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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 12  |  Page : 957-963

Capecitabine monotherapy in advanced breast cancer resistant to anthracycline and taxane: A meta-analysis


1 Department of Integrative Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China
2 The Second Department of Breast Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

Date of Web Publication11-Dec-2018

Correspondence Address:
Zhansheng Jiang
Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Hexi District, Tianjin
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187384

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 > Abstract 


Background: Capecitabine monotherapy is usually used for advanced breast cancer (ABC) resistant to anthracycline and taxane, but there are still many other options too. Our meta-analysis assessed whether capecitabine monotherapy was superior or noninferior to the other regimens in ABC pretreated with anthracycline and taxane.
Materials and Methods: PubMed databases and abstracts from the proceedings of American Society of Clinical Oncology and San Antonio Breast Cancer Symposium were searched for randomized controlled trials that compared capecitabine monotherapy with other regimens for ABC progression after anthracycline- and taxane-treatment. Hazard ratios (HRs) were used for progression-free survival (PFS) and overall survival (OS). Risk ratios (RRs) were used for overall response rate (ORR) and Grade 3–4 drug-related adverse events. All statistical analyses were conducted with RevMan 5.3 software, and statistical significance was defined as P < 0.05.
Results: In total, 4671 patients from eight trials were included. Target therapy as treatment group was involved in four trials, and the other four trials were merely chemotherapy in treatment group. Our study indicated that capecitabine monotherapy was not superior but also noninferior to the other regimens in ORR (RR = 1.32−95% confidence interval [CI] 0.98–1.77, P = 0.07), PFS (HR = 1.03, 95% CI 0.85–1.25, P = 0.76), and OS (HR = 0.96, 95% CI 0.88–1.05, P = 0.40). Subgroup analysis showed that both the other chemotherapy regimens and target drugs failed to improve efficacy compared with capecitabine monotherapy, and target drugs could shorten PFS (HR = 1.22, 95% CI 1.06–1.39, P = 0.004). Incidences of Grade 3–4 hematology toxicity in other regimens group significantly increased compared with capecitabine monotherapy.
Conclusions: Our meta-analysis demonstrated that capecitabine monotherapy could be the first choice for ABC pretreated with anthracycline and taxane due to its efficacy and low toxicity.

Keywords: Advanced breast cancer, capecitabine, chemotherapy, meta-analysis, resistance


How to cite this article:
Jiang Z, Yang Y, Li L, Yue Z, Lan L, Pan Z. Capecitabine monotherapy in advanced breast cancer resistant to anthracycline and taxane: A meta-analysis. J Can Res Ther 2018;14, Suppl S5:957-63

How to cite this URL:
Jiang Z, Yang Y, Li L, Yue Z, Lan L, Pan Z. Capecitabine monotherapy in advanced breast cancer resistant to anthracycline and taxane: A meta-analysis. J Can Res Ther [serial online] 2018 [cited 2019 Sep 20];14:957-63. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/957/187384




 > Introduction Top


Breast cancer is the most common malignant disease among women worldwide. Despite remarkable advances in early breast cancer including diagnostic techniques, surgery, and neoadjuvant/adjuvant treatment, 30% of patients get recurrent disease or develop metastases.[1],[2] Meanwhile, an additional 6–7% patients present with metastatic disease at diagnosis.[3] The second international consensus guidelines for advanced breast cancer (ABC) point out that the goals of ABC treatment are to optimize both length and quality of life, and regarding the use of chemotherapy, the main recommendation relates to the sequential use of single agents, with combination chemotherapy reserved for situations of visceral crisis, rapidly progressive or highly symptomatic disease.[4]

