleoside analogues, hinders the synthesis of RNA particularly in tumor cells. In breast cancer cells with high proliferative activity, the concentration of the key enzyme TP is essentially higher than in other tissues, and even in tumors that are in chemotherapyresistant areas with an inadequate blood supply, the concentration of 5-FU in tumor tissues has been reported to be 127 times higher than in the blood, accounting for the high selectivity of capecitabine. Due to its specific antitumor activity, capecitabine can stop tumor cell proliferation with better tolerability, higher efficiency and lower toxicity compared with other chemotherapies. Paclitaxel, docetaxel, gemcitabine, vinorelbine, and other cytotoxic drugs can upregulate the activity of the TP enzyme (6-10), thus inducing a synergistic anti-tumor effect enhancement with capecitabine without increasing adverse side effects. Therefore, capecitabine or capecitabine-based combination therapies show unique advantages in the treatment of metastatic breast cancer. According to reports in the literature, when using capecitabine as first-line treatment for advanced breast cancer, the ORR was as high as 30-36%, and was 15-28% when used as the second-line treatment for anthracycline and/or taxane-resistant metastatic breast cancer patients (11-14). The ORR of docetaxel + capecitabine (TX), gemcitabine + capecitabine (GX), and vinorelbine + capecitabine (NX) combination therapies was 40-60% (15,16). The existing data thus support the suitability for long-term application. In China, a retrospective analysis by Huang et al. (3) evaluated capecitabine maintenance therapy (CMT) in recurrent or metastatic breast cancer patients after an initial response to a capecitabine combination chemotherapy with a median treatment duration of 3 months. The results showed that 32.2% of the patients had clinical benefits and 81% maintained the original therapeutic efficacy, with an MTTP of 4 months. However, as it was a single-arm study, no control data were available, and at present there are limited reports on CMT. Based on the single-arm research by Huang et al. (3), the present study was designed to further examine the efficacy and safety of CMT for metastatic breast cancer, with a non-capecitabine maintenance control group, after initial relief or stability was achieved with capecitabine-based combination therapy.

Patients and Methods

Study population

A total of 139 female advanced breast cancer patients who were treated at our hospital between March 2008 and May 2012 were included in this study. The inclusion criteria were 1) pathologically confirmed recurrent or metastatic breast cancer; 2) Karnofsky performance status (KPS) score of 80-100 and expected survival time > 6 months; 3) detectable response evaluation criteria in solid tumors (RECIST) (17); 4) treated with a capecitabine combination chemotherapy; 5) good compliance with the prescribed medication and regular follow-up; 6) signed informed consent. The research was approved by the Ethics Committee of the General Hospital of the Chinese People's Liberation Army and informed consent was obtained from all participants.

Therapy methods

All patients included in this study received 900-1000 mg / [m.sup.2] capecitabine (orally, twice a day on D1-14, combined with 70-75 mg / [m.sup.2] docetaxel (intravenous drip, D1; TX regimen), 900-1000 mg/m2 gemcitabine (intravenous drip, D1 and 8; GX regimen) or 20-25 mg / [m.sup.2] vinorelbine (intravenous drip, D1 and 8; NX regimen) based on their previous therapy and recurrence/metastasis status. The therapeutic efficacy was evaluated after every 2 of the 21day capecitabine chemotherapy cycles. Patients who completed 4-8 cycles and achieved disease control [complete relief (CR), partial relief (PR), or stable disease (SD)] were given CMT (50 patients), other maintenance treatments or no treatment (37 patients) based on the chemotherapy efficacies, adverse reactions and the willingness of the patients. Maintenance continued until disease progression or appearance of intolerable side effects.

Assessment of therapy efficacy

According to the RECIST, assessment of therapy efficacy can be divided into CR, PR, SD, and progression of disease (PD). Based on the common toxicity grading criteria of the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3 (NCICTC V3.0) (18), subacute, acute, and long-term adverse reactions were evaluated and classified as: 0 (none), I (minor reaction), II (moderate reaction), III (severe reaction), IV (serious life-threatening adverse reaction). The primary endpoint was time to progression (TTP) of disease beginning at the start of treatment, including death, or no disease progression at the last investigation. Secondary endpoints included the ORR (ORR = CR+PR), disease control rate (DCR=CR+PR+SD), and CBR (CBR = CR + PR + SD > 6 months) as well as safety.

