Abstract
OBJECTIVE In China, vinorelbine plus an anthracycline is a common neoadjuvant regimen for locally-advanced breast cancer (LABC). Pegylated liposomal doxorubicin (PLD) is an alternate anthracycline formulation with a more favorable safety profile compared with conventional anthracyclines.
METHODS In this open-label trial, 61 women with LABC received up to 6 cycles of PLD 30 mg/m2 on Day 1 and vinorelbine 25 mg/m2 on Days 1 and 8 every 21 days. Hormone receptor and/or HER2 status was not routinely available.
RESULTS The overall clinical response rate (primary efficacy endpoint) was 80% (95% CI: 68%-89%). Two patients achieved a pathological complete response (3%), with 75% having their tumor down-staged, and 89% proceeding to tumor resection. The most frequent nonhematologic adverse events were stomatitis, fever, rash, and palmar-plantar erythrodysesthesia, with none considered serious. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 10% and 2% of patients, respectively.
CONCLUSION PLD plus vinorelbine demonstrated comparable efficacy to conventional anthracyclines plus vinorelbine in the neoadjuvant treatment of LABC, but may offer safety advantages.
keywords
- breast cancer
- anthracycline
- doxorubicin
- pegylated liposomal doxorubicin
- PLD
- vinorelbine
- locally-advanced
- neoadjuvant
Introduction
The treatment of locally-advanced breast cancer (LABC) remains a clinical challenge. Unlike early breast cancer, it has long been recognized that LABC cannot be cured by surgery alone[1,2]. Neoadjuvant therapy was pioneered in patients with LABC in an attempt to improve outcomes and now represents the standard of care in this setting[3]. The role of neoadjuvant therapy has evolved to encompass patients with large volume disease to achieve operability and in patients with lower volume disease to decrease the incidence of ipsilateral recurrences and determine chemosensitivity.
Antineoplastic treatment of breast cancer centers on the use of anthracycline-based combination chemotherapy[4-6]. In China, a regimen of vinorelbine plus conventional anthracyclines is commonly used in the adjuvant and neoadjuvant settings and is supported by trials demonstrating efficacy of the combination in women with breast cancer[7-9].
Despite the benefits of conventional anthracyclines, the acute and late toxicities associated with these agents, such as myelosuppression, alopecia, and cardiotoxicity, remain a clinical problem. Pegylated liposomal doxorubicin (PLD) has been shown to be equally effective, but better tolerated than conventional anthracyclines and to be active as neoadjuvant therapy[10-12]. The combination of PLD and vinorelbine has demonstrated efficacy and tolerability in individuals with advanced breast cancer and thus represents a rational regimen in the neoadjuvant setting[13-15].
This open-label, single arm multicenter trial combined vinorelbine with PLD to evaluate its safety and efficacy as neoadjuvant therapy in patients with LABC.
Patients and Methods
Women at least 18 years of age with a histologic or cytologic diagnosis of breast cancer were enrolled. All had previously untreated locally-advanced disease (stage IIb, IIIa, or IIIb), at least one target lesion with a minimum lesion size as per RECIST criteria, ECOG performance status < 2, left ventricular ejection fraction (LVEF) greater than or equal to the institutional lower limit of normal, and normal bone marrow, renal, and hepatic function, unless abnormal due to tumor involvement[16]. Patients were excluded from enrollment if they were pregnant or breast feeding, had a history of cardiac disease (New York Heart Association class II or greater), uncontrolled infection, symptomatic brain metastases, or prior radiation therapy to more than one third of hemopoietic sites.
This study was performed in accordance with good clinical practices and complied with requirements established by the Declaration of Helsinki. It was approved by the local ethics committee. All patients gave informed consent.
Eligible patients received up to 6 cycles of neoadjuvant chemotherapy with PLD 30 mg/m2 administered over 1 h on Day 1 and vinorelbine 25 mg/m2 administered over 1 h on Days 1 and 8 every 21 days followed by surgery. The protocol stipulated that the PLD dose be delayed, reduced, or discontinued at the discretion of the investigator in the event of palmar-plantar erythrodysesthesia (PPE), neutropenia, thrombocytopenia, elevated bilirubin levels, stomatitis, infusion reaction, or any grade 3 or 4 adverse events [National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0].
The primary efficacy variable was overall clinical response rate (cCR and cPR) in the intent-to-treat (ITT) population. Secondary efficacy variables were pathological complete response rate (pCR), tumor down-staging, and resection rate. Response was evaluated after 2 cycles of treatment to determine if additional cycles were needed before surgery or if an other treatment should be implemented. Target and non-target lesions were assessed for response using RECIST criteria[16]. At the time of surgery, lesions were assessed for pathological response. Using a slice thickness of 3 to 5 μm, a pCR was defined as no microscopic evidence of residual viable tumor cells (invasive or noninvasive) in all resected breast tissues and axillary lymph nodes.
Patients underwent physical examination, routine hematologic monitoring, and urinalysis at baseline and at the start of each cycle. An echocardiogram and ECG were performed at the same intervals. Adverse events were graded using the NCI-CTC, version 3.0.
A sample size of approximately 60 patients was calculated as to provide a precision of at least 12% for the two-sided 95% confidence interval (CI) for response rate. Demographic data were reported as the mean, median, standard deviation, and/or range (continuous variables) or summarized by frequency and percentage (categorical variables). Overall response, pCR, tumor down-staging, and resection were presented as the frequency and percentage with the two-sided confidence interval.