Anthracycline or taxane-based chemotherapy regimen is the first choice for ABC although these two drugs are generally used in neoadjuvant or adjuvant therapy. However, treatment decisions are difficult to make once ABC patients progressed after first-line therapy including taxane or anthracycline.[5] There are still no standardized regimens so far after the failure of anthracycline and taxane therapy. Capecitabine, vinorelbine, eribulin, ixabelilone, bevacizumab plus chemotherapy, and even combination chemotherapy were reasonable alternative. The safety and efficacy of therapy become equally important factors affecting the choice of treatment for patients with heavily pretreated metastatic breast cancer at present. Hence, there is a growing trend to use oral capecitabine as salvage chemotherapy due to its modest benefit and less toxicity.[6] Nevertheless, a series of clinical studies tried to find some superior regimens compared with capecitabine monotherapy, and the results are not identical.[7],[8],[9],[10],[11],[12],[13],[14] The objective of our meta-analysis is to assess the efficacy and safety of capecitabine monotherapy in ABC patients pretreated with anthracycline and taxane.


 > Materials and Methods Top


Search strategy

Two investigators (JZS and YZS) independently carried out a systematic search from January 1998 to October 2015, using PubMed database. We also reviewed the meeting abstracts of the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium for the last 10 years. Searches were limited to human clinical trials published in English. The key words were capecitabine, breast cancer, advanced, or metastatic. Eligible studies had to meet the following inclusion criteria: randomized controlled trials (RCTs) involving patients with advanced or metastatic breast cancer; studies comparing capecitabine monotherapy versus other regimens as salvage treatment in patients with anthracycline- and taxane-pretreated.

Data extraction

Two investigators (LLA and LLI) extracted data independently, using a prepared information form. Any disagreement was discussed and resolved by consensus in a meeting with a third investigator. The following data were extracted from included studies: authors, publication year, study phase, number of patients, treatment regimens, randomization method, and the results of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse event (AEs). We contacted the corresponding authors to obtain additional information that was not reported in the articles. The quality of the RCTs included in the meta-analysis was evaluated using the Jadad scoring system to appraise the measures of method of randomization, double-blinding procedure, method of allocation concealment, and withdrawals.[15]

Statistical analysis

The analysis was carried out using RevMan 5.3 software (http://tech.cochrane.org/). The relative risk (RR) was used to calculate the ORRs and Grade 3 and 4 drug-related AEs. Generic inverse variance was used to analyze the hazard ratios (HRs) and their 95% confidence intervals (CIs) of PFS and OS obtained from the articles directly and the author's reply. The heterogeneity of study outcomes was assessed by the Chi-square test or I2 statistics. Heterogeneity was considered statistically significant when the P < 0.05 or I2 > 50%. If significant heterogeneity existed, data were analyzed using a random-effects model; otherwise, a fixed-effects model was used.


 > Results Top


Eligible studies

Based on the search strategy, eight studies were selected from 525 relevant articles. A flow chart showing the identification of the RCTs for inclusion is depicted in [Figure 1]. The eight trials enrolled 4617 advanced or metastatic breast cancer patients, of whom 2340 received a capecitabine monotherapy and 2331 received other regimens. All the control groups of eight trials were capecitabine monotherapy, and other chemotherapy regimens and target therapy regimens were, respectively, half in the experimental groups. The study details are shown in [Table 1] and [Figure 1].
Figure 1: Study selection

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Table 1: Characteristics of randomized controlled trials included in the meta-analysis

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Overall response rate

Eight trials reported the outcome of ORR and 4397 patients were included in the analysis. The pooled results of ORR showed that there was no significant improvement of other regimens compared with capecitabine monotherapy in the patients with anthracycline- and taxane-pretreated ABC (RR 1.32, 95% CI 0.98–1.77, P = 0.07). A random-effect model was used because statistically significant heterogeneity was found between the trials (P < 0.01, I2 = 80%). The subgroup analysis revealed that RR was 1.45 (95% CI 1.00–2.12, P = 0.05) for other chemotherapy regimens and 1.16 (95% CI 0.68–1.97, P = 0.59) for target therapy, both they was no statistical significant difference [Figure 2].
Figure 2: Forest plot of meta-analysis on the overall response rate. (a) Forest plot of all clinical trials. (b) Forest plot of sub-analysis of the other chemotherapy regimens. (c) Forest plot of sub-analysis of the target therapy regimens

