Background
Anthracyclines are among the most active drugs in advanced breast cancer, with response rates as single agents of approximately 30% to 50%, and anthracycline-based regimens have been shown to determine significant advantages in response rate and progression free survival over non- anthracycline-containing regimens [
1,
2]. The potential benefit of conventional anthracyclines, mainly doxorubicin, is limited by the risk of cardiac dysfunction, clearly related to cumulative dose, and as a result it might be necessary to withdraw treatment or to avoid re-treatment even in potential responders patients.
To minimize toxic effects, doxorubicin has often been replaced by epirubicin (EPI), known to be as active as the parent compound and with lower toxicity, particularly cardiac toxicity [
3‐
6]. As dose-response concerns, higher EPI doses, both as single agent and in combination regimens, seem to be more efficacious than lower doses [
7‐
10].
Vinorelbine (VNB) has established activity as single-agent in breast cancer, both as first-line and salvage treatment [
11,
12], and its good tolerance profile makes it an excellent candidate for combination regimens, so it was a logical step to combine VNB with anthracyclines, and the combination with doxorubicin yielded a 74% of response rate, a median duration of response of 12 months and a median survival of 27.5 months as first-line treatment [
13]. Other trials employing this combinations confirmed positive results [
14‐
16]. Preliminary results of a randomized phase III trial comparing VNB 25 mg/m
2 on days 1,8 in combination with EPI 90 mg/m
2, with EPI as single agent, showed a trend for higher response rate (50% vs 42%) and a significantly longer progression free survival (10.1 vs 8.2 months) for the combination arm [
17]. An our previous clinical study with EPI/VNB combination as first-line treatment showed a very high activity (70.6% of response rate) and acceptable toxicity [
18]; another our experience testing the sequential administration of docetaxel for 4 cycles followed by 4 cycles of EPI/VNB as first-line treatment for advanced disease, confirmed activity and tolerability of the regimen [
19].
Incapsulating drugs in liposomes determine improvement of solubility and stability of the drug, and prevent a rapid degradation; moreover, specific toxicities are potentially lowered and the efficacy increased, achieving a higher therapeutic index [
20]. Liposomal anthracyclines exhibit efficacies comparable with those of conventional anthracyclines, but with better safety profiles [
21‐
24]. In particular, data from retrospective analyses showed that liposomal anthracyclines significant reduced the risk of cardiotoxicity compared with conventional anthracyclines [
25]. Phase III trials comparing pegylated liposomal doxorubicin (PLD) with conventional anthracyclines confirmed similar efficacy and lower toxicity than doxorubicin [
24,
26], and results of several studies have shown that PLD is effective in combination with other drugs including taxanes, cyclophosphamide, gemcitabine [
27]. As cardiotoxicity concerns, in a retrospective analysis a low incidence of cardiac side effects were reported, even at cumulative doses higher than 500 mg/m
2 [
28]. The combination of PLD with VNB was investigated in anthracycline pretreated patients, with promising results and manageable toxicity [
29,
30], but at the time we design the present study no information about its first-line use in comparison with a conventional anthracycline-containing regimen were available, so we carried out a prospective multicenter phase II randomized trial of EPI/VNB versus PLD/VNB as first-line treatment for advanced disease in patients not previously treated with adjuvant anthracyclines.
Patients and Methods
Patient selection
Patients with histologically proven advanced breast cancer not previously treated with adjuvant anthracyclines were enrolled. Eligibility criteria included a life expectancy > 3 months, 18 to 75 years of age, WHO performance status ≤ 3, measurable/assessable disease, adequate bone marrow (absolute neutrophil count ≥1,500, platelet count ≥ 100,000, haemoglobin ≥ 11 g/dL), renal and liver function (total bilirubin and creatinine <1.25 times the upper normal limits), and a normal cardiac function (left ventricular ejection fraction LVEF ≥ 50% by echocardiography). Patients were excluded from the study if they had active cardiac diseases or significant arrhythmias, pre-existent neuropathy, or had received prior chemotherapy treatment for advanced disease, prior exposure to anthracyclines and or vinorelbine, or if they had prior or concomitant malignant disease, except appropriately treated basal cell carcinoma of the skin or in situ carcinoma of the cervix. Previous adjuvant chemotherapy with cyclophosphamide, methotrexate, fluorouracil or similar regimens were allowed, but an interval of two months should have elapsed; hormonal adjuvant treatment and radiotherapy must have been discontinued for at least 4 weeks before study entry. The protocol was approved by the ethical committees of each participant centers, and was carried out according to Helsinki declaration and in accordance with the International Conference on Harmonization Good Clinical Practice guidelines.
