Abstract
Background/Aim: Pegylated liposomal doxorubicin (PLD) has been proven to be an effective antitumor drug for metastatic breast cancer, with less toxicity than conventional anthracycline. Our objective was to evaluate the efficacy and safety of PLD-based adjuvant chemotherapy compared to conventional chemotherapy for patients with stages I-III Triple-negative breast cancer (TNBC). Patients and Methods: A total of 162 patients, histologically proven to have TNBC at stages I–III between 2003 and 2010, were enrolled to evaluate the impact of PLD- and non-PLD-based adjuvant chemotherapy by using the end-pint of overall survival (OS) and relapse-free survival (RFS). Results: Forty-nine (30.2%) patients received PLD-based adjuvant chemotherapy and 113 (69.8%) a non-PLD regimen, including 84 (52%) patients receiving non-PLD anthracycline. The Kaplan–Meier calculation indicated no differences in RFS and OS between the PLD and non-PLD groups. Multivariate analysis adjusted for tumor size and lymph node status also revealed similar RFS (HR=0.86, 95% CI=0.43-1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41-1.79, p=0.692) for PLD-based chemotherapy compared with non-PLD-based. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia (25% vs. 41.6%, respectively; p=0.054) and significantly higher incidence of hand–foot syndrome (16.3% vs. 4.4%, respectively; p=0.010). Conclusion: PLD-based adjuvant chemotherapy was as effective as conventional chemotherapy for patients with TNBC. PLD is an alternative for patients with TNBC when conventional anthracycline is inappropriate.
Triple-negative breast cancer (TNBC), defined as the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), represents approximately 15% of breast cancers (1). Patients with TNBC usually have a poorer prognosis than those with hormone receptor-positive breast cancer because TNBC shows a higher relapse rate and specific anti-hormone and targeted-therapies are not available (2). In addition, TNBC metastasizes more frequently into the visceral organs than hormone receptor-positive breast cancer (3), further down-grading the prognosis.
Anthracyclines and taxanes are the mainstay chemotherapy agents for breast cancer. In TNBC, adjuvant chemotherapy with anthracycline and taxane produced a lower relapse rate and an improved overall survival (OS) rate (4, 5). However, conventional anthracycline can produce serious adverse effects. Dilated cardiomyopathy is the major toxicity, causing heart failure in patients receiving high cumulative doses of anthracycline (6). Other adverse effects, such as neutropenia and alopecia, diminish the patient's quality of life (7).
Pegylated liposomal doxorubicin (PLD), a formulation of doxorubicin-encapsulated liposomes, is sterically stabilized by grafting polyethylene glycol onto the liposomal surface (8). The pegylated liposomal encapsulation reduces the plasma levels of the free drug, as well as reducing toxicity to normal tissues (9). PLD has a longer circulation half-life of approximately 73.9 h compared to doxorubicin's half-life of less than 10 min (9). Prolonged circulation permits a greater uptake probability of PLD liposomes by the tumor cells. In a previous pharmarcokinetic study, PLD accumulated selectively in metastatic breast cancer tissue, resulting in 10-fold higher intracellular drug concentrations compared to the adjacent normal tissue (10). PLD has been proven to have low toxicity, reduced adverse cardiac effects, and enhanced antitumor activity.
For metastatic breast cancer, PLD has been demonstrated to be an effective treatment agent. Compared to vinorelbine-based salvage chemotherapy (vinorelbine or mitomycin C plus vinblastine), patients receiving PLD had a similar progression-free survival (PFS) and OS for their taxane-refractory metastatic breast cancer (9). The PLD-docetaxel combination had significantly greater efficacy than docetaxel alone in patients with metastatic breast cancer who had experienced a relapse after prior adjuvant anthracycline therapy, without an increase in cardiac toxicity (11). Monotherapy of PLD as the first-line therapy for advanced breast cancer in elderly patients led to a median time-to-progression of 5.7 months and OS of more than 20 months (12). Therefore, PLD is an effective chemotherapy agent without additive cardiac toxicity for metastatic breast cancer. However, whether PLD can also serve as effective chemotherapy in the adjuvant setting after mastectomy has not been well studied.
In the present study, we aimed to evaluate the efficacy and safety profile of PLD in the adjuvant setting. Because TNBC is characterized by a high relapse rate and a lack of anti-hormone/targeted therapy, it is appropriate for evaluating the efficacy of adjuvant chemotherapy. We retrospectively identified patients with TNBC who were diagnosed and received adjuvant chemotherapy at the China Medical University Hospital (Taiwan), and compared the efficacy and safety between PLD-based and non-PLD-based chemotherapy regimens.