Statistical methods

Intention-to-treat (ITT) and PP (per-protocol) analyses were used in this study; ITT analysis was used for the treatment of all subjects, while subjects for PP analysis were those who meet the inclusion criteria and strictly complied with the protocol.

The SPSS19.0 software (IBM, USA) was utilized for all statistical analyses, and measurement data are reported as median, while count data are reported as the rate of distribution and percentage. A chi-square test was used for the comparison between groups (Pearson [chi]2 test, two-tailed test, and a value of P < 0.05 was considered to be statistically significant). Kaplan-Meier curves were calculated for the survival analyses and a log-rank test was used to compare survival data. Multivariate Cox survival regression analysis was conducted using a backward stepwise method (the statistical level of significance determined with the Wald test was P < 0.05).

Results

ITT and PP analyses

In the ITT population, 91 patients received a first-line and 48 patients received a second-line chemotherapy or higher; 89 patients were treated with a TX, 45 patients with a GX, and 5 patients with an NX combination chemotherapy. The median number of chemotherapy cycles was 6 (1-45). In the PP population, 80 patients received a first-line and 43 patients a second-line chemotherapy or higher; 80 patients were given a TX, 39 patients a GX, and 4 patients an NX combination chemotherapy, including 8 who received a combined Herceptin therapy. The median number of chemotherapy cycles for the PP patients was 6 (2-8). In the PP population, PD did not develop in the 87 patients who completed 4-8 chemotherapy cycles, 50 of whom entered sequentially into the CMT group. The median number of maintenance treatment cycles was 5 (1-37); 6 patients had 16 or more cycles, and 12 patients had 10 or more.

The remaining 37 patients given the combined chemotherapies, who did not reach PD, and did not accept capecitabine maintenance treatment, were combined and included in the non-CMT group. According to the estrogen receptor/progesterone receptor (ER/PR) and Her-2 receptor status, previous treatments and patient agreement, 16 were given endocrine maintenance therapies, 6 received single agent chemotherapies such as gemcitabine or paclitaxel, 1 was medicated with a Herceptin treatment and 1 was treated with local radiotherapy. The other 13 patients did not continue any treatment.

Baseline characteristics of the CMT vs non-CMT groups

One hundred and thirty-nine patients met the initial inclusion criteria, including 50 cases in the CMT and 37 cases in non-CMT groups. No significant differences in baseline characteristics, such as the median age at registration, the median KPS score, menstrual status, the median age of definite diagnosis, the median diseasefree survival (DFS), postoperative pathologic staging, histological classification and grading, hormone receptor status, HER2, Ki-67, Luminal type (19), metastatic sites, number of metastatic lesions, and previous treatments were detected between the two groups (Table 1). Therefore, TTP, as well as ORR, DCR, CBR and safety were unbiased and comparable between the two groups.

Therapeutic efficacy

TTP. All of the 139 patients were assessable for the safety evaluation in this study, but 16 were lost to follow-up, leaving 123 patients for the efficacy evaluation. The overall TTP of these 123 patients from the beginning of the chemotherapy to disease progression was 6.05 months (95%CI = 4.92 - 7.17 months) The median duration of combination chemotherapy was 4.17 months (1.05 - 9.0 months), while the second line treatment MTTP of the 50 patients in the CMT group was 4.11 months (95%CI = 3.34 - 4.87 months), and for the non-CMT patients it was 2.0 months (95%CI = 1.63 - 2.38 months). There was a significant difference in therapeutic efficacy between CMT and non-CMT patients. The MTTP for the complete treatment was 9.43 months (95%CI = 8.3810.48 months), for the CMT group 4.5 months (95%CI = 4.22 - 4.78 months) P = 0.004, and for the non CMT group (Figure 1, Table 2), being about two times higher in the CMT patients.

Correlations between the MTTPs of the included patients with clinical features (ER/PR status, Her-2 status, menstrual status, DFS, with or without gut metastasis, number of metastatic lesions) were further analyzed and no correlation could be detected through multiple regression analyses (Table 2). As shown in Table 3, a multivariate Cox regression analysis demonstrated that the metastasis recurrence rate risks in the non-CMT group, second or more line chemotherapy and premenopausal patients were 2.676, 2.260, 1.905 times the CMT group.