Treatment
Patients were centrally assigned according to a computer generated random list to receive either (arm A) EPI 90 mg/m2 i.v. on day 1 plus VNB 25 mg/m2 i.v on days 1 and 5, with granulocyte colony-stimulating factor (G-CSF) subcutaneously on days 7-12 of each cycle, or (arm B) PLD 40 mg/m2 i.v. on day 1, plus VNB 30 mg/m2 on days 1 and 15. Cycles were repeated every 21 days in arm A, and every 28 days in arm B, for a maximum of 8 cycles. Treatment was continued until disease progression, severe toxicity, patient refusal. Antiemetic treatment consisted of an antiserotonin agent plus desamethasone in a 15 min infusion before starting chemotherapy. Treatment was postponed by a maximum of 2 weeks if the absolute neutrophil count was less than 1,500/ μL or the platelet count was less than 100,000/ μL. A 25% drugs dose-reduction was planned in case of grade 4 neutropenic fever, as well as in case of grade 3 mucositis or neurotoxicity. G-CSF was administered in arm B in case of grade 4 neutropenic fever, and prophylactively in the subsequent cycles. Treatment was discontinued in case of grade 4 neurotoxicity, mucositis, palmar plantar erythrodisesthesia (PPE), treatment delay longer than 2 weeks, or in case of cardiotoxicity, defined as LVEF decrease ≥ 20% from baseline, or ≥10% but with a value below 50%, or any symptoms of congestive heart failure or arrhythmias even in absence of LVEF decrease. Hematologic assessment was done on days 1 and 12 of every cycle in arm A, and on days 1 and 14 in arm B, and whenever useful at discretion of investigator.
Pretreatment and Follow Up Studies
Pretreatment investigations included complete blood count and chemistry, chest x-ray, bone scan, CT abdomen, LVEF evaluation by echocardiography, and other site-specific imaging as appropriate. Echocardiography with LVEF evaluation had to be performed every 3 cycles, or whenever indicated at discretion of investigator; during the follow-up LVEF had to be determined every 6 months.
Evaluation of Response and Toxicity
Tumor assessment was performed every 3 cycles, or whenever appropriate, and responses were evaluated according to RECIST criteria [
31]. Progression free survival (PFS) was calculated starting from the date of randomization to the date of disease progression, refusal or death from any cause; overall survival (OS) was calculated starting from the date of randomization to the date of death or last follow up evaluation. Toxicity was assessed in each cycle according to National Cancer Institute Common Toxicity Criteria (version 3.0).
Statistical Methods
The primary objective of the study was to evaluate the overall response rate of the two regimens, secondarily toxicity, progression free survival and overall survival.
The study was designed as a phase II trial with a random assignement to a calibration arm A and to an experimental arm B. The sample size for arm B was calculated according to the design described by A'Hern [
32]. A sample size of 53 patients was considered sufficient to give a 90% probability of rejecting a baseline response rate of 35% with an exact 5% one-sided significance test when the true response rate was 55%. The drug regimen should have been considered for further studies if at least 25 responses were observed. The calibration arm had the same sample size. No formal comparison was planned. The objective response rate have been reported with its 95% confidence interval. All patients enrolled were considered in the intention-to-treat population (ITT). This population have been evaluated for the efficacy analysis, which was performed also on evaluable patients. Subjects who assumed at least one dose of drug have been considered as denominator in the safety analysis.
The time to event analysis was performed according the Kaplan-Meier method.
Discussion
Currently, there is no "gold standard" therapy for metastatic breast cancer, and treatment decisions must be based on patient and tumor characteristics, and on prior treatments. In the scenario of patients presenting with advanced disease, still exists a subgroup who have received only endocrine adjuvant therapy, or adjuvant chemotherapy with CMF or CMF-like regimens and, less frequently, there is a small cohort treated with adjuvant taxanes-based or other anthracycline-free regimens; moreover, there are also anthracycline pretreated patients with a very long free-interval, to be considered still anthracycline sensitive. In all these patient cohorts there is still the option to employ an anthracycline-based regimen as first-line treatment for advanced disease, mostly in hormonal receptor and/or Her-2 negative tumors, where a "targeted" therapy is not available.