Patients and Methods
Patients. There were 287 patients histologically proven to have TNBC at stages I-III at China Medical University Hospital between January 2003 and December 2009. Thirty-one patients, who were lost to follow-up or did not have detailed information, were excluded; 67 patients, who did not receive adjuvant chemotherapy, and 27 patients, who were treated with oral tegafur-uracil alone, were also excluded from this study. Finally, a total of 162 patients were enrolled for further analysis. This study was approved by the Institutional Review Board of the China Medical University Hospital (CMUH102-REC1-098).
The clinical and pathological characteristics of all the patients were retrospectively reviewed. Clinical characteristics included age at diagnosis, diagnostic date, chemotherapy, radiotherapy, recurrence date, and date of death. The histopathology of the breast tumor was assessed by pathologists. Classification of tumor size was measured according to the seventh edition of the American Joint Committee on Cancer staging (AJCC) system (13). ER, PR, and HER2 were determined by immunohistochemical staining. ER and PR were considered negative when fewer than 10% of the tumor cells exhibited positive staining. For HER2 staining, a score of 3+ was considered positive; a specimen with a score of 2+ was determined by fluorescence in situ hybridization analysis. The tumor histological grade was defined by the Nottingham combined histological grading system. (14) Lymphovascular invasion (LVI) and perineural invasion (PNI) were also examined.
Adjuvant chemotherapy. At China Medical University Hospital, adjuvant chemotherapy was required to be given within four weeks after mastectomy. The non-PLD anthracycline-containing regimens included doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2 (AC) for four courses; cyclophosphamide at 600 mg/m2, epirubicin at 90-100 mg/m2, and 5-fluorouracil at 600 mg/m2 (CEF) for six courses; and cyclophosphamide at 600 mg/m2, doxorubicin at 50-60 mg/m2, and 5-fluorouracil at 600 mg/m2 (CAF) for 4-6 courses. Two kinds of regimens of PLD-based adjuvant therapy were used for the patients with TNBC: PLD-cyclophosphamide (PLD at 40 mg/m2 and cyclophosphamide at 600 mg/m2) and PLD-cisplatin (PLD at 40 mg/m2 and cisplatin at 75 mg/m2) for 4-6 courses. Taxane (paclitaxel or docetaxel) was usually administered sequentially after four courses of AC or CEF, such as a regimen of four courses of AC plus four courses of triweekly docetaxel 75 mg/m2.
The choice of PLD- or non-PLD-based adjuvant chemotherapy was determined by the physicians in discussion with the patients. In Taiwan, all of the residents are requested to participate in the National Health Insurance scheme (by law), which provides conventional anthracycline and taxane as adjuvant chemotherapy agents. PLD is not included and had to be paid for by the patients themselves. The major reasons the patients chose PLD were concern over cardiac toxicity, alopecia, neutropenia, and performance status.
Post-mastectomy radiation therapy (PMRT). PMRT was prescribed according to the 2011 St Gallen Breast Cancer Consensus (15). Patients received PMRT if their tumor size was greater than 5 cm and more than three lymph nodes were involved by breast cancer. Patients who were treated with conservative surgery also received PMRT.
Statistical methods. The primary goal of the study was to analyze the efficacy of PLD in the adjuvant setting, including a comparison of RFS and OS between the PLD- and non-PLD-based chemotherapies. We also evaluated the survival difference between the PLD and non-liposomal anthracycline-based adjuvant chemotherapies. OS and RFS were analyzed using the Kaplan–Meier method. Cox's proportional hazards model was used to determine the hazards ratios (HR) and corresponding 95% confidence interval (CI) for various factors and chemotherapies for the RFS and OS.
The secondary goal was to record and compare the safety profiles between the PLD- and non-PLD-based adjuvant therapies. The adverse effects were retrospectively reviewed using chart records and included nausea, vomiting, and other clinical symptoms/signs, as well as laboratory data. The grade of adverse effects was recorded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. (16) Independent t-tests and χ2 tests were used to compare the patient characteristics and adverse effects between the two groups. All statistical assessment was two-sided and evaluated at the 0.05 level of significance.
Clinical and pathological characteristics of patients treated with and without pegylated liposomal doxorubicin (PLD) for triple-negative breast cancer.