ORR, CBR, and DCR outcomes of CMT and non-CMT medications. Comparisons of ORR and CBR in the CMT and non-CMT groups demonstrated that ORR was not significantly different (58 vs 51.4%), but that CBR was significantly better in the CMT patients (86 vs 54.1%; P = 0.001). Comparing first- and second-line treatments, the first-line therapy ORR outcome was 55% (twice that of the second-line treatment) and the first-line therapy CBR outcome was 63.8% (1.7 times that of the second-line treatment). Correlation analyses between ORR, DCR, and CBR with clinical pathological features demonstrated no correlations of ORR, DCR, CBR with ER/PR, Her-2 and menstrual status, DFS, with or without metastasis, and number of metastatic lesions (Table 4).

Safety analysis

All 139 patients who received at least one cycle of chemotherapy were assessable for a safety evaluation. The main adverse reactions in this study were gastrointestinal side effects (67.6%), decreased white blood cells (76.3%) and palmar-plantar erythrodysesthesia (PPE, 58.3%), and the incidence of grade III-IV severity of these adverse reactions in the combination chemotherapy were 7.2, 25.9, and 10.8%, respectively. In the 50 CMT patients, the incidence of gastrointestinal side effects, leukopenia and PPE was 66, 70, 64%, while the grade III-IV incidence of these adverse reactions was 4, 20, and 8%. In the nonCMT group, the incidence of gastrointestinal side effects, leukopenia and PPE was 67.6, 73, 62.2%; the incidence of grade III-IV events was 5.4,24.3, and 10.8%. Overall, there were no significant differences of the adverse reactions between the CMT and non-CMT groups (Table 5). In this study, therapy was discontinued in 8.6% of the patients due to adverse reactions (12 / 139), and dose reduction or dose delay of capecitabine was necessary in 3.6% (5/139). The frequency of dose adjustments in the CMT was 10% (5 / 50), including dose reduction or delay, which could be reversed after symptomatic treatments. During the study period, no patients died from therapy-related adverse reactions and no serious adverse events occurred.

[FIGURE 1 OMITTED]

Discussion

Chemotherapy plays an important role in the treatment of advanced breast cancer; the effectiveness of first-line combination chemotherapies is up to 60-80% (2,20,21). In the present study, we found that ORR, DCR and CBR of the first-line chemotherapy were 55.0, 91.3, and 63.8% and were 26.5, 79.1, and 37.2% for the second-line chemotherapy. The differences in outcome between first-and secondline chemotherapies achieved or almost achieved statistical significance (Table 4). On the other hand, there were various follow-up treatment strategies for metastatic breast cancer patients after response to combined chemotherapy: continuing combination chemotherapy until disease progression or intolerance, replacement of the therapy regimens, or maintenance therapy with a single agent used in the initial, combined chemotherapy. Research has shown that maintenance therapy could significantly prolong the MTTP (19 vs 8 months) compared with the control group in complete remission patients, but toxic side effects were also increased (22). Therefore, which chemotherapy drug should be chosen for maintenance therapy after initial treatment with a combination of drugs is still a clinical issue.

This study summarized the efficacy and safety of CMT in patients after initial disease control status using a first-line capecitabine-based combination chemotherapy. The results suggest that CMT resulted in a better therapeutic efficacy for advanced breast cancer treatments, with an MTTP of 9.43 months, which was longer than that of the non-CMT group (4.5 months, P = 0.004). While the ORRs in the two groups (58 vs 51.4%, P = 0.538) were well matched, 86% CMT patients, but only 54.1% in the non-CMT group (P = 0.001), enjoyed clinical benefits (CBR) for more than 6 months, which suggested that CMT can extend the therapeutic efficacy after an initial combination therapy. The MTTP of the 50 CMT patients was 4.11 months, while tumors of 3 patients (6%) continued to shrink, reaching PR; 38 patients (76%) maintained the therapeutic efficacy of the initial combined chemotherapy at the first evaluation. The ORR, DCR and CBR of 6, 82, 48%, respectively, were similar to those reported in the literature (3), and 6 patients continued the CMT for more than 1 year. Twelve patients who did not develop PD still continued CMT at the time of data cutoff.