The results of the present study confirm the activity of both anthracycline-based chemotherapy regimens for anthracycline-naïve advanced breast cancer patients, even if lower than expected. Response rate, progression free survival and overall survival observed in experimental arm B were comparable to those obtained in the "calibration" EPI/VNB arm. As toxicity concerns, both regimens were tolerable, with a higher incidence of febrile neutropenia and G3 alopecia in arm A, and of grade 3 mucositis and cutaneous toxicity in arm B. As cardiotoxicity concerns, the relatively low cumulative EPI dose delivered (≤ 720 mg/m2) did not allow to evidence significant clinical cardiotoxicity in the arm A, with only one case of arrhythmia, and a transient and asymptomatic in LVEF decrease occurring in 2 patients (3.7%), leading to a discontinuation of chemotherapy after 5 and 6 cycles, and with a complete recovery within two months.
Analyzing literature data, the EPI/VNB regimen is among the active, non-taxane, anthracycline-containing combinations for breast cancer treatment, as confirmed by definite results of the Scandinavian Breast Trial Group [
33], and other trials [
18], but some instances of clinical cardiac toxicity in terms of congestive heart failure or cardiomyopathy have been reported, with an incidence of asymptomatic LVEF decrease ranging from 20%-30% [
33,
34], so there is an urgent need of introduce new active and safer regimens for anthracycline-sensitive breast cancer patients, and a recent metanalysis showed a significant lower rate of both clinical and subclinical heart failure in patients treated with liposomal anthracyclines, compared with conventional doxorubicin [
35].
A number of phase II trials have recently evaluated PLD in combination regimens with cyclophosphamide, paclitaxel, docetaxel, gemcitabine, VNB, and with biological agent such as trastuzumab or lapatinib, with response rates ranging from 31% to 75%, frequently occurring even in anthracycline pretreated patients [
36], and with negligible cardiotoxicity. In details, the PLD/VNB combination was recently employed in two phase II trials in heavily pretreated patients, yielding a response rate of 36% and 39%, without any cardiac toxicity [
37,
38]. Two more recent reports with PLD/VNB combination as first-line treatment in elderly patients confirmed the good overall clinical response rate (36% and 50%, respectively), and
t he high tolerability of the regimen [
39,
40] suggesting, due to the safety profile of the combination, the employment also in such "frail" patient population.
An increasingly pertinent question in patients relapsing following adjuvant anthracyclines is whether there is a role for anthracycline rechallenge in those with a long free-interval. As a result of a high cardiac risk associated with increasing cumulative anthracycline dose, patients are often denied re-treatment in advanced setting; the choice of a liposomal anthracycline allows the possibility of re-treating an anthracycline-responsive disease without substantially increasing the cardiac risk [
36]; this option should not be excluded in fact, and some evidences come from a recent report on first- line chemotherapy selection in adjuvant anthracycline-pretreated patients, where no differences have been found between CMF-based and anthracycline-containing regimens for their impact on the outcome of first-line anthracycline treatment [
41]. By this point of view, even if our results are in anthracycline-naïve patients, the activity and the low toxicity profile observed suggest that the choice of a liposomal formulation can offer the chance of a more tolerable regimen maintaing conventional anthracyclines efficacy.
The results of the present trial indicated both EPI/VNB and PLD/VNB as two reasonable choices as first-line treatment for women with relapsed breast cancer not previously treated with adjuvant anthracyclines; since advanced breast cancer is still an incurable disease, the goals of treatments are symptoms palliation with minimal toxicity, and survival prolongation, possibly with regimens active against cancer but also preserving patient's quality of life; in this context, our results are encouraging, confirming the feasibility and efficacy of two anthracycline-containing regimens and, particularly, of a regimen devoided of cardiac toxicity and of other severe side effects, such as PLD/VNB; the choice of this combination could offer a better quality of life and, hopefully, a better outcome to metastatic breast cancer patients.
Competing interests
The authors declare that they have no competing interests.
Authors' contributions
PV, GC, ML designed the study; FG, DS, GF, PP, CB, EV, AC, LP, AL, LDL collected and assembled the data, DG performed the statistical analysis, PV and LDL wrote the manuscript. All authors read and approved the final manuscript.