Results
Patients' characteristics and chemotherapy regimens. A total of 162 patients with TNBC were enrolled in the study, out of which 49 (30.2%) received PLD-based adjuvant chemotherapy and 113 (69.8%) received non-PLD regimens. Patients were categorized into the PLD and non-PLD groups for further analysis. The median follow-up time was 47.05 months (range=12.20-97.94 months). Patients receiving the non-PLD-based chemotherapy had a slightly higher trend for T3-4 (p=0.084) and N2-3 disease (p=0.105), but this was not significantly different between the PLD and non-PLD groups. Other clinical and pathological parameters were similar for the two patient groups (Table I).
The majority of patients (82.1%) were treated with anthracycline-containing chemotherapy regimens (including PLD and non-PLD anthracycline); 20 patients received taxane, and 14 patients received cisplatin in their adjuvant chemotherapy protocol. Forty-nine patients (30.2%) had PLD-based treatment; 43 of them received PLD-cyclophosphamide and the other 6 patients received PLD-cisplatin. The actual number treatment courses of PLD-cyclophosphamide was a mean of 3.6 (range=2-6). The non-PLD anthracycline-containing regimens included AC in 16 patients, and CEF or CAF in 59 patients. Twenty patients received a taxane-containing regimen; 15 patients were treated with taxane chemotherapy sequentially after AC or CEF; 4 patients were treated with taxane plus cisplatin; and one was treated with taxane plus gemcitabine chemotherapy. Twenty-four patients were treated with CMF.
Risk of relapse of triple-negative breast cancer according to clinical factors.
Factors related to tumor relapse. Among the clinical parameters, a univariate analysis showed that larger tumor size (T3 and T4), advanced lymph node involvement, and PNI were related to significantly poor RFS. Other factors, including age (>50 years vs. <50 years), histological grade, LVI and PMRT, did not influence the RFS. For the multivariate analysis, the T4 classification (HR=22.69, 95% CI=4.04–127.24, p<0.0001), advanced lymph node involvement (N1: HR=4.21, 95% CI=1.60–11.08, p=0.004; N3, HR=26.24, 95% CI=6.64-103.70, p<0.001), and N2 (with borderline difference: HR=3.77, 95% CI=0.83–16.22, p=0.076) were independent risk factors associated with tumor recurrence, after adjusting for age, T classification, lymph node status, histological grade, LVI, PNI, and radiation therapy (Table II). The significance of N2 was probably only borderline because of the fewer number of patients (n=17). Other clinical and pathologic factors were not relevant to tumor relapse.
Significant adverse effects compared between pegylated liposomal doxorubicin (PLD)-based and non-PLD-based chemotherapy.
Efficiency of PLD-based adjuvant chemotherapy. The Kaplan–Meier analysis did not show any difference in the RFS and OS between the patients who received PLD- and those receiving non-PLD-based adjuvant chemotherapy (Figure 1A, 5-year RFS, PLD vs. non-PLD: 66.7±7.8% vs. 69.6±4.5%, p=0.983; Figure 1C, 5-year OS, PLD vs. non-PLD: 68.1±8.2% vs. 70.2±4.7%, p=0.840). There was also no difference in the RFS and OS between the patients who received PLD and those receiving non-PLD anthracycline-containing adjuvant therapy (Figure 1B, 5-year RFS, PLD vs. non-PLD anthracycline: 66.7±7.8% vs. 65.9±5.4%, p=0.722; Figure 1D, 5-year OS, PLD vs. non-PLD: 68.1±8.2% vs. 67.0±5.7%, p=0.665).
Because tumor size and lymph node status were factors significantly associated with patient survival, we adjusted for these two factors in the multivariate model analysis. Patients who received PLD-based adjuvant chemotherapy had similar RFS (HR=0.86, 95% CI=0.43–1.73, p=0.678) and OS (HR=0.86, 95% CI=0.41-1.79, p=0.692) as compared to the non-PLD-based chemotherapy. The RFS (HR=0.83, 95% CI 0.40–1.70, p=0.603) and OS (HR=0.89, 95% CI 0.42-1.90, p=0.893) of the PLD-treated patient group were also not different from those of the non-PLD anthracycline-treated group. These findings illustrate that the efficacy of PLD-based adjuvant chemotherapy was equivalent to conventional adjuvant therapy.