The feasibility of using other drugs for maintenance treatment of recurrent or metastatic breast cancer should also be evaluated, because for metastatic breast cancer with positive hormone receptors (i.e., ER/PR), endocrine drugs can also be used for maintenance therapy. In addition, HER2-targeting drugs, such as trastuzumab and lapatinib have also been selected as maintenance therapy for breast cancer patients with positive HER2 receptors (23). A few prospective clinical trials have obtained results showing that continuous application of trastuzumab until disease progress offers clinical benefits, suggesting that the progression-free survival of patients can be prolonged with anti-HER2-targeted therapy after progression of the disease (24). In this study, 16 of the 37 non-CMT patients received an endocrine maintenance therapy consistent with their ER/PR and Her-2 receptor statuses. The hormone receptor-positive patients were first considered to accept chemotherapy in case of a failed previous endocrine therapy or a low ER/PR-positive ratio. If the benefit of an endocrine maintenance therapy was thought to be greater than or equal to chemotherapy, endocrine maintenance therapies were considered as first treatment choice, but the MTTP of these patients was only 2.27 months, which was significantly less than that of the CMT group. Based on our safety analysis of capecitabine as maintenance treatment, there were no significant differences of hematological and non-hematological toxicity between the CMT and non-CMT groups, which suggests that CMT did not increase toxicity effects, and has a favorable safety profile.

Taken together, we should first consider breast cancer as "chronic disease" for the development of treatment options and not only focus on first-line chemotherapy regimens, but also on maintenance therapies to be considered after response to first-line medications. Continuous maintenance therapy is recommended with a single chemotherapy agent being administered after initial response to combination chemotherapy. Furthermore, anti-tumor treatment is long-term medication, and the choice of drugs should be based on patient compliance. Therefore, the ideal chemotherapy drug should be effective as monotherapy, the toxicity should be low, and it should be easy to use over the long term, like the oral capecitabine used in this study. A limitation of this analysis is the small sample size, but the results warrant additional phase III clinical trials and comparison with alternative, effective maintenance therapy drugs.

In summary, CMT extended the therapeutic efficacy of primary, combined chemotherapy, and ensured good quality of life for patients, thereby making it a new option for a second-line maintenance medication for advanced breast cancer therapy.

http://dx.doi.org/10.1590/1414-431X20133168

Received April 16, 2013. Accepted August 21, 2013. First published online November 25, 2013.

Acknowledgments

We thank all the staff from Department of Medical Oncology, General Hospital of the Chinese People's Liberation Army (PLAGH), for their support. Research supported by grants from the Wu Jieping Fund (#320.6752.1230).

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*These authors contributed equally to this study.

Correspondence: S.C. Jiao and/or J.L. Yang, Department of Medical Oncology, General Hospital of the Chinese People's Liberation Army (PLAGH), No. 28 Fuxing Road, Haidian District, Beijing, 100853, China. Fax: +86- 10-6823-8924. E-mail: jiaoshunchangBM@163.com and/or yangjunlanBM@163.com

W. Si [1,2], Y.Y. Zhu [1], Y. Li [1], P. Gao [1], C. Han [1], J.H. You [1], R.X. Linghu [1], S.C. Jiao [1] and J.L. Yang [1]

[1]Department of Medical Oncology, General Hospital of the Chinese People's Liberation Army, Haidian District, Beijing, China

[2]School of Medicine, Nankai University, Tianjin, China
Table 1. Baseline characteristics of the capecitabine maintenance
therapy (CMT) and the non-CMT groups.