Results
A total of 61 women were enrolled from January 2006 to July 2006, received at least one dose of study medication and underwent at least one post-baseline assessment (ITT population). The following hospitals enrolled patients in the trial: Fudan Shanghai Cancer Center (Shanghai), Cancer Institute & Hospital of Chinese Academy of Medical Sciences (Beijing), Xijing Hospital (Xi’an), Shandong Cancer Hospital (Jinan), Fujian Provincial Cancer Hospital (Fuzhou), Shanghai 6th People’s Hospital (Shanghai), Sun Yat-Sen Memorial Hospital (Guangzhou), 307 Hospital of PLA (Beijing), and Liaoning Province Cancer Hospital (Shenyang). The median number of completed cycles in the ITT population was 4 (range, 1-6). Fifty-seven women completed 2 cycles, 32 completed 4 cycles, and 21 completed 6 cycles. The mean age was 48 years. Most women were premenopausal (62%) and had stage IIB (36%) or IIIA (41%) disease at baseline (Table 1). Hormone receptor and/or HER2 status were not routinely available from all patients.
Baseline characteristics in 61 women in the ITT population.
Efficacy
Overall clinical response in the ITT population was 80.3% (95% CI: 68.2%-89.4%), with 6 patients (9.8%) achieving a cCR (Table 2). Clinical down-staging after neoadjuvant chemotherapy but before surgery was achieved in 46 patients (75.4%) (Table 3). Fifty-four patients (88.5%; 95% CI: 77.8%-95.3%) underwent surgery for tumor resection. A pCR was achieved in 1 of 54 patients (1.85%; 95% CI: 0.047% - 9.8%).
Clinical response (ITT population).
Change in clinical stage from baseline to completion of chemotherapy, but before surgery (ITT population).
Safety
Adverse events were reported in 47.5% of patients, with the most frequent being stomatitis, fever, rash, and PPE (Table 4). There were no serious adverse events or deaths. No patients experienced treatment delays or dose modifications due to an adverse event. Alopecia, common in patients treated with conventional doxorubicin, was reported in 4.9% of patients.
Treatment-related adverse events in 5% or more of patients (ITT).
Hematologic adverse events, which included neutropenia and thrombocytopenia, were primarily grades 1 and 2. Grade 3 or 4 neutropenia and thrombocytopenia were reported in 21.3% and 1.6% of patients, respectively.
Discussion
Worldwide, breast cancer is the most common malignancy in females with 1.15 million new cases annually, accounting for 23% of all cancers. Breast cancer is of particular concern in China, where the age standardized breast cancer incidence was 18.7 per 100,000 in 2002 and the incidence is reportedly increasing at an annual rate of 3% to 4%[17]. In response to the growing threat of breast cancer, a massive campaign has been implemented to address the lack of awareness of the disease in this region. While the use and study of taxanes, hormones, and biological therapies in the neoadjuvant setting is increasing, and anthracyclines remain a standard of care in this setting.
In the limited number of randomized controlled trials assessing neoadjuvant anthracycline-based therapy, the overall response rates ranged from 61% to 85%[6,18-20]. In the phase III TOPIC 2 trial, neoadjuvant vinorelbine plus epirubicin was compared with the standard breast cancer regimen of conventional doxorubicin plus cyclophosphamide in 451 women with operable breast cancer. Efficacy results were nearly identical with the 2 treatments. In the vinorelbine plus epirubicin arm, the overall clinical response was 74%, cCR 24%, and pCR 12%. Dose reduction was required in 20% of the patients in the vinorelbine plus epirubicin group. Grade 3-4 toxicity in both conventional anthracycline-containing groups were numerous and included alopecia (46%-60%), thrombophlebitis (10%-36%), neutropenia (8%-38%), and leukopenia (26%-21%)[6].
These data are consistent with phase II studies in which PLD was administered in combination with cyclophosphamide or paclitaxel in the neoadjuvant setting, yielding response rates of 73% and 71%, respectively, and less myelosuppression and alopecia than conventional doxorubicin[11,12].
In our phase II study, we observed an overall clinical response of 80% and a pCR in 1 patient with the combination of PLD plus vinorelbine in women with LABC. This overall response rate is similar to that achieved in phase III randomized trials of neoadjuvant therapy. Efficacy is also supported by the high down-staging and tumor resection rates achieved. Low rates of alopecia, PPE, and grade 3 or 4 neutropenia support the substitution of PLD for conventional doxorubicin in this regimen.
Although clinical cardiotoxicity is uncommon with anthracyclines in the neoadjuvant setting, subclinical cardiotoxicity is an important concern. Myocardial damage occurs with administration of the first anthracycline dose and the risk of cardiotoxicity increases as the cumulative dose increases[21,22]. Most patients treated with neoadjuvant anthracyclines receive doses well below the threshold for clinical cardiotoxicity. However, individuals treated in the neoadjuvant setting will require additional treatment in the adjuvant and ultimately the metastatic settings. Upon reaching the threshold cumulative dose for clinical cardiotoxicity, patients may be denied additional anthracycline treatment in these settings. PLD carries a considerably lower risk of cardiotoxicity compared with conventional doxorubicin and its use in the neoadjuvant setting may allow anthracycline administration to be repeated as required[10,23].
Conclusions
The combination of PLD and vinorelbine is active in the neoadjuvant treatment of LABC, yielding response rates similar to those achieved in phase III randomized trials. Additional benefits included tumor down-staging in 75% of patients and a tumor resection rate of 89%. The treatment was well tolerated. PLD plus vinorelbine is a rational alternative for neoadjuvant therapy in LABC.
Conflict of interest statement
No potential conflicts of interest were disclosed.
Acknowledgments
We would like to thank the Phillips Group for technical assistance and Schering Corp. (China), a Division of Merck & Co. provided the study drug, Caelyx® and a research grant.
- Received December 19, 2009.
- Accepted February 9, 2010.
- Copyright © 2010 by Tianjin Medical University Cancer Institute & Hospital and Springer
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