Adverse effects. The overall incidences of grade 3 and 4 toxicities in the PLD-based adjuvant chemotherapy were similar to those of the non-PLD chemotherapy and non-PLD anthracycline-containing chemotherapy (Table III). The sub-group analysis showed that grade 3-4 neutropenia occurred less frequently with PLD-based chemotherapy (25.0%) than non-PLD-based chemotherapy (41.6%, p=0.054). The PLD-based chemotherapy was significantly associated with a higher incidence of grade 3-4 hand–foot syndrome (16.3%), as compared to the incidence with non-PLD-based chemotherapy (4.4%, p=0.010) and non-PLD-based anthracycline chemotherapy (2.4%, p=0.003). Grade 3-4 anemia was not different between the PLD and non-PLD chemotherapies. All patients received antiemetic agents, including serotonin receptor antagonist. The occurrence of grade 3-4 nausea and vomiting was slightly higher in the non-PLD group but without any statistical difference.
Among the 162 patients, no patient was diagnosed as having heart failure after the adjuvant chemotherapy by the retrospective chart review. Heart function was evaluated in a small proportion of patients by ultrasound. Before adjuvant chemotherapy, the mean left ventricle contractility was 59.25% [standard deviation (SD)=5.65%] and 63.5% (SD=2.12%) in 16 patients of the non-PLD anthracycline-treated group and three patients of the PLD-treated group, respectively. After adjuvant chemotherapy, the mean left ventricle contractility was 56.9% (SD=5.71%) and 61.9% (SD=4.73%) in 12 patients of non-PLD anthracycline-treated group and seven patients of the PLD-treated group, respectively.
Discussion
To our knowledge, this is the first and largest cohort study to analyze PLD-based adjuvant chemotherapy for breast cancer. Our data suggested that the efficacy of PLD-based adjuvant chemotherapy was similar to conventional treatments for TNBC. Patients receiving PLD-based chemotherapy had a relatively lower incidence of grade 3-4 neutropenia, but a significantly higher incidence of hand–foot syndrome.
Kaplan–Meier analyses of relapse-free survival (A,B) and overall survival (C,D) for patients treated with pegylated liposomal doxorubicin based chemotherapy versus those treated with non-PLD adjuvant chemotherapy (A,C), and for patients treated with non-PLD anthracycline versus those treated with PLD (B,D) adjuvant chemotherapy.
The incidence of anthracycline-induced congestive heart failure was found to increase in relation to the total dose of administered drug, especially when the cumulative dose of the doxorubicin exceeded 550 mg/m2 of body-surface area (17, 18). Although no patients developed cardiac toxicity in this study, in patients receiving non-PLD anthracycline, old age along with previous cardiac disease will amplify the development of doxorubicin-induced cardiomyopathy (19, 20). Thus, this patient group is not appropriate for receiving conventional anthracycline. In addition, if anthracycline was used in the adjuvant chemotherapy, it was not considered in the metastatic setting because of the increased risk of cardiotoxicity. However, PLD is different from conventional anthracycline. A phase III trial showed that PLD had comparable efficacy and significantly reduced cardiac toxicity as compared to doxorubicin in the first-line treatment of metastatic breast cancer (16). In addition, an anthracycline re-challenge with PLD also showed PLD to be more effective, with fewer cardiac toxicities in patients with metastatic breast cancer who had previously been treated with adjuvant conventional anthracycline-based chemotherapy (21, 22).
All of the evidence from clinical observations and trials revealed equal or superior efficacy of PLD-based chemotherapy compared with doxorubicin for metastatic breast cancer. However, it was not known whether the efficacy of adjuvant PLD-based chemotherapy was similar to conventional anthracycline. In our study, we selected patients with TNBC to examine the efficacy of PLD-based adjuvant chemotherapy. TNBC is characterized by a high relapse rate and absence of anti-hormone/targeted therapy, thus the dilution of the potential magnitude of chemotherapy effect size by anti-hormone and anti-HER2 therapy can be avoided (23). Our results showed PLD-based adjuvant chemotherapy offered similar efficacy in the adjuvant setting when compared with conventional chemotherapy, including a comparison with conventional anthracycline.