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Progression-free survival

The HR and 95% CI of PFS data were available in seven trials. No significant difference in PFS was found between the two arms (HR = 1.03; 95% CI 0.85–1.25, P = 0.76). Heterogeneity of effect among the seven RCTs was significant (P < 0.01, I2 = 84%), and HR was calculated using a random-effect model. The results of our subgroup analysis for PFS showed that HR was 0.86 (95% CI 0.69–1.07, P = 0.18) in other chemotherapy regimens. However, the data indicated that PFS was significantly shorter with target therapy than with capecitabine monotherapy (HR = 1.22, 95% CI 1.06–1.39, P = 0.004) [Figure 3].
Figure 3: Forest plot of meta-analysis on the progression-free survival. (a) Forest plot of all clinical trials. (b) Forest plot of sub-analysis of the other chemotherapy regimens. (c) Forest plot of sub-analysis of the target therapy regimens

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Overall survival

Five out of eight trials reported the HR and 95% CI of OS. Heterogeneity of effect among the five RCTs was absent (P = 0.18, I2 = 37%), and HR was calculated using a fixed-effect model. The result indicated that other regimens failed to prolong OS (HR = 0.96, 95% CI 0.88–1.05, P = 0.40). The sub-analysis was not done on account of the few trials included [Figure 4].
Figure 4: Forest plot of meta-analysis on the overall survival

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Safety

Common drug-related AEs were reported in all included trials. The focus of our analysis is Grade 3 or 4 AEs, which are listed in [Table 2]. Incidences of hematologic toxicity were much more common of other regimens compared with capecitabine monotherapy, such as anemia, leukopenia, neutropenia, and thrombocytopenia. Incidences of nausea, vomiting, diarrhea, and hand–foot syndrome were no statistical significant difference between two groups.
Table 2: Outcomes of Grade 3 or 4 drug-related adverse events for other regimens therapy versus capecitabine chemotherapy

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 > Discussion Top


This meta-analysis aimed to assess the safety and efficacy of capecitabine monotherapy in patients with anthracycline- and taxane-pretreated ABC. Our study found that capecitabine monotherapy was equal to the other regimens, including the other chemotherapy regimens and target therapy which could even causes negative effect on PFS.

The primary goals in ABC are palliation of symptoms and improvement of quality of life. Polychemotherapy is not routinely used in most patients. They are only applied to the patients with rapidly progressing and/or symptomatic visceral disease. Ixabepilone is a semisynthetic analog of epothilone B demonstrating particularly high antimicrotubule activity and low susceptibility to drug resistance.[16] Ixabepilone plus capecitabine was approved in patients with ABC pretreated or resistant to anthracyclines and taxanes in 2007 by the Food and Drug Administration because the combination demonstrated superior efficacy to capecitabine alone.[7] However, this regimen was canceled by the National Comprehensive Cancer Network guidelines since 2013 because they failed to prolong OS after long time follow-up.[9] The vinorelbine/gemcitabine doublet was also usually used in patients with anthracycline- and taxane-pretreated ABC. A Phase II study published by Stathopoulos et al.[17] observed encouraging results with an ORR of 54%, a median PFS of 6 months and a median OS of 11.5 months. Nevertheless, subsequent Phase III trial did not demonstrate the superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS, OS and ORR.[12]

Besides the combination regimens, single-agent vinorelbine could be used in patients suffering from ABC previously treated by anthracycline and taxane.[18],[19] However, the ORR was 20.0% and the median PFS was <4 months with single-agent vinorelbine, which was inferior to capecitabine monotherapy (ORR 28%; PFS 4.9 months).[6] Eribulin is a nontaxane microtubule dynamics inhibitor belonging to the halichondrin class of antineoplastic agents.[20] which has been prescribed as monotherapy for patients with ABC who have previously received at least two treatment regimens.[21] Nevertheless, it was failed in a Phase III study to affirm eribulin's superiority to capecitabine with regard to OS and PFS.[14]