Baseline characteristics CMT Non-CMT
in patients without PD

Number 50 37
Median age at registration 44 (24-69) 46 (34-64)
 / years (range)
Median KPS score 90 (80, 90) 90 (80, 100)
 90-100 45 (90%) 33 (89.2%)
 80 5 (10%) 4 (10.8%)
Menstrual status
 Premenopausal 35 (70%) 26 (70.3%)
 Postmenopausal 15 (30%) 11 (29.7%)
Median definite diagnosis 40.5 (22-60) 42 (30-63)
 / years (range)
 < 35 14 (28%) 6 (16.2%)
 [greater than 36 (72%) 31 (83.8%)
 or equal to] 35
Median DFS/months (range) 45.2 (1.5-189.4) 36.6 (10.7-95.8)
Postoperative
 pathological staging
 I 2 (4%) 5 (13.5%)
 II 16 (32%) 12 (32.4%)
 III 17 (34%) 9 (24.3%)
 IV 10 (20%) 6 (16.2%)
 Not clear 5 (10%) 5 (13.5%)
Histological classification
 Invasive ductal carcinoma 45 (90%) 33 (89.2%)
 Invasive lobular carcinoma 1 (2%) 1 (2.7%)
 Other 4 (8%) 3 (8.1%)
Histological grading
 I 1 (2%) 0 (0%)
 I-II 0 (0%) 1 (2.7%)
 II 10 (20%) 10 (27%)
 II-III 3 (6%) 0 (0%)
 III 14 (28%) 9 (24.3%)
 No grading 22 (44%) 17 (45.9%)
Hormone receptor status
 Positive 35 (70%) 29 (78.4%)
 Negative 15 (30%) 8 (21.6%)
Her-2 status
 Positive 18 (36%) 12 (32.4%)
 Negative 29 (58%) 23 (62.2%)
 Unknown 3 (6%) 2 (5.4%)
Ki-67
 < 25 14 (28%) 7 (18.9%)
 25-50 5 (10%) 4 (10.8%)
 50-75 3 (6%) 2 (5.4%)
 > 75 4 (8%) 4 (10.8%)
 Unknown 24 (48%) 20 (54.1%)
Luminal type*
 A 8 (16%) 5 (13.5%)
 B1 19 (38%) 18 (48.6%)
 B2 9 (18%) 7 (18.9%)
 Her-2 9 (18%) 5 (13.5%)
 Basal 5 (10%) 2 (5.4%)
Metastatic sites
 Gut metastasis 31 (62%) 27 (73%)
 No gut metastasis 19 (38%) 10 (27%)
 Lung 22 (44%) 16 (43.2%)
 Liver 16 (32%) 12 (32.4%)
 Brain 5 (10%) 4 (10.8%)
 Bone 34 (68%) 23 (62.2%)
 Lymph node 17 (34%) 15 (40.5%)
 Walls of the chest 8 (16%) 6 (16.2%)
Number of metastatic lesions
 1 23 (46%) 12 (32.4%)
 2 11 (22%) 10 (27%)
 3 11 (22%) 9 (24.3%)
 > 4 5 (10%) 6 (16.3%)
Previous treatment
 Antharcycline 42 (84%) 33 (89.2%)
 Taxanes 37 (74%) 25 (67.6%)
 Antharcycline and 33 (66%) 23 (62.2%)
 taxanes

Data are reported as number (%) or median (range).
PD: progression of disease; KPS: Karnofsky performance status; DFS:
disease-free survival. Luminal A: eR / PR+, HER2 -, Ki - 67#14%,
Luminal B: ER / PR +, HER2 -, Ki - 67 [less than or equal to] 14%
or ER/PR +, HER2 + . Her - 2: ER -, PR -, HER2 +, Basal-like: ER -,
PR -, HER2 -. There were no significant differences between the
groups (P > 0.05, Pearson chi-square test).

Table 2. Correlation of MTTP with
clinical pathological characteristics.

Sub-group N MTTP (months)

With/without CMT
 CMT 50 9.43
 Non-CMT 37 4.50
First line/multiple-line chemotherapy
 First-line chemotherapy 80 7.33
 Second- or multiple-line chemotherapy 43 4.99
ER/PR level
 Positive 87 6.18
 Negative 36 5.95
Her-2 level
 Positive 47 6.18
 Negative 70 5.95
 Unknown 6
Menstrual status
 Premenopausal 83 7.00
 Postmenopausal 40 5.26
DFS
 [less than or equal to] 3 years 49 5.55
 > 3 years 54 6.31
 Palliative treatments 20
With/without gut metastasis
 Without 34 8.05
 With 89 5.59
Number of metastatic lesions
 [less than or equal to] 2 76 5.95
 > 2 47 6.18

Sub-group P HR 95%CI

With/without CMT 0.004 1.95 1.24-3.07
 CMT
 Non-CMT
First line/multiple-line chemotherapy 0.056 1.46 0.99-2.15
 First-line chemotherapy
 Second- or multiple-line chemotherapy
ER/PR level 0.179 1.32 0.88-1.99
 Positive
 Negative
Her-2 level 0.495 1.14 0.78-1.68
 Positive
 Negative
 Unknown
Menstrual status 0.455 1.16 0.79-1.71
 Premenopausal
 Postmenopausal
DFS 0.126 1.37 0.92-2.05
 [less than or equal to]3 years
 > 3 years
Palliative treatments
With/without gut metastasis 0.147 1.37 0.90-2.08
Without
With
Number of metastatic lesions 0.510 1.14 0.78-1.66
 [less than or equal to]2
 >2

MTTP: median time to progression; CMT: capecitabine maintenance
therapy; ER / PR: estrogen receptor/progesterone receptor; DFS:
disease-free survival. The Log-rank test was used for analyses.

Table 3. Multivariate Cox regression analysis
of median time to progression.

Clinicopathological Wald RR P 95%CI
 characteristics

With/without capecitabine 12.994 2.676 0.000 1.567-4.569
 maintenance therapy
First-line/multiple-line 6.379 2.260 0.012 1.200-4.254
 chemotherapy
Menstrual status 3.888 1.905 0.049 1.004-3.614

Table 4. Correlation analysis between ORR,
DCR and CBR with clinical pathological characteristics.

Sub-group ORR n/N P DCR n/N

With/without CMT 0.538
 With CMT 58.0 29/50
 Without CMT 51.4 19/37
First-line/multiple 0.002
 -line chemotherapy
 First-line 55.0 44/80 91.3 73/80
 Second- or multiple-line 26.5 11/43 79.1 34/43
 chemotherapy
ER/PR level 0.969
 Positive 44.8 39/87 87.4 76/87
 Negative 44.4 16/36 86.1 31/36
Her-2 level 0.912
 Positive 44.7 21/47 87.2 41/47
 Negative 45.7 32/70 85.7 60/70
Menstrual status 0.965
 Premenopausal 44.6 37/83 86.7 72/83
 Postmenopausal 45.0 18/40 87.5 35/40
DFS 0.590
 [less than or equal to] 42.0 21/49 83.7 41/49
 3 years
 > 3 years 48.1 26/54 87.0 47/54
With/without 0.626
 gut metastasis
 Without 41.2 14/34 91.2 31/34
 With 46.1 41/89 85.4 76/89
Number of metastatic 0.995
 lesions
 [less than or equal to] 2 44.7 34/76 21 67/76
 > 2 44.7 21/47 85.3 40/47

Sub-group P CBR n/N P

With/without CMT 0.001
 With CMT 86.0 43/50
 Without CMT 54.1 20/37
First-line/multiple 0.056 0.005
 -line chemotherapy
 First-line 63.8 51/80
 Second- or multiple-line 37.2 16/43
 chemotherapy
ER/PR level 0.852 0.877
 Positive 54.0 47/87
 Negative 55.6 20/36
Her-2 level 0.815 0.788
 Positive 53.2 25/47
 Negative 55.7 39/70
Menstrual status 0.907 0.489
 Premenopausal 56.6 47/83
 Postmenopausal 50.0 20/40
DFS 0.629 0.645
 [less than or equal to] 51.0 25/49
 3 years
 > 3 years 55.6 30/54
With/without 0.394 0.159
 gut metastasis
 Without 64.7 22/34
 With 50.6 45/89
Number of metastatic 0.625 0.223
 lesions
 [less than or equal to] 2 55.3 42/76
 > 2 53.2 25/47

ORR: objective response rate; DCR: disease control rate;
CBR: clinical benefit rate; CMT: capecitabine maintenance
therapy; ER/PR: estrogen receptor/progesterone receptor;
DFS: disease-free survival. The Pearson chi-square test
was used for analyses.

Table 5. Therapy-related adverse reactions.

Classification of adverse CMT (n=50) non-CMT (n=37)

 reactions n (%) III/IV (%) n (%)

Adverse reactions of
 the hematological system
 Leukopenia 35 (70%) 10 (20%) 27 (73%)
 Decrease of platelets 6 (12%) 1 (2%) 5 (13.5%)
Non-hematological
 adverse reactions
 Gastrointestinal side 33 (66%) 2 (4%) 25 (67.6%)
 effects
 Abnormal liver function 3 (6%) 1 (2%) 3 (8.1%)
 PPE 32 (64%) 4 (8%) 23 (62.2%)

Classification of adverse non-CMT (n=37) P
 reactions
 III/IV (%) n III/IV

Adverse reactions of
 the hematological system
 Leukopenia 9 (24.3%) 0.762 0.629
 Decrease of platelets 1 (2.7%) 0.834 0.829
Non-hematological
 adverse reactions
 Gastrointestinal side 2 (5.4%) 0.966 0.757
 effects
 Abnormal liver function 0 (0%) 0.701 0.387
 PPE 4 (10.8%) 0.860 0.654

CMT: capecitabine maintenance therapy; III/IV: grade III/IV
leukopenia; PPE: palmar-plantar erythrodysesthesia. The
Pearson chi-square test was used for statistical analyses.
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Author:Si, W.; Zhu, Y.Y.; Li, Y.; Gao, P.; Han, C.; You, J.H.; Linghu, R.X.; Jiao, S.C.; Yang, J.L.
Publication:Brazilian Journal of Medical and Biological Research
Article Type:Report
Geographic Code:9CHIN
Date:Dec 1, 2013
Words:5593
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