In addition to reducing cardiac toxicity, our results showed a decrease in the incidence of grade 3-4 neutropenia of borderline significance. Reductions in grade 3-4 neutropenia and other hemorrhagic toxicities were also observed in other PLD-based chemotherapies for metastatic breast, ovarian and other cancer types (24, 25, 26). The advantages of PLD benefit its combination with other agents and could improve patient adherence to the chemotherapy protocol without delay or early termination. Adjuvant polychemotherapy was demonstrated to result in a significantly reduced risk of recurrence (age <50 years: HR=0.73, age 50–69 years: HR=0.82) in patients with ER-poor breast cancer by a meta-analysis from the Early Breast Cancer Trialists' Collaborative Group (27). Taxane is another important chemotherapy agent proven to reduce breast cancer recurrence, but its use also results in frequent grade 3-4 neutropenia. Since TNBC is a highly malignant cancer type associated with a superior tumor relapse rate and inferior RFS and OS, intensive chemotherapy, such as a combination of taxane and anthracycline, could improve the RFS, OS, and diminish tumor relapse in TNBC (28, 29). In a phase III adjuvant docetaxel for node-positive breast cancer, chemotherapy with docetaxel, doxorubicin, and cyclophosphamide combination resulted in a favorable RFS over that with fluorouracil, doxorubicin and cyclophosphamide combination in adjuvant chemotherapy for TNBC. However, a combination of anthracycline and taxane caused a significantly higher frequency of grade 3-4 neutropenia, even though the study selected patients with Karnofsky performance scales of 80% or more (30). When compared with docetaxel monotherapy for metastatic breast cancer, PLD-plus-docetaxel did not increase the incidence of grade 3-4 neutropenia, and the combination chemotherapy significantly improved the response rate and time-to-progression (31). Therefore, PLD instead of anthracycline may be an alternative choice without reduced efficacy, especially for elderly patients and those whose performance is not good enough for conventional anthracycline. This strategy may improve adherence without decreasing dose intensity and may be more suitable for combination with taxane for chemotherapy of TNBC to reduce tumor relapse rate.
There are several limitations to our research and of PLD. First off, our research was a retrospective study. To accurately establish the efficacy of PLD-based adjuvant chemotherapy still requires well-designed prospective trials. However, strict inclusion and exclusion criteria may limit study progress and further application in general patients. Recently, a multicenter trial prospectively investigated PLD and metronomic cyclophosphamide plus methotrexate as adjuvant chemotherapy for elderly patients with breast cancer, but slow and inadequate enrollment during two years was reported. In the 36-patient analysis, the efficacy of PLD was 78%, with a breast cancer-free interval of three years; the author concluded that PLD was a reasonable option for elderly patients with endocrine nonresponsive breast cancer (23). In our study, we demonstrated that the RFS and OS were equal for the PLD-treated and non-PLD-treated groups. This result corresponds with the conclusion of the CASA trial. Secondly, the adverse effects of symptoms such as nausea, vomiting, and hand–foot syndrome were very difficult to record comprehensively in a retrospective study. Our data showed a high probability of hand–foot syndrome with the PLD-based chemotherapy; these results were compatible with the adverse effects of previous prospective trials on metastatic breast cancer (8). Thirdly, for PLD itself, hand–foot syndrome is the major toxicity which reduces patient quality of life. Hand–foot syndrome is palmar-plantar erythrodysesthesia associated with certain chemotherapeutic agents, including PLD, capecitabine, and several tyrosine kinase inhibitors (29). Early detection, adequate dose modification, and topical ointment treatment can help to maintain skin integrity (29, 30). Inflammatory reaction is the possible mechanism and selected cyclooxygenase-2 inhibitor may prevent hand–foot syndrome (31). Reactive oxygen species and chemokines were found to be involved in the pathogenesis of palmar-plantar erythrodysesthesia. Trapping the reactive oxygen species may be a good choice and can be developed to prevent hand–foot syndrome in the future (32).
In conclusion, the efficacy of PLD was comparable to commonly used agents, such as conventional anthracycline, in adjuvant chemotherapy for TNBC. A PLD-based regimen is, therefore, a good alternative adjuvant therapeutic option for patients inappropriate for conventional anthracycline, especially for patients with previous cardiac disease or old age. In order to validate the efficacy of PLD-based adjuvant chemotherapy in general patients, further prospective study is required.
Acknowledgements
This work was supported in part by China Medical University (CMU100-NTU-002), China Medical University Hospital (Grant DMR-101-068), research grants from the National Science Council (NSC 101-2314-B-039-019), research grants from the Taiwan Department of Health, China Medical University Hospital Cancer Research Center of Excellence (MOHW103-TD-B-111-03), and the International Research-Intensive Centers of Excellence in Taiwan, National Science Council, (I-RiCE, NSC103-2911-I-002-303).
Footnotes
-
Conflicts of Interest
The Authors declare they have no conflicts of interest.
- Received July 28, 2014.
- Revision received September 15, 2014.
- Accepted September 22, 2014.
- Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
