Abstract
Aim: Weekly paclitaxel is widely used in the treatment of metastatic breast cancer (MBC). Our aim was to test its efficacy and tolerability as a second-line therapy for MBC in daily oncology practice. Patients and Methods: Paclitaxel (90 mg/m2) was given intravenously three times weekly in a 4-week cycle to 91 patients with disease progression after hormonal (42%) or cytostatic therapy (57%). The median age was 54 years; metastatic sites were the lung (39%), liver (52%) and bone (47%). 64% of patients had more than one site of metastasis. Results: Median time-to-progression was 7.5 months (range=6.5-8.5 months) and median overall survival time was 20.1 months (range=13.7-26.5 months). We observed 10 complete (12%) and 37 partial (43%) responses (an overall response rate of 55%). Severe side-effects were rare (grade 3-4 neutropenia 13% and septic episodes in three cases). Conclusion: Weekly paclitaxel was shown to be an effective and well-tolerated treatment for advanced breast cancer.
Treatment of metastatic breast cancer is still a challenge. During the past decade the greatest success has been achieved with adjuvant chemoimmunotherapy in the treatment of early breast cancer (1-5). In addition, combinations and sequential use of targeted therapy has also been shown to increase overall survival of patients with metastatic breast cancer by several months or even years. However, even modern chemotherapy without targeted agents in breast cancer may lead to a clinically modest, but statistically significant increase in overall survival (6-8). The human epidermal growth factor receptor-2 (HER2)-targeted monoclonal antibody treatments used in advanced breast cancer include trastuzumab, pertuzumab and trastuzumab emtansine (9-11).
In spite of the new agents, the primary goal of chemotherapy in metastatic breast cancer remains nonetheless to improve the quality of survival by reducing disease-related symptoms. Both cytotoxic and endocrine therapies have been proven to be effective by themselves and in combination (7, 8, 12, 13). Anthracyclines and taxanes are the most active drugs whether alone or in combination (14-18). Their combination may improve the response rate and time-to-progression compared to single-agent treatment, but their impact on overall survival is not clear according to the current literature (8, 14, 15). Both docetaxel and paclitaxel are taxanes widely used in the treatment of metastatic breast cancer. Their side-effects differ: docetaxel has more bone marrow toxicity, while paclitaxel causes neurotoxicity (5). The primary end-points of the present national multi-intuitional study were tolerability and response rates to weekly administration of paclitaxel. Secondary end-points were time-to-progression and survival.
Patients and Methods
Patients. Ninety-nine patients with advanced breast cancer were included in this study. Patients had to have progressive metastatic or local disease, and less than two either hormonal or chemotherapy regimens for metastatic disease (Table I). All were ambulant and had measurable or evaluable disease and sufficient renal, liver and bone marrow functions. Patients with a history of brain metastases were not eligible for inclusion.
Treatment schedule. Pre-medications for paclitaxel included dexamethasone (20 mg intravenously (i.v.) 60 min before), promethasine (50 mg intramuscularly 60 min before) and ranitidine (50 mg i.v. 30-60 min before). Paclitaxel at 90 mg/m2 as a 1-h infusion without infusion pump was given on days 1, 8 and 15 in a cycle of 28 days. Treatment was recommended to be continued up to objective signs of disease progression or intolerable toxicity.
Evaluation of response and toxicity. Responses were evaluated according to WHO guidelines (16) and side-effects according to CTAE-NCI criteria (Common Terminology Criteria (CTC) v.2.0. Available at http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). A panel of oncologists and one radiologist (RJ) reviewed all responses.
Ethical Committee of Tampere University Hospital approved the study (R099164M). All patients were informed of the study aims and protocol and signed a consent form.
Results
Patients. The median age of the patients was 53.8 (range=34-74) years. The most common sites of metastases were the liver (52%), bone (47%) and lungs (39%) (Table I). Over half of the patients (64%) had over one site of metastasis. A total of 57% of patients had received previous chemotherapy and 42% previous hormone therapy for advanced disease. Additional patient characteristics are shown in Table I. For 44% of the patients, weekly paclitaxel was first-line, for 42% second-line and for 14% third-line cytostatic treatment for advanced breast cancer.
Efficacy. The median time-to-disease progression (TTP) was 7.5 (range=6.5-8.5) months from the beginning of the treatment (Table II). The median survival time from commencement of the weekly paclitaxel treatment was 20.1 (range=13.7-26.5) months (Figure 1). A median number of five cycles (range=1-13) was delivered. We recorded 10 complete (12%) and 37 partial responses (43%), for a relative response rate of 47/91 (51%) in intent-to-treat analyses and 55% in the evaluable patients. In addition, there were 27 cases of stable disease (31%). Progression-free survival and overall survival are shown in Figures 1 and 2, respectively.
Side-effects. Baseline toxicity was evaluated in all patients and only three patients did not complain of any side-effects either due to previous treatment of advanced disease or due to metastases. During the treatment, adverse events were carefully evaluated in 91 evaluable patients (Table III). In general, treatment was quite well-tolerated. Anaemia and thrombocytopenia were usually mild. Only one grade 3 anaemia occurred. Grade 3-4 neutropenia was recoded in 12 patