Efficacy of capecitabine in patients with locally advanced or metastatic breast cancer with or without prior treatment with fluoropyrimidine: a retrospective study

Efficacy of capecitabine in patients with locally advanced or metastatic breast cancer with or... Purpose We conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs). Methods The charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use). Results Overall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02–1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67–1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32–1.67 (short RFI), and 1.00–1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups. Conclusions Extra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence. Keywords Breast neoplasms · Capecitabine · Efficacy · Safety · Fluoropyrimidine Introduction Breast cancer is the most common cause of death from can- cer in female patients [1]. Although the early breast cancer is curable with resection with or without neoadjuvant or adjuvant treatment, advanced breast cancer (ABC) remains Electronic supplementary material The online version of this incurable. Chemotherapy is one of the important treatment article (https ://doi.org/10.1007/s0028 0-018-3617-5) contains options to achieve the goal for ABC, which is to prolong supplementary material, which is available to authorized users. survival and to maintain quality of life. While anthracy- clines and taxanes are used for the first-line chemotherapy * Akihiko Shimomura ashimomu@ncc.go.jp for ABC, in addition to their usage in neoadjuvant and adju- vant settings, no single standard regimen exists after failure Department of Breast and Medical Oncology, National of these agents [2]. Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Capecitabine is an orally available fluoropyrimidine Tokyo 104-0045, Japan 2 (FP), and a prodrug of 5-fluorouracil (5-FU). It is designed Keio University Graduate School of Medicine, 35 to deliver 5-FU preferentially to tumor tissue to enhance Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology efficacy, and reduce toxicities in the gastrointestinal tract and followed by a 7-day rest period in a 21-day cycle, (2) bone marrow. Its route of administration and its favorable 850 mg/m twice daily for 21 days, followed by a 7-day rest toxicity profile, with little alopecia and neuropathy, make it period in a 28-day cycle. The dosing was adjusted according an attractive option for some patients. Phase II trials have to modifications recommended by the FDA [ 14], by adverse revealed the efficacy and safety of capecitabine for ABC events, or as per the physicians’ judgment. Treatment cycles after failure of anthracyclines and taxanes [3–6]. Moreo- were repeated until disease progression or unacceptable tox- ver, a phase III trial has shown the benefit of capecitabine icity, or until the patients’ wish to terminate treatment. in combination with lapatinib in human epidermal growth factor receptor 2 [HER2]-positive patients [7]. Capecitabine Assessment is also often used as a comparator in phase III trials [8, 9]. In addition to capecitabine, other FPs such as 5-FU, Tumor response was assessed according to the Response tegafur-uracil (UFT), and doxifluridine have been used in Evaluation Criteria in Solid Tumors, version 1.1 [15] by neoadjuvant and adjuvant therapies for breast cancer. As computed tomography scans. Confirmation of response was such, some patients with ABC receiving capecitabine have not required. Response rate (RR) was defined as the propor - a previous history of treatment with other FPs. Re-challenge tion of patients who achieved complete or partial response, of chemotherapeutic agents has been assessed in other can- while disease control rate (DCR) was defined as the propor - cers [10–12]. However, aside from a few studies providing tion of patients who achieved complete, partial, or stable limited results, separately assessing patients either with or disease as best response. Progression-free survival (PFS) without prior use of FPs [4, 13], the efficacy of capecitabine was defined as the time from the initiation of capecitabine in patients with ABC who have received FPs for the early monotherapy, until either clinical or objective disease pro- breast cancer has not been studied sufficiently. gression, or death. Overall survival (OS) was defined as the Therefore, we conducted a retrospective study to assess time from the initiation of capecitabine monotherapy until the efficacy and safety of capecitabine in patients with ABC death. Relapse-free interval (RFI) was defined as the time with or without prior treatment with FPs. from definitive surgery for breast cancer until recurrence. Adverse events (AEs) were assessed according to the Com- mon Terminology Criteria for Adverse Events, version 4.0. Patients and methods Statistical analysis Patients The study was designed to compare the efficacy (RR, DCR, We reviewed the medical records of patients with patho- PFS, and OS) and safety (frequency of grade 3 or worse logically confirmed locally advanced or metastatic breast AEs, AEs requiring hospitalization, and discontinuation cancer, with the previous treatment with surgery of curative due to AEs) of capecitabine between the FP group and the intent. All patients had undergone palliative chemotherapy non-FP group. Nominal variables and continuous variables with capecitabine as monotherapy between July 2008 and were compared by Fisher’s exact test and the Mann–Whitney December 2016 at the National Cancer Center Hospital U test, respectively. Only patients with target lesions were (Tokyo, Japan). Patients who had received FP-containing analyzed for RR and DCR. Survival curves were obtained regimens as neoadjuvant or adjuvant therapy before capecit- by the Kaplan–Meier method, and differences between the abine were assigned to the FP group; patients who had never two groups were assessed by the log-rank test. Hazard ratios received FPs were assigned to the non-FP group. Patients (HRs) and confidence intervals (CIs) were estimated by the who received more than one FP before capecitabine, who Cox proportional hazards model. Baseline characteristics received FPs for purposes other than perioperative (neoad- with p value < 0.10 in univariate analysis were adjusted for juvant or adjuvant) therapy, and those with insufficient base- in multivariate analysis. HRs were adjusted for additional line data were excluded from the analysis. This study was baseline characteristics in various multivariate analysis mod- approved by the National Cancer Center Institutional Review els. HRs were also estimated for subgroups by biomarkers: Board (No. 2016-491). Because this study was retrospective the triple-negative subgroup, the hormone-positive sub- in nature, written informed consent was not obtained. This group, and the hormone-negative subgroup. To assess the study was publicized via the web page of the hospital. impact of prior use of FPs on survival outcomes by RFI, HRs for PFS and OS were also estimated separately for short Treatment RFI and long RFI. Continuous variables were divided into two groups at median. Tests were considered significant if Patients received oral capecitabine by one of the following the two-sided p value was < 0.05. Analyses were performed dosing regimens: (1) 1250 mg/m twice daily for 14 days, with EZR software (Saitama Medical Center, Jichi Medical 1 3 Cancer Chemotherapy and Pharmacology University, Saitama, Japan), which is a graphical user inter- Table 1 Patient characteristics face for R (The R foundation for Statistical Computing, FP Non-FP p value Vienna, Austria) [16]. n 105 183 Age  Median [range] 60 [25–84] 59 [32–81] 0.361 Results ECOG PS  0 (%) 46 (43.8) 85 (46.4) 0.246 Patients  1 (%) 50 (47.6) 91 (49.7)  2 (%) 9 (8.6) 7 (3.8) Overall, 288 patients were included in the analysis: 105 were Biomarker included in the FP group and 183 in the non-FP group (Sup-  ER (%) 84 (80.0) 149 (81.4) 0.758 plementary Fig. 1). Baseline patient characteristics did not  PgR (%) 76 (72.4) 129 (70.5) 0.788 differ significantly between the two groups (Table  1). The  HER2 (%) 6 (5.8) 6 (3.3) 0.365 median age was 60 (range 25–84) years in the FP group Organs involved and 59 (range 32–81) years in the non-FP group (p = 0.361).  Bone (%) 64 (61.0) 102 (55.7) 0.457 The median number of the previous lines of chemotherapy  Liver (%) 53 (50.5) 105 (57.4) 0.270 for advanced disease was 1 (range 0–4; p = 0.182) in both  Lymph node (%) 46 (43.8) 84 (45.9) 0.806 groups. The median RFI was 3.85 (range 0.27–20.11) years  Lung (%) 46 (43.8) 79 (43.2) 1.000 in the FP group and 4.24 (range 0.27–27.07) years in the No. of organs involved non-FP group (p = 0.369). In the FP group, 86 (81.9%), 8  Median [range] 2 [1–5] 2 [1–7] 0.067 (7.6%), and 11 (10.5%) patients had received 5-FU, UFT, Previous treatment and doxifluridine, respectively, for a neoadjuvant or adju -  Endocrine therapy 88 (83.8) 151 (82.5) 0.871 vant therapy. The initial diagnosis (preoperative, clinical) (%) was stages I, II, and III in 10 (13.0%), 45 (58.4%), and  Anthracycline (%) 91 (86.7) 154 (84.2) 0.610 22 (28.6%) patients in the FP group, respectively, and 16  Taxane (%) 100 (95.2) 168 (91.8) 0.340 (10.5%), 107 (70.4%), and 29 (19.1%) patients in the non-FP No. of Cx lines group, respectively (p = 0.175). The median follow-up time  Median [range] 1 [0–4] 1 [0–4] 0.182 was 12.5 (range 0.1–95.6) months. RFI (years)  Median [range] 3.85 [0.27–20.11] 4.24 [0.27–27.07] 0.369 Progression‑free survival and overall survival Stage  I 10 (13.0) 16 (10.5) 0.175 The PFS period was significantly shorter in the FP group  II 45 (58.4) 107 (70.4) than in the non-FP group (median 4.6 vs 5.9 months; HR for  III 22 (28.6) 29 (19.1) the FP group compared with the non-FP group: 1.33; 95% FP type CI 1.03–1.72, p = 0.029; Fig.  1). In multivariate analysis  5-FU 86 (81.9) – adjusting for baseline characteristics selected by univariate  UFT 8 (7.6) – analysis (age, Eastern Cooperative Oncology Group [ECOG]  Doxifluridine 11 (10.5) – performance status [PS], estrogen receptor [ER], number Capecitabine schedule [No.] of organs involved, previous endocrine therapy, previ-  21 days/cycle 63 (60.0) 98 (53.6) 0.325 ous taxane use, and RFI), PFS was worse in the FP group  28 days/cycle 42 (40.0) 85 (46.4) than in the non-FP group (HR 1.33; 95% CI 1.02–1.73; p = 0.036; Table 2). The median OS was 21.3 months in the FP fluoropyrimidine, ECOG Eastern Cooperative Oncology Group, PS performance status, ER estrogen receptor, PgR progesterone FP group and 23.9 months in the non-FP group (HR 1.17; receptor, HER2 human epidermal growth factor receptor 2, Cx chem- 95% CI 0.84–1.63; p = 0.344). The HR adjusted for baseline otherapy, RFI relapse-free interval, 5-FU 5-fluorouracil, UFT tegafur/ characteristics selected by univariate analysis (age, ECOG uracil PS, ER, HER2, bone metastasis, liver metastasis, No. of a For advanced disease organs involved, previous therapy [endocrine, anthracycline, Preoperative clinical stage and taxane], RFI, and preoperative stage) was 1.00 (95% CI 0.67–1.50; p = 0.994; Table 3). Of note, preoperative stage baseline characteristics: liver and lung metastasis, all bio- was not selected by univariate analysis for multivariate anal- ysis of PFS; it was selected for multivariate analysis of OS. marker characteristics, all previous treatment characteristics, and age ≥ 35 vs < 35 instead of ≥ 60 vs < 60 (considering The HRs for PFS and OS largely did not change in addi- tional multivariate models further adjusting for different that age < 60 was associated with worse PFS and OS than 1 3 Cancer Chemotherapy and Pharmacology ab Median (95% CI)HR (95% CI) p Median (95% CI)HR (95% CI) p 1.0 1.0 FP 4.6 (3.5-5.7)1.33 (1.03-1.72) 0.029 FP 21.3 (12.5-33.1)1.17 (0.84-1.63) 0.344 Non-FP 5.9 (5.0-6.8) Non-FP 23.9 (21.0-28.4) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 010203040 020406080 Time (months) Time (months) FP 1050 23 32 FP 1050 30 53 Non-FP 1833 57 12 7 Non-FP 1832 67 24 8 Number at risk Number at risk Fig. 1 Kaplan–Meier curves of a progression-free survival, b overall survival. FP fluoropyrimidine, HR hazard ratio, CI confidence interval was age < 60 in univariate analysis, and that age ≥ 35 has frequent cause of discontinuation due to AEs in both groups been reported to be a negative prognostic factor for the early (2.9 vs 2.7%). There were no treatment-related deaths. The breast cancer, although its prognostic effect is still unclear in frequencies of dose interruptions and reductions did not dif- an advanced disease setting [17]) (Supplementary Table 1). fer significantly between the two groups (dose interruptions Prior FP use was not linked to PFS and OS, in the analysis 44.8 vs 53.0%, p = 0.221; dose reductions 39.0 vs 49.7%, performed according to biomarker status (Supplementary p = 0.087). Table 2). The HRs for PFS and OS in the FP group compared with the non-FP group were also estimated separately for short Discussion RFI and long RFI, with a cutoff at 4 years (median RFI) (Table 4). The multivariate-adjusted HRs for PFS were 1.56 In this study, we retrospectively evaluated the efficacy and (95% CI 1.06–2.28; p = 0.025) with short RFI, and 1.11 safety of capecitabine monotherapy for the treatment of (95% CI 0.76–1.60; p = 0.597) with long RFI. The multi- ABC in patients who had received other FPs for neoadjuvant variate-adjusted HRs for OS were 1.23 (95% CI 0.68–2.21; or adjuvant therapy. Although OS did not differ significantly p = 0.489) with short RFI, and 0.77 (95% CI 0.40–1.47; with prior FP use, PFS was worse in patients with prior FP p = 0.427) with long RFI. A trend for larger HRs for PFS use. The detrimental effect of prior FP use on survival out- and OS in the FP group with short RFI than in that with comes seemed larger in patients with the early recurrence long RFI was also observed with different cutoffs of RFI after surgery than in those with late recurrence. The safety (Supplementary Table 3). profile did not differ significantly by prior FP use. In addition to its use in ABC, the efficacy of capecitabine Tumor response has been explored in the early breast cancer treatment. A recent meta-analysis of randomized-controlled studies dem- Tumor response among patients with target lesions is onstrated that addition of capecitabine to standard chemo- shown in Supplementary Table 4. The RR (FP vs non-FP) therapy improves survival outcomes in the early breast was 13.8 vs 21.0% (p = 0.173) and DCR was 54.0 vs 59.9% cancer, particularly in triple-negative breast cancer [18]. In (p = 0.418). addition to the clinical trial CREATE-X, which showed the efficacy of adjuvant capecitabine in patients with residual Safety disease after neoadjuvant chemotherapy [13], several other trials evaluating adjuvant capecitabine in high-risk patients Table 5 shows the frequency of AEs by group. There was no are ongoing [18]. Such studies may lead to incorporation of significant difference between the two groups in grade 3 or capecitabine into the standard perioperative treatment. The worse AEs, AEs requiring hospitalization, or treatment dis- current study did not assess patients who had used capecit- continuation due to AEs. Hand–foot syndrome was the most abine as perioperative FP. Nevertheless, given the efficacy 1 3 Progression-free Survival Probability Overall Survival Probability Cancer Chemotherapy and Pharmacology Table 2 Univariate and Univariate Multivariate multivariate analyses of progression-free survival HR (95% CI) p value HR (95% CI) p value Age  ≥ 60 vs < 60 0.72 (0.56–0.92) 0.009 0.76 (0.59–0.99) 0.046 ECOG PS  1 vs 0 1.28 (1.00–1.65) 0.052 1.19 (0.92–1.54) 0.184  2 vs 0 1.89 (1.06–3.36) 0.031 1.60 (0.89–2.88) 0.116 ER  + vs − 0.64 (0.47–0.87) 0.004 0.94 (0.58–1.53) 0.813 PgR  + vs − 1.04 (0.79–1.37) 0.773 HER2  + vs − 1.48 (0.81–2.72) 0.204 Bone metastasis  + vs − 1.07 (0.83–1.38) 0.594 Liver metastasis  + vs − 1.14 (0.89–1.46) 0.300 Lymph node metastasis  + vs − 1.20 (0.94–1.54) 0.142 Lung metastasis  + vs − 1.15 (0.89–1.47) 0.281 No. of metastatic organs  ≥ 2 vs < 2 1.39 (1.00–1.94) 0.050 1.47 (1.02–2.11) 0.037 Endocrine therapy  + vs − 0.62 (0.45–0.86) 0.004 0.59 (0.35–0.98) 0.042 Anthracycline  + vs − 1.33 (0.93–1.88) 0.115 Taxane  + vs − 1.59 (0.94–2.69) 0.081 1.25 (0.73–2.14) 0.412 No. of Cx lines  ≥ 1 vs < 1 1.09 (0.82–1.43) 0.563 FP  FP vs non-FP 1.33 (1.03–1.72) 0.030 1.33 (1.02–1.73) 0.036 RFI (years)  Continuous (per year) 0.99 (0.96–1.01) 0.299  ≥ 4 vs < 4 0.73 (0.57–0.93) 0.012 0.85 (0.64–1.11) 0.229 Stage  II vs I 1.05 (0.67–1.63) 0.833  III vs I 0.85 (0.51–1.41) 0.527 Capecitabine schedule  28 vs 21 days 1.10 (0.86–1.41) 0.464 Cox proportional hazards model. Covariates with p value < 0.10 were adjusted in multivariate analysis HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, PS performance sta- tus, ER estrogen receptor, PgR progesterone receptor, HER2 human epidermal growth factor receptor 2, Cx chemotherapy, FP fluoropyrimidine, RFI relapse-free survival For advanced disease Preoperative clinical stage of FPs as perioperative therapies as well as in advanced dis- treatment options in patients with ABC after perioperative ease, our results provide insights for clinicians considering FPs. 1 3 Cancer Chemotherapy and Pharmacology Table 3 Univariate and Univariate Multivariate multivariate analyses of overall survival HR (95% CI) p value HR (95% CI) p value Age  ≥ 60 vs < 60 0.71 (0.52–0.98) 0.037 0.95 (0.65–1.40) 0.802 ECOG PS  1 vs 0 2.01 (1.44–2.81) < 0.001 2.22 (1.51–3.27) < 0.001  2 vs 0 4.96 (2.57–9.57) < 0.001 6.89 (3.11–15.29) < 0.001 ER  + vs − 0.62 (0.43–0.89) 0.011 0.35 (0.16–0.75) 0.007 PgR  + vs − 0.93 (0.66–1.31) 0.673 HER2  + vs − 1.93 (0.94–3.95) 0.073 3.82 (1.53–9.52) 0.004 Bone metastasis  + vs − 1.39 (1.00–1.92) 0.047 1.23 (0.79–1.93) 0.365 Liver metastasis  + vs − 1.62 (1.18–2.23) 0.003 1.75 (1.12–2.75) 0.014 Lymph node metastasis  + vs − 1.30 (0.95–1.79) 0.100 Lung metastasis  + vs − 0.85 (0.61–1.17) 0.314 No. of metastatic organs  ≥ 2 vs < 2 1.73 (1.11–2.69) 0.015 1.29 (0.72–2.32) 0.385 Endocrine therapy  + vs − 0.61 (0.41–0.91) 0.016 1.15 (0.53–2.48) 0.722 Anthracycline  + vs − 1.49 (0.93–2.38) 0.098 0.78 (0.42–1.46) 0.441 Taxane  + vs − 1.92 (0.90–4.11) 0.093 1.37 (0.45–4.19) 0.580 No. of Cx lines  ≥ 1 vs < 1 0.93 (0.66–1.31) 0.687 FP  FP vs non-FP 1.17 (0.84–1.63) 0.345 1.00 (0.67–1.50) 0.994 RFI (years)  Continuous (per year) 0.97 (0.94–1.01) 0.123  ≥ 4 vs < 4 0.71 (0.52–0.98) 0.035 0.98 (0.66–1.46) 0.914 Stage  II vs I 1.67 (0.93–3.00) 0.084 1.57 (0.84–2.92) 0.160  III vs I 1.21 (0.62–2.37) 0.570 1.05 (0.51–2.16) 0.901 Capecitabine schedule  28 vs 21 days 1.08 (0.79–1.49) 0.634 Cox proportional hazards model. Covariates with p value < 0.10 were adjusted in multivariate analysis HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, PS performance sta- tus, ER estrogen receptor, PgR progesterone receptor, HER2 human epidermal growth factor receptor 2, Cx chemotherapy, FP fluoropyrimidine, RFI relapse-free survival For advanced disease Preoperative clinical stage Capecitabine may be less effective in patients with prior adjusting for baseline characteristics. In addition, capecit- FP use. In this study, PFS was significantly worse in the FP abine appears to be slightly less active after the use of FPs, group, which was confirmed by various multivariate models as shown in subgroup analyses reported in a limited number 1 3 Cancer Chemotherapy and Pharmacology Table 4 Univariate and multivariate analyses of progression-free and Table 5 Adverse events of Grade 3 or higher overall survival for the FP group compared with the non-FP group by FP Non-FP p value relapse-free survival n 105 183 RFI (years) Univariate Multivariate All (%) 27 (25.7) 51 (27.9) 0.783 HR (95% CI) p value HR (95% CI) p value Hematological (%) 17 (16.2) 30 (16.4) 1.000 PFS Leukopenia (%) 2 (1.9) 12 (6.6) 0.092  < 4 1.49 (1.02–2.18) 0.037 1.56 (1.06–2.28) 0.025 Neutropenia (%) 9 (8.6) 15 (8.2) 1.000  ≥ 4 1.19 (0.83–1.70) 0.344 1.11 (0.76–1.60) 0.597 Anemia (%) 4 (3.8) 9 (4.9) 0.775 OS Thrombocytopenia (%) 4 (3.8) 5 (2.7) 0.728  < 4 1.28 (0.81–2.04) 0.288 1.23 (0.68–2.21) 0.489 Febrile neutropenia (%) 1 (1.0) 2 (1.1) 1.000  ≥ 4 1.01 (0.63–1.62) 0.959 0.77 (0.40–1.47) 0.427 Nonhematological (%) 16 (15.2) 31 (16.9) 0.743 Fatigue (%) 0 (0.0) 0 (0.0) NA Cox proportional hazards model Anorexia (%) 2 (1.9) 1 (0.5) 0.301 FP fluoropyrimidine, RFI relapse-free survival, HR hazard ratio, CI Nausea (%) 1 (1.0) 1 (0.5) 1.000 confidence interval, PFS progression-free survival, OS overall sur - vival Vomiting (%) 0 (0.0) 1 (0.5) 1.000 Adjusting for covariates with p value < 0.10 in univariate analysis Diarrhea (%) 1 (1.0) 2 (1.1) 1.000 except for RFI < 4 vs ≥ 4 years Mucositis (%) 0 (0.0) 1 (0.5) 1.000 HFS (%) 6 (5.7) 5 (2.7) 0.217 Bilirubin increased (%) 1 (1.0) 2 (1.1) 1.000 of the previous studies. In one trial, the response rate of AST increased (%) 7 (6.7) 14 (7.7) 0.818 capecitabine for ABC was 13% in patients with prior 5-FU ALT increased (%) 8 (7.6) 15 (8.2) 1.000 use and 18% (p = 0.48) in those without prior 5-FU use [4]. Creatinine increased (%) 0 (0.0) 0 (0.0) NA Moreover, in the CREATE-X trial, the HR for disease-free a b Other (%) 1 (1.0) 2 (1.1) 1.000 survival with adjuvant capecitabine compared with control c d Hospitalization (%) 3 (2.9) 4 (2.2) 0.708 was 0.75 (95% CI 0.53–1.05) with prior 5-FU use, and 0.63 e f Discontinuation (%) 3 (2.9) 6 (3.3) 1.000 (95% CI 0.40–0.99) without prior 5-FU use (p = 0.56) [13]. Although capecitabine may remain as a treatment option for FP fluoropyrimidines, HFS hand–foot syndrome, AST aspartate ami- ABC pretreated with FPs based on the absence of significant notransferase, ALT alanine aminotransferase, NA not assessed OS differences by prior FP use, we should be aware that it Lung infection grade 3 may be less active in ABC patients with prior FP use than Lung infection grade 3 and enterocolitis infectious grade 3 in those without prior FP use. Lung infection grade 3 and anorexia grade 3 (2 patients) The effect of prior FP use seemed to differ between the d Lung infection grade 3, enterocolitis infectious grade 3, diarrhea early recurrence (short RFI) and late recurrence (long RFI). grade 3, and mucositis grade 3 We used RFI to compare patients with prior FP use and those Hand–foot syndrome grade 3 (2 patient), hand–foot syndrome grade without prior FP use. The previous studies that assessed re- Hand–foot syndrome grade 3 (2 patient), hand–foot syndrome grade challenge with a chemotherapeutic agent in other cancers 2 (3 patients), diarrhea grade 3 reported that drug-free interval (time since last administra- tion of the drug until relapse) is predictive of the efficacy of re-challenge [10–12]. However, drug-free interval may early recurrence indicates failure of perioperative treatment be dependent upon the nature of the tumor (aggressive or including FPs, in which case inefficacy of capecitabine could indolent). In addition, these studies did not include a com- also be suspected. parison group (patients without prior drug use) and may In the current study, potential die ff rences in preoperative have compared a group with a better prognosis (long drug- tumor extent were analyzed. It is possible that a higher percent- free interval) with a group with poorer prognosis (shorter age of patients in the FP group may have had advanced preop- drug-free interval). In the present study, patients with prior erative stage disease necessitating neoadjuvant chemotherapy FP use with the early recurrence and those with late recur- that contained FPs, compared with that in the non-FP group. It rence were compared with RFI-matched patients without is also possible that preoperative stages may have affected the prior FP use, and the difference in the impact of prior FP outcomes of treatment with capecitabine. However, preopera- use by length of RFI was assessed. Prior FP use in patients tive diagnosis did not have a clear effect on PFS or OS. The with late recurrence appeared to have a less adverse impact HR for PFS seemed to be similar regardless of preoperative on survival outcomes. In contrast, in those with the early diagnosis in the univariate analysis. For OS, while preopera- recurrence, prior FP use seemed to be detrimental to survival tive diagnosis was selected for multivariate analysis, there was outcomes. This outcome is biologically plausible, since the no apparent dose–response relationship between preoperative 1 3 Cancer Chemotherapy and Pharmacology diagnosis and OS in the univariate analysis. Although data References of preoperative stage were not available in some patients, we 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo evaluated the effect of difference in preoperative stage on the M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and outcomes, and minimized the potential bias due to such a dif- mortality worldwide: sources, methods and major patterns in ference between patients with and without prior preoperative GLOBOCAN 2012. Int J Cancer 136(5):E359–386. https ://doi. FP use. org/10.1002/ijc.29210 2. Partridge AH, Rumble RB, Carey LA, Come SE, Davidson NE, There are limitations to this study. First, it remains unclear Di Leo A, Gralow J, Hortobagyi GN, Moy B, Yee D, Brund- whether other chemotherapeutic regimens are more efficacious age SB, Danso MA, Wilcox M, Smith IE (2014) Chemotherapy than capecitabine in patients with unfavorable outcomes of and targeted therapy for women with human epidermal growth capecitabine (those with prior FP use and early recurrence). factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guide- Studies comparing capecitabine with other agents should be line. J Clin Oncol 32(29):3307–3329. https ://doi.org/10.1200/ conducted in such patients. Second, it was a retrospective study jco.2014.56.7479 of a limited sample size and event numbers. For example, peri- 3. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, operative data were difficult to collect, since many patients had Osterwalder B, Burger HU, Brown CS, Griffin T (1999) Mul- ticenter phase II study of capecitabine in paclitaxel-refractory surgery in various hospitals, several years prior to capecitabine metastatic breast cancer. J Clin Oncol 17(2):485–493. https://doi. treatment. In addition, the assessment of PFS and OS by bio- org/10.1200/jco.1999.17.2.485 markers was not sufficient for the small number of patients in 4. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, the subgroups. Furthermore, data on the adherence to treat- Kolbl H, Janicke F, Kieback DG, Kuhn W, Schindler AE, Mohr- mann S, Kaufmann M, Luck HJ (2003) Multicenter phase II study ment were not obtainable from the medical records. Third, the of oral capecitabine (Xeloda®) in patients with metastatic breast study population was heterogeneous regarding perioperative cancer relapsing after treatment with a taxane-containing therapy. chemotherapy, which included various regimens. Ann Oncol 14(8):1227–1233 In conclusion, the use of capecitabine requires extra cau- 5. Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, Osterwalder B (2001) Multicenter, Phase II study of capecitabine tion when it is considered for ABC with prior FP use, since in taxane-pretreated metastatic breast carcinoma patients. Cancer PFS seems to be inferior in ABC patients with prior FP use 92(7):1759–1768 than in those without prior FP use. The RFI may be a factor 6. Fumoleau P, Largillier R, Clippe C, Dieras V, Orfeuvre H, Les- to consider when clinicians select treatment for patients with imple T, Culine S, Audhuy B, Serin D, Cure H, Vuillemin E, Morere JF, Montestruc F, Mouri Z, Namer M (2004) Multicentre, prior FP use, as the adverse effect of prior FP use seems to be phase II study evaluating capecitabine monotherapy in patients larger in patients with the early recurrence after surgery, (cases with anthracycline- and taxane-pretreated metastatic breast where inefficacy of prior perioperative treatment including cancer. Eur J Cancer 40(4):536–542. https ://doi.org/10.1016/j. FPs is suspected). Whether patients with ABC who received ejca.2003.11.007 7. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, perioperative FP should receive agents other than capecitabine Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, requires further elucidation. Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Acknowledgements We would like to express our sincere thanks to Dr. Rubin S, Stein S, Geyer CE (2008) A phase III randomized com- Kuchiba for her advice on statistical considerations. parison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on Funding None. trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112(3):533–543. https://doi.or g/10.1007/s1054 9-007-9885-0 Compliance with ethical standards 8. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing Conflict of interest The authors have declared no conflicts of interest. AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in Ethical approval This article does not contain any interventional stud- patients with previously treated metastatic breast cancer. J Clin ies with human participants performed by any of the authors. This Oncol 23(4):792–799 study was approved by the ethics committee of each participating hos- 9. Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova pital and was performed in accordance with the 1964 Helsinki declara- G, Olivo MS, He Y, Dutcus CE, Cortes J (2015) Phase III open- tion and its later amendments or comparable ethical standards. label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer pre- Informed consent Informed consent was not required for this study. viously treated with an anthracycline and a taxane. J Clin Oncol 33(6):594–601. https ://doi.org/10.1200/JCO.2013.52.4892 10. Shitara K, Morita S, Fujitani K, Kadowaki S, Takiguchi N, Hira- Open Access This article is distributed under the terms of the Crea- bayashi N, Takahashi M, Takagi M, Tokunaga Y, Fukushima R, tive Commons Attribution 4.0 International License (http://creat iveco Munakata Y, Nishikawa K, Takagane A, Tanaka T, Sekishita Y, mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Sakamoto J, Tsuburaya A (2012) Combination chemotherapy tion, and reproduction in any medium, provided you give appropriate with S-1 plus cisplatin for gastric cancer that recurs after adju- credit to the original author(s) and the source, provide a link to the vant chemotherapy with S-1: multi-institutional retrospective Creative Commons license, and indicate if changes were made. 1 3 Cancer Chemotherapy and Pharmacology analysis. Gastric Cancer 15(3):245–251. https ://doi.org/10.1007/ 14. Food US, Administration D (2016) Prescribing information. https s1012 0-011-0101-x ://www .acces sdat a .fda.gov/dr ugs atfda _docs/label /2016/02089 11. Ardizzoni A, Manegold C, Debruyne C, Gaafar R, Buchholz E, 6s039 lbl.pdf. Accessed 16 Aug 2017 Smit EF, Lianes P, ten Velde G, Bosquee L, Legrand C, Neu- 15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent maier C, King K (2003) European organization for research and D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubin- treatment of cancer (EORTC) 08957 phase II study of topote- stein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J can in combination with cisplatin as second-line treatment of (2009) New response evaluation criteria in solid tumours: revised refractory and sensitive small cell lung cancer. Clin Cancer Res RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. 9(1):143–150https ://doi.org/10.1016/j.ejca.2008.10.026 12. Takashima A, Shirao K, Hirashima Y, Takahari D, Okita N, Akat- 16. Kanda Y (2013) Investigation of the freely available easy-to- suka S, Nakajima TE, Matsubara J, Yasui H, Asakawa T, Kato use software ‘EZR’ for medical statistics. Bone Marrow Transpl K, Hamguchi T, Muro K, Yamada Y, Shimada Y (2008) Chemo- 48(3):452–458. https ://doi.org/10.1038/bmt.2012.244 sensitivity of patients with recurrent esophageal cancer receiving 17. Fredholm H, Eaker S, Frisell J, Holmberg L, Fredriksson I, Lind- perioperative chemotherapy. Dis Esophagus 21(7):607–611. https man H (2009) Breast cancer in young women: poor survival ://doi.org/10.1111/j.1442-2050.2008.00821 .x despite intensive treatment. PLoS One 4(11):e7695. https ://doi. 13. Masuda N, Lee S-J, Ohtani S, Im Y-H, Lee E-S, Yokota I, Kuroi org/10.1371/journ al.pone.00076 95 K, Im S-A, Park B-W, Kim S-B, Yanagita Y, Ohno S, Takao S, 18. Natori A, Ethier JL, Amir E, Cescon DW (2017) Capecitabine Aogi K, Iwata H, Jeong J, Kim A, Park K-H, Sasano H, Ohashi in early breast cancer: a meta-analysis of randomised con- Y, Toi M (2017) Adjuvant capecitabine for breast cancer after trolled trials. Eur J Cancer 77:40–47. https ://doi.org/10.1016/j. preoperative chemotherapy. N Engl J Med 376(22):2147–2159. ejca.2017.02.024 https ://doi.org/10.1056/NEJMo a1612 645 1 3 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Cancer Chemotherapy and Pharmacology Springer Journals

Efficacy of capecitabine in patients with locally advanced or metastatic breast cancer with or without prior treatment with fluoropyrimidine: a retrospective study

Free
9 pages
Loading next page...
 
/lp/springer_journal/efficacy-of-capecitabine-in-patients-with-locally-advanced-or-GnwRlhJe0T
Publisher
Springer Berlin Heidelberg
Copyright
Copyright © 2018 by The Author(s)
Subject
Medicine & Public Health; Oncology; Pharmacology/Toxicology; Cancer Research
ISSN
0344-5704
eISSN
1432-0843
D.O.I.
10.1007/s00280-018-3617-5
Publisher site
See Article on Publisher Site

Abstract

Purpose We conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs). Methods The charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use). Results Overall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02–1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67–1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32–1.67 (short RFI), and 1.00–1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups. Conclusions Extra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence. Keywords Breast neoplasms · Capecitabine · Efficacy · Safety · Fluoropyrimidine Introduction Breast cancer is the most common cause of death from can- cer in female patients [1]. Although the early breast cancer is curable with resection with or without neoadjuvant or adjuvant treatment, advanced breast cancer (ABC) remains Electronic supplementary material The online version of this incurable. Chemotherapy is one of the important treatment article (https ://doi.org/10.1007/s0028 0-018-3617-5) contains options to achieve the goal for ABC, which is to prolong supplementary material, which is available to authorized users. survival and to maintain quality of life. While anthracy- clines and taxanes are used for the first-line chemotherapy * Akihiko Shimomura ashimomu@ncc.go.jp for ABC, in addition to their usage in neoadjuvant and adju- vant settings, no single standard regimen exists after failure Department of Breast and Medical Oncology, National of these agents [2]. Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Capecitabine is an orally available fluoropyrimidine Tokyo 104-0045, Japan 2 (FP), and a prodrug of 5-fluorouracil (5-FU). It is designed Keio University Graduate School of Medicine, 35 to deliver 5-FU preferentially to tumor tissue to enhance Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan Vol.:(0123456789) 1 3 Cancer Chemotherapy and Pharmacology efficacy, and reduce toxicities in the gastrointestinal tract and followed by a 7-day rest period in a 21-day cycle, (2) bone marrow. Its route of administration and its favorable 850 mg/m twice daily for 21 days, followed by a 7-day rest toxicity profile, with little alopecia and neuropathy, make it period in a 28-day cycle. The dosing was adjusted according an attractive option for some patients. Phase II trials have to modifications recommended by the FDA [ 14], by adverse revealed the efficacy and safety of capecitabine for ABC events, or as per the physicians’ judgment. Treatment cycles after failure of anthracyclines and taxanes [3–6]. Moreo- were repeated until disease progression or unacceptable tox- ver, a phase III trial has shown the benefit of capecitabine icity, or until the patients’ wish to terminate treatment. in combination with lapatinib in human epidermal growth factor receptor 2 [HER2]-positive patients [7]. Capecitabine Assessment is also often used as a comparator in phase III trials [8, 9]. In addition to capecitabine, other FPs such as 5-FU, Tumor response was assessed according to the Response tegafur-uracil (UFT), and doxifluridine have been used in Evaluation Criteria in Solid Tumors, version 1.1 [15] by neoadjuvant and adjuvant therapies for breast cancer. As computed tomography scans. Confirmation of response was such, some patients with ABC receiving capecitabine have not required. Response rate (RR) was defined as the propor - a previous history of treatment with other FPs. Re-challenge tion of patients who achieved complete or partial response, of chemotherapeutic agents has been assessed in other can- while disease control rate (DCR) was defined as the propor - cers [10–12]. However, aside from a few studies providing tion of patients who achieved complete, partial, or stable limited results, separately assessing patients either with or disease as best response. Progression-free survival (PFS) without prior use of FPs [4, 13], the efficacy of capecitabine was defined as the time from the initiation of capecitabine in patients with ABC who have received FPs for the early monotherapy, until either clinical or objective disease pro- breast cancer has not been studied sufficiently. gression, or death. Overall survival (OS) was defined as the Therefore, we conducted a retrospective study to assess time from the initiation of capecitabine monotherapy until the efficacy and safety of capecitabine in patients with ABC death. Relapse-free interval (RFI) was defined as the time with or without prior treatment with FPs. from definitive surgery for breast cancer until recurrence. Adverse events (AEs) were assessed according to the Com- mon Terminology Criteria for Adverse Events, version 4.0. Patients and methods Statistical analysis Patients The study was designed to compare the efficacy (RR, DCR, We reviewed the medical records of patients with patho- PFS, and OS) and safety (frequency of grade 3 or worse logically confirmed locally advanced or metastatic breast AEs, AEs requiring hospitalization, and discontinuation cancer, with the previous treatment with surgery of curative due to AEs) of capecitabine between the FP group and the intent. All patients had undergone palliative chemotherapy non-FP group. Nominal variables and continuous variables with capecitabine as monotherapy between July 2008 and were compared by Fisher’s exact test and the Mann–Whitney December 2016 at the National Cancer Center Hospital U test, respectively. Only patients with target lesions were (Tokyo, Japan). Patients who had received FP-containing analyzed for RR and DCR. Survival curves were obtained regimens as neoadjuvant or adjuvant therapy before capecit- by the Kaplan–Meier method, and differences between the abine were assigned to the FP group; patients who had never two groups were assessed by the log-rank test. Hazard ratios received FPs were assigned to the non-FP group. Patients (HRs) and confidence intervals (CIs) were estimated by the who received more than one FP before capecitabine, who Cox proportional hazards model. Baseline characteristics received FPs for purposes other than perioperative (neoad- with p value < 0.10 in univariate analysis were adjusted for juvant or adjuvant) therapy, and those with insufficient base- in multivariate analysis. HRs were adjusted for additional line data were excluded from the analysis. This study was baseline characteristics in various multivariate analysis mod- approved by the National Cancer Center Institutional Review els. HRs were also estimated for subgroups by biomarkers: Board (No. 2016-491). Because this study was retrospective the triple-negative subgroup, the hormone-positive sub- in nature, written informed consent was not obtained. This group, and the hormone-negative subgroup. To assess the study was publicized via the web page of the hospital. impact of prior use of FPs on survival outcomes by RFI, HRs for PFS and OS were also estimated separately for short Treatment RFI and long RFI. Continuous variables were divided into two groups at median. Tests were considered significant if Patients received oral capecitabine by one of the following the two-sided p value was < 0.05. Analyses were performed dosing regimens: (1) 1250 mg/m twice daily for 14 days, with EZR software (Saitama Medical Center, Jichi Medical 1 3 Cancer Chemotherapy and Pharmacology University, Saitama, Japan), which is a graphical user inter- Table 1 Patient characteristics face for R (The R foundation for Statistical Computing, FP Non-FP p value Vienna, Austria) [16]. n 105 183 Age  Median [range] 60 [25–84] 59 [32–81] 0.361 Results ECOG PS  0 (%) 46 (43.8) 85 (46.4) 0.246 Patients  1 (%) 50 (47.6) 91 (49.7)  2 (%) 9 (8.6) 7 (3.8) Overall, 288 patients were included in the analysis: 105 were Biomarker included in the FP group and 183 in the non-FP group (Sup-  ER (%) 84 (80.0) 149 (81.4) 0.758 plementary Fig. 1). Baseline patient characteristics did not  PgR (%) 76 (72.4) 129 (70.5) 0.788 differ significantly between the two groups (Table  1). The  HER2 (%) 6 (5.8) 6 (3.3) 0.365 median age was 60 (range 25–84) years in the FP group Organs involved and 59 (range 32–81) years in the non-FP group (p = 0.361).  Bone (%) 64 (61.0) 102 (55.7) 0.457 The median number of the previous lines of chemotherapy  Liver (%) 53 (50.5) 105 (57.4) 0.270 for advanced disease was 1 (range 0–4; p = 0.182) in both  Lymph node (%) 46 (43.8) 84 (45.9) 0.806 groups. The median RFI was 3.85 (range 0.27–20.11) years  Lung (%) 46 (43.8) 79 (43.2) 1.000 in the FP group and 4.24 (range 0.27–27.07) years in the No. of organs involved non-FP group (p = 0.369). In the FP group, 86 (81.9%), 8  Median [range] 2 [1–5] 2 [1–7] 0.067 (7.6%), and 11 (10.5%) patients had received 5-FU, UFT, Previous treatment and doxifluridine, respectively, for a neoadjuvant or adju -  Endocrine therapy 88 (83.8) 151 (82.5) 0.871 vant therapy. The initial diagnosis (preoperative, clinical) (%) was stages I, II, and III in 10 (13.0%), 45 (58.4%), and  Anthracycline (%) 91 (86.7) 154 (84.2) 0.610 22 (28.6%) patients in the FP group, respectively, and 16  Taxane (%) 100 (95.2) 168 (91.8) 0.340 (10.5%), 107 (70.4%), and 29 (19.1%) patients in the non-FP No. of Cx lines group, respectively (p = 0.175). The median follow-up time  Median [range] 1 [0–4] 1 [0–4] 0.182 was 12.5 (range 0.1–95.6) months. RFI (years)  Median [range] 3.85 [0.27–20.11] 4.24 [0.27–27.07] 0.369 Progression‑free survival and overall survival Stage  I 10 (13.0) 16 (10.5) 0.175 The PFS period was significantly shorter in the FP group  II 45 (58.4) 107 (70.4) than in the non-FP group (median 4.6 vs 5.9 months; HR for  III 22 (28.6) 29 (19.1) the FP group compared with the non-FP group: 1.33; 95% FP type CI 1.03–1.72, p = 0.029; Fig.  1). In multivariate analysis  5-FU 86 (81.9) – adjusting for baseline characteristics selected by univariate  UFT 8 (7.6) – analysis (age, Eastern Cooperative Oncology Group [ECOG]  Doxifluridine 11 (10.5) – performance status [PS], estrogen receptor [ER], number Capecitabine schedule [No.] of organs involved, previous endocrine therapy, previ-  21 days/cycle 63 (60.0) 98 (53.6) 0.325 ous taxane use, and RFI), PFS was worse in the FP group  28 days/cycle 42 (40.0) 85 (46.4) than in the non-FP group (HR 1.33; 95% CI 1.02–1.73; p = 0.036; Table 2). The median OS was 21.3 months in the FP fluoropyrimidine, ECOG Eastern Cooperative Oncology Group, PS performance status, ER estrogen receptor, PgR progesterone FP group and 23.9 months in the non-FP group (HR 1.17; receptor, HER2 human epidermal growth factor receptor 2, Cx chem- 95% CI 0.84–1.63; p = 0.344). The HR adjusted for baseline otherapy, RFI relapse-free interval, 5-FU 5-fluorouracil, UFT tegafur/ characteristics selected by univariate analysis (age, ECOG uracil PS, ER, HER2, bone metastasis, liver metastasis, No. of a For advanced disease organs involved, previous therapy [endocrine, anthracycline, Preoperative clinical stage and taxane], RFI, and preoperative stage) was 1.00 (95% CI 0.67–1.50; p = 0.994; Table 3). Of note, preoperative stage baseline characteristics: liver and lung metastasis, all bio- was not selected by univariate analysis for multivariate anal- ysis of PFS; it was selected for multivariate analysis of OS. marker characteristics, all previous treatment characteristics, and age ≥ 35 vs < 35 instead of ≥ 60 vs < 60 (considering The HRs for PFS and OS largely did not change in addi- tional multivariate models further adjusting for different that age < 60 was associated with worse PFS and OS than 1 3 Cancer Chemotherapy and Pharmacology ab Median (95% CI)HR (95% CI) p Median (95% CI)HR (95% CI) p 1.0 1.0 FP 4.6 (3.5-5.7)1.33 (1.03-1.72) 0.029 FP 21.3 (12.5-33.1)1.17 (0.84-1.63) 0.344 Non-FP 5.9 (5.0-6.8) Non-FP 23.9 (21.0-28.4) 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0.0 0.0 010203040 020406080 Time (months) Time (months) FP 1050 23 32 FP 1050 30 53 Non-FP 1833 57 12 7 Non-FP 1832 67 24 8 Number at risk Number at risk Fig. 1 Kaplan–Meier curves of a progression-free survival, b overall survival. FP fluoropyrimidine, HR hazard ratio, CI confidence interval was age < 60 in univariate analysis, and that age ≥ 35 has frequent cause of discontinuation due to AEs in both groups been reported to be a negative prognostic factor for the early (2.9 vs 2.7%). There were no treatment-related deaths. The breast cancer, although its prognostic effect is still unclear in frequencies of dose interruptions and reductions did not dif- an advanced disease setting [17]) (Supplementary Table 1). fer significantly between the two groups (dose interruptions Prior FP use was not linked to PFS and OS, in the analysis 44.8 vs 53.0%, p = 0.221; dose reductions 39.0 vs 49.7%, performed according to biomarker status (Supplementary p = 0.087). Table 2). The HRs for PFS and OS in the FP group compared with the non-FP group were also estimated separately for short Discussion RFI and long RFI, with a cutoff at 4 years (median RFI) (Table 4). The multivariate-adjusted HRs for PFS were 1.56 In this study, we retrospectively evaluated the efficacy and (95% CI 1.06–2.28; p = 0.025) with short RFI, and 1.11 safety of capecitabine monotherapy for the treatment of (95% CI 0.76–1.60; p = 0.597) with long RFI. The multi- ABC in patients who had received other FPs for neoadjuvant variate-adjusted HRs for OS were 1.23 (95% CI 0.68–2.21; or adjuvant therapy. Although OS did not differ significantly p = 0.489) with short RFI, and 0.77 (95% CI 0.40–1.47; with prior FP use, PFS was worse in patients with prior FP p = 0.427) with long RFI. A trend for larger HRs for PFS use. The detrimental effect of prior FP use on survival out- and OS in the FP group with short RFI than in that with comes seemed larger in patients with the early recurrence long RFI was also observed with different cutoffs of RFI after surgery than in those with late recurrence. The safety (Supplementary Table 3). profile did not differ significantly by prior FP use. In addition to its use in ABC, the efficacy of capecitabine Tumor response has been explored in the early breast cancer treatment. A recent meta-analysis of randomized-controlled studies dem- Tumor response among patients with target lesions is onstrated that addition of capecitabine to standard chemo- shown in Supplementary Table 4. The RR (FP vs non-FP) therapy improves survival outcomes in the early breast was 13.8 vs 21.0% (p = 0.173) and DCR was 54.0 vs 59.9% cancer, particularly in triple-negative breast cancer [18]. In (p = 0.418). addition to the clinical trial CREATE-X, which showed the efficacy of adjuvant capecitabine in patients with residual Safety disease after neoadjuvant chemotherapy [13], several other trials evaluating adjuvant capecitabine in high-risk patients Table 5 shows the frequency of AEs by group. There was no are ongoing [18]. Such studies may lead to incorporation of significant difference between the two groups in grade 3 or capecitabine into the standard perioperative treatment. The worse AEs, AEs requiring hospitalization, or treatment dis- current study did not assess patients who had used capecit- continuation due to AEs. Hand–foot syndrome was the most abine as perioperative FP. Nevertheless, given the efficacy 1 3 Progression-free Survival Probability Overall Survival Probability Cancer Chemotherapy and Pharmacology Table 2 Univariate and Univariate Multivariate multivariate analyses of progression-free survival HR (95% CI) p value HR (95% CI) p value Age  ≥ 60 vs < 60 0.72 (0.56–0.92) 0.009 0.76 (0.59–0.99) 0.046 ECOG PS  1 vs 0 1.28 (1.00–1.65) 0.052 1.19 (0.92–1.54) 0.184  2 vs 0 1.89 (1.06–3.36) 0.031 1.60 (0.89–2.88) 0.116 ER  + vs − 0.64 (0.47–0.87) 0.004 0.94 (0.58–1.53) 0.813 PgR  + vs − 1.04 (0.79–1.37) 0.773 HER2  + vs − 1.48 (0.81–2.72) 0.204 Bone metastasis  + vs − 1.07 (0.83–1.38) 0.594 Liver metastasis  + vs − 1.14 (0.89–1.46) 0.300 Lymph node metastasis  + vs − 1.20 (0.94–1.54) 0.142 Lung metastasis  + vs − 1.15 (0.89–1.47) 0.281 No. of metastatic organs  ≥ 2 vs < 2 1.39 (1.00–1.94) 0.050 1.47 (1.02–2.11) 0.037 Endocrine therapy  + vs − 0.62 (0.45–0.86) 0.004 0.59 (0.35–0.98) 0.042 Anthracycline  + vs − 1.33 (0.93–1.88) 0.115 Taxane  + vs − 1.59 (0.94–2.69) 0.081 1.25 (0.73–2.14) 0.412 No. of Cx lines  ≥ 1 vs < 1 1.09 (0.82–1.43) 0.563 FP  FP vs non-FP 1.33 (1.03–1.72) 0.030 1.33 (1.02–1.73) 0.036 RFI (years)  Continuous (per year) 0.99 (0.96–1.01) 0.299  ≥ 4 vs < 4 0.73 (0.57–0.93) 0.012 0.85 (0.64–1.11) 0.229 Stage  II vs I 1.05 (0.67–1.63) 0.833  III vs I 0.85 (0.51–1.41) 0.527 Capecitabine schedule  28 vs 21 days 1.10 (0.86–1.41) 0.464 Cox proportional hazards model. Covariates with p value < 0.10 were adjusted in multivariate analysis HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, PS performance sta- tus, ER estrogen receptor, PgR progesterone receptor, HER2 human epidermal growth factor receptor 2, Cx chemotherapy, FP fluoropyrimidine, RFI relapse-free survival For advanced disease Preoperative clinical stage of FPs as perioperative therapies as well as in advanced dis- treatment options in patients with ABC after perioperative ease, our results provide insights for clinicians considering FPs. 1 3 Cancer Chemotherapy and Pharmacology Table 3 Univariate and Univariate Multivariate multivariate analyses of overall survival HR (95% CI) p value HR (95% CI) p value Age  ≥ 60 vs < 60 0.71 (0.52–0.98) 0.037 0.95 (0.65–1.40) 0.802 ECOG PS  1 vs 0 2.01 (1.44–2.81) < 0.001 2.22 (1.51–3.27) < 0.001  2 vs 0 4.96 (2.57–9.57) < 0.001 6.89 (3.11–15.29) < 0.001 ER  + vs − 0.62 (0.43–0.89) 0.011 0.35 (0.16–0.75) 0.007 PgR  + vs − 0.93 (0.66–1.31) 0.673 HER2  + vs − 1.93 (0.94–3.95) 0.073 3.82 (1.53–9.52) 0.004 Bone metastasis  + vs − 1.39 (1.00–1.92) 0.047 1.23 (0.79–1.93) 0.365 Liver metastasis  + vs − 1.62 (1.18–2.23) 0.003 1.75 (1.12–2.75) 0.014 Lymph node metastasis  + vs − 1.30 (0.95–1.79) 0.100 Lung metastasis  + vs − 0.85 (0.61–1.17) 0.314 No. of metastatic organs  ≥ 2 vs < 2 1.73 (1.11–2.69) 0.015 1.29 (0.72–2.32) 0.385 Endocrine therapy  + vs − 0.61 (0.41–0.91) 0.016 1.15 (0.53–2.48) 0.722 Anthracycline  + vs − 1.49 (0.93–2.38) 0.098 0.78 (0.42–1.46) 0.441 Taxane  + vs − 1.92 (0.90–4.11) 0.093 1.37 (0.45–4.19) 0.580 No. of Cx lines  ≥ 1 vs < 1 0.93 (0.66–1.31) 0.687 FP  FP vs non-FP 1.17 (0.84–1.63) 0.345 1.00 (0.67–1.50) 0.994 RFI (years)  Continuous (per year) 0.97 (0.94–1.01) 0.123  ≥ 4 vs < 4 0.71 (0.52–0.98) 0.035 0.98 (0.66–1.46) 0.914 Stage  II vs I 1.67 (0.93–3.00) 0.084 1.57 (0.84–2.92) 0.160  III vs I 1.21 (0.62–2.37) 0.570 1.05 (0.51–2.16) 0.901 Capecitabine schedule  28 vs 21 days 1.08 (0.79–1.49) 0.634 Cox proportional hazards model. Covariates with p value < 0.10 were adjusted in multivariate analysis HR hazard ratio, CI confidence interval, ECOG Eastern Cooperative Oncology Group, PS performance sta- tus, ER estrogen receptor, PgR progesterone receptor, HER2 human epidermal growth factor receptor 2, Cx chemotherapy, FP fluoropyrimidine, RFI relapse-free survival For advanced disease Preoperative clinical stage Capecitabine may be less effective in patients with prior adjusting for baseline characteristics. In addition, capecit- FP use. In this study, PFS was significantly worse in the FP abine appears to be slightly less active after the use of FPs, group, which was confirmed by various multivariate models as shown in subgroup analyses reported in a limited number 1 3 Cancer Chemotherapy and Pharmacology Table 4 Univariate and multivariate analyses of progression-free and Table 5 Adverse events of Grade 3 or higher overall survival for the FP group compared with the non-FP group by FP Non-FP p value relapse-free survival n 105 183 RFI (years) Univariate Multivariate All (%) 27 (25.7) 51 (27.9) 0.783 HR (95% CI) p value HR (95% CI) p value Hematological (%) 17 (16.2) 30 (16.4) 1.000 PFS Leukopenia (%) 2 (1.9) 12 (6.6) 0.092  < 4 1.49 (1.02–2.18) 0.037 1.56 (1.06–2.28) 0.025 Neutropenia (%) 9 (8.6) 15 (8.2) 1.000  ≥ 4 1.19 (0.83–1.70) 0.344 1.11 (0.76–1.60) 0.597 Anemia (%) 4 (3.8) 9 (4.9) 0.775 OS Thrombocytopenia (%) 4 (3.8) 5 (2.7) 0.728  < 4 1.28 (0.81–2.04) 0.288 1.23 (0.68–2.21) 0.489 Febrile neutropenia (%) 1 (1.0) 2 (1.1) 1.000  ≥ 4 1.01 (0.63–1.62) 0.959 0.77 (0.40–1.47) 0.427 Nonhematological (%) 16 (15.2) 31 (16.9) 0.743 Fatigue (%) 0 (0.0) 0 (0.0) NA Cox proportional hazards model Anorexia (%) 2 (1.9) 1 (0.5) 0.301 FP fluoropyrimidine, RFI relapse-free survival, HR hazard ratio, CI Nausea (%) 1 (1.0) 1 (0.5) 1.000 confidence interval, PFS progression-free survival, OS overall sur - vival Vomiting (%) 0 (0.0) 1 (0.5) 1.000 Adjusting for covariates with p value < 0.10 in univariate analysis Diarrhea (%) 1 (1.0) 2 (1.1) 1.000 except for RFI < 4 vs ≥ 4 years Mucositis (%) 0 (0.0) 1 (0.5) 1.000 HFS (%) 6 (5.7) 5 (2.7) 0.217 Bilirubin increased (%) 1 (1.0) 2 (1.1) 1.000 of the previous studies. In one trial, the response rate of AST increased (%) 7 (6.7) 14 (7.7) 0.818 capecitabine for ABC was 13% in patients with prior 5-FU ALT increased (%) 8 (7.6) 15 (8.2) 1.000 use and 18% (p = 0.48) in those without prior 5-FU use [4]. Creatinine increased (%) 0 (0.0) 0 (0.0) NA Moreover, in the CREATE-X trial, the HR for disease-free a b Other (%) 1 (1.0) 2 (1.1) 1.000 survival with adjuvant capecitabine compared with control c d Hospitalization (%) 3 (2.9) 4 (2.2) 0.708 was 0.75 (95% CI 0.53–1.05) with prior 5-FU use, and 0.63 e f Discontinuation (%) 3 (2.9) 6 (3.3) 1.000 (95% CI 0.40–0.99) without prior 5-FU use (p = 0.56) [13]. Although capecitabine may remain as a treatment option for FP fluoropyrimidines, HFS hand–foot syndrome, AST aspartate ami- ABC pretreated with FPs based on the absence of significant notransferase, ALT alanine aminotransferase, NA not assessed OS differences by prior FP use, we should be aware that it Lung infection grade 3 may be less active in ABC patients with prior FP use than Lung infection grade 3 and enterocolitis infectious grade 3 in those without prior FP use. Lung infection grade 3 and anorexia grade 3 (2 patients) The effect of prior FP use seemed to differ between the d Lung infection grade 3, enterocolitis infectious grade 3, diarrhea early recurrence (short RFI) and late recurrence (long RFI). grade 3, and mucositis grade 3 We used RFI to compare patients with prior FP use and those Hand–foot syndrome grade 3 (2 patient), hand–foot syndrome grade without prior FP use. The previous studies that assessed re- Hand–foot syndrome grade 3 (2 patient), hand–foot syndrome grade challenge with a chemotherapeutic agent in other cancers 2 (3 patients), diarrhea grade 3 reported that drug-free interval (time since last administra- tion of the drug until relapse) is predictive of the efficacy of re-challenge [10–12]. However, drug-free interval may early recurrence indicates failure of perioperative treatment be dependent upon the nature of the tumor (aggressive or including FPs, in which case inefficacy of capecitabine could indolent). In addition, these studies did not include a com- also be suspected. parison group (patients without prior drug use) and may In the current study, potential die ff rences in preoperative have compared a group with a better prognosis (long drug- tumor extent were analyzed. It is possible that a higher percent- free interval) with a group with poorer prognosis (shorter age of patients in the FP group may have had advanced preop- drug-free interval). In the present study, patients with prior erative stage disease necessitating neoadjuvant chemotherapy FP use with the early recurrence and those with late recur- that contained FPs, compared with that in the non-FP group. It rence were compared with RFI-matched patients without is also possible that preoperative stages may have affected the prior FP use, and the difference in the impact of prior FP outcomes of treatment with capecitabine. However, preopera- use by length of RFI was assessed. Prior FP use in patients tive diagnosis did not have a clear effect on PFS or OS. The with late recurrence appeared to have a less adverse impact HR for PFS seemed to be similar regardless of preoperative on survival outcomes. In contrast, in those with the early diagnosis in the univariate analysis. For OS, while preopera- recurrence, prior FP use seemed to be detrimental to survival tive diagnosis was selected for multivariate analysis, there was outcomes. This outcome is biologically plausible, since the no apparent dose–response relationship between preoperative 1 3 Cancer Chemotherapy and Pharmacology diagnosis and OS in the univariate analysis. Although data References of preoperative stage were not available in some patients, we 1. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo evaluated the effect of difference in preoperative stage on the M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and outcomes, and minimized the potential bias due to such a dif- mortality worldwide: sources, methods and major patterns in ference between patients with and without prior preoperative GLOBOCAN 2012. Int J Cancer 136(5):E359–386. https ://doi. FP use. org/10.1002/ijc.29210 2. Partridge AH, Rumble RB, Carey LA, Come SE, Davidson NE, There are limitations to this study. First, it remains unclear Di Leo A, Gralow J, Hortobagyi GN, Moy B, Yee D, Brund- whether other chemotherapeutic regimens are more efficacious age SB, Danso MA, Wilcox M, Smith IE (2014) Chemotherapy than capecitabine in patients with unfavorable outcomes of and targeted therapy for women with human epidermal growth capecitabine (those with prior FP use and early recurrence). factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guide- Studies comparing capecitabine with other agents should be line. J Clin Oncol 32(29):3307–3329. https ://doi.org/10.1200/ conducted in such patients. Second, it was a retrospective study jco.2014.56.7479 of a limited sample size and event numbers. For example, peri- 3. Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, operative data were difficult to collect, since many patients had Osterwalder B, Burger HU, Brown CS, Griffin T (1999) Mul- ticenter phase II study of capecitabine in paclitaxel-refractory surgery in various hospitals, several years prior to capecitabine metastatic breast cancer. J Clin Oncol 17(2):485–493. https://doi. treatment. In addition, the assessment of PFS and OS by bio- org/10.1200/jco.1999.17.2.485 markers was not sufficient for the small number of patients in 4. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, the subgroups. Furthermore, data on the adherence to treat- Kolbl H, Janicke F, Kieback DG, Kuhn W, Schindler AE, Mohr- mann S, Kaufmann M, Luck HJ (2003) Multicenter phase II study ment were not obtainable from the medical records. Third, the of oral capecitabine (Xeloda®) in patients with metastatic breast study population was heterogeneous regarding perioperative cancer relapsing after treatment with a taxane-containing therapy. chemotherapy, which included various regimens. Ann Oncol 14(8):1227–1233 In conclusion, the use of capecitabine requires extra cau- 5. Blum JL, Dieras V, Lo Russo PM, Horton J, Rutman O, Buzdar A, Osterwalder B (2001) Multicenter, Phase II study of capecitabine tion when it is considered for ABC with prior FP use, since in taxane-pretreated metastatic breast carcinoma patients. Cancer PFS seems to be inferior in ABC patients with prior FP use 92(7):1759–1768 than in those without prior FP use. The RFI may be a factor 6. Fumoleau P, Largillier R, Clippe C, Dieras V, Orfeuvre H, Les- to consider when clinicians select treatment for patients with imple T, Culine S, Audhuy B, Serin D, Cure H, Vuillemin E, Morere JF, Montestruc F, Mouri Z, Namer M (2004) Multicentre, prior FP use, as the adverse effect of prior FP use seems to be phase II study evaluating capecitabine monotherapy in patients larger in patients with the early recurrence after surgery, (cases with anthracycline- and taxane-pretreated metastatic breast where inefficacy of prior perioperative treatment including cancer. Eur J Cancer 40(4):536–542. https ://doi.org/10.1016/j. FPs is suspected). Whether patients with ABC who received ejca.2003.11.007 7. Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, perioperative FP should receive agents other than capecitabine Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, requires further elucidation. Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Acknowledgements We would like to express our sincere thanks to Dr. Rubin S, Stein S, Geyer CE (2008) A phase III randomized com- Kuchiba for her advice on statistical considerations. parison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on Funding None. trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 112(3):533–543. https://doi.or g/10.1007/s1054 9-007-9885-0 Compliance with ethical standards 8. Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing Conflict of interest The authors have declared no conflicts of interest. AP, Langmuir V, Rugo HS (2005) Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in Ethical approval This article does not contain any interventional stud- patients with previously treated metastatic breast cancer. J Clin ies with human participants performed by any of the authors. This Oncol 23(4):792–799 study was approved by the ethics committee of each participating hos- 9. Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova pital and was performed in accordance with the 1964 Helsinki declara- G, Olivo MS, He Y, Dutcus CE, Cortes J (2015) Phase III open- tion and its later amendments or comparable ethical standards. label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer pre- Informed consent Informed consent was not required for this study. viously treated with an anthracycline and a taxane. J Clin Oncol 33(6):594–601. https ://doi.org/10.1200/JCO.2013.52.4892 10. Shitara K, Morita S, Fujitani K, Kadowaki S, Takiguchi N, Hira- Open Access This article is distributed under the terms of the Crea- bayashi N, Takahashi M, Takagi M, Tokunaga Y, Fukushima R, tive Commons Attribution 4.0 International License (http://creat iveco Munakata Y, Nishikawa K, Takagane A, Tanaka T, Sekishita Y, mmons.or g/licenses/b y/4.0/), which permits unrestricted use, distribu- Sakamoto J, Tsuburaya A (2012) Combination chemotherapy tion, and reproduction in any medium, provided you give appropriate with S-1 plus cisplatin for gastric cancer that recurs after adju- credit to the original author(s) and the source, provide a link to the vant chemotherapy with S-1: multi-institutional retrospective Creative Commons license, and indicate if changes were made. 1 3 Cancer Chemotherapy and Pharmacology analysis. Gastric Cancer 15(3):245–251. https ://doi.org/10.1007/ 14. Food US, Administration D (2016) Prescribing information. https s1012 0-011-0101-x ://www .acces sdat a .fda.gov/dr ugs atfda _docs/label /2016/02089 11. Ardizzoni A, Manegold C, Debruyne C, Gaafar R, Buchholz E, 6s039 lbl.pdf. Accessed 16 Aug 2017 Smit EF, Lianes P, ten Velde G, Bosquee L, Legrand C, Neu- 15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent maier C, King K (2003) European organization for research and D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubin- treatment of cancer (EORTC) 08957 phase II study of topote- stein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J can in combination with cisplatin as second-line treatment of (2009) New response evaluation criteria in solid tumours: revised refractory and sensitive small cell lung cancer. Clin Cancer Res RECIST guideline (version 1.1). Eur J Cancer 45(2):228–247. 9(1):143–150https ://doi.org/10.1016/j.ejca.2008.10.026 12. Takashima A, Shirao K, Hirashima Y, Takahari D, Okita N, Akat- 16. Kanda Y (2013) Investigation of the freely available easy-to- suka S, Nakajima TE, Matsubara J, Yasui H, Asakawa T, Kato use software ‘EZR’ for medical statistics. Bone Marrow Transpl K, Hamguchi T, Muro K, Yamada Y, Shimada Y (2008) Chemo- 48(3):452–458. https ://doi.org/10.1038/bmt.2012.244 sensitivity of patients with recurrent esophageal cancer receiving 17. Fredholm H, Eaker S, Frisell J, Holmberg L, Fredriksson I, Lind- perioperative chemotherapy. Dis Esophagus 21(7):607–611. https man H (2009) Breast cancer in young women: poor survival ://doi.org/10.1111/j.1442-2050.2008.00821 .x despite intensive treatment. PLoS One 4(11):e7695. https ://doi. 13. Masuda N, Lee S-J, Ohtani S, Im Y-H, Lee E-S, Yokota I, Kuroi org/10.1371/journ al.pone.00076 95 K, Im S-A, Park B-W, Kim S-B, Yanagita Y, Ohno S, Takao S, 18. Natori A, Ethier JL, Amir E, Cescon DW (2017) Capecitabine Aogi K, Iwata H, Jeong J, Kim A, Park K-H, Sasano H, Ohashi in early breast cancer: a meta-analysis of randomised con- Y, Toi M (2017) Adjuvant capecitabine for breast cancer after trolled trials. Eur J Cancer 77:40–47. https ://doi.org/10.1016/j. preoperative chemotherapy. N Engl J Med 376(22):2147–2159. ejca.2017.02.024 https ://doi.org/10.1056/NEJMo a1612 645 1 3

Journal

Cancer Chemotherapy and PharmacologySpringer Journals

Published: Jun 5, 2018

References

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off