A large of laboratory data suggest that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis. Antiangiogenesis therapy has played an important role in the whole process of breast cancer treatment.[22] Bevacizumab, a humanized monoclonal antibody directed against all isoforms of vascular endothelial growth factor-A, has been confirmed to improve the ORR and prolong PFS when it combined with chemotherapy in the first- and second-line treatment of ABC by a number of studies.[23],[24],[25] However, the treatment of patients with anthracycline- and taxane-pretreated ABC is generally greater than or equal to second-line. Thus, addition of bevacizumab to capecitabine produced a significant increase in RR, but this did not translate into improved PFS or OS in a Phase III trial.[11] Another such drug is sunitinib, an oral inhibitor of multiple receptor tyrosine kinases, which has been approved for the treatment of advanced renal cell carcinoma, imatinib- or intolerant-resistant gastrointestinal stromal tumor, and metastatic pancreatic neuroendocrine tumor. Unfortunately, sunitinib monotherapy attained less effect than capecitabine in patients with anthracycline- and taxane-pretreated ABC, and even shortened the PFS.[10] Subsequent researchers continued to perform a randomized Phase III trial to compare sunitinib plus capecitabine with single-capecitabine. The result was not much better than previous research, sunitinib plus capecitabine failed to improve the clinical outcome of patients with ABC patients pretreated with anthracyclines and taxanes too.[13] These results imply that anti-angiogenesis therapy cannot play the key role in the treatment of patients with anthracycline- and taxane-pretreated ABC. Enzastaurin, a novel oral serine/threonine kinase inhibitor that targets protein kinase C/phosphoinositol-3-kinase/protein kinase B pathways to inhibit proliferation, induce apoptosis, and suppress tumor angiogenesis.[26] The combination of enzastaurin plus capecitabine was safe and effective in patients with ABC showed in a Phase I study,[27] nevertheless, the subsequent Phase II study was unable to find the preferable survival outcomes relative to capecitabine alone in ABC patients. Lilly pharmaceuticals have decided to give up enzastaurin clinical development.

The most common AE of Grade 3–4 is listed in [Table 2]. Hematologic AEs were more frequent and more severe in the other regimens than capecitabine monotherapy because the combination therapy was common in the experimental group, especially double chemotherapy drugs that could result in the worsen suppression of bone marrow. There was no significant difference in nonhematologic AEs including hand-foot syndrome between the other regimens and the monotherapy arm because capecitabine was applied in the experimental group of five trials. Moreover, the incidences of Grade 3–4 neuropathy in ixabepilone plus capecitabine group and Grade 3–4 hypertension in bevacizumab/sunitinib group were more frequent than capecitabine monotherapy.

Our meta-analysis has several limitations. First, significant heterogeneity existed among the studies used to assess the effect of PFS and ORR, probably because the difference of the results of these trials was so distinct. Nevertheless, the heterogeneity of OS which was the most meaningful index for ABC is not statistically significant. Second, the data of PFS and OS is not intact, especially the HR and 95% CI of OS are reported by only five trials. Third, publication bias is also a concern in all forms of meta-analyses.


 > Conclusion Top


In summary, this analysis indicates that capecitabine monotherapy is still the first choice for patients with anthracycline- and taxane-pretreated ABC. The other regimens fail to improve ORRs and prolong the PFS, no matter other chemotherapy regimens or target therapy, and these regimens could cause more severe bone marrow suppression. A recent study affirmed that estrogen receptor positivity and single-organ metastasis could be useful predictive markers for better PFS of capecitabine monotherapy in anthracycline- and taxane-pretreated ABC patients.[28] We think that the discovery of precise target is much more promising than the development of new therapy regimens in patients with anthracycline- and taxane-pretreated ABC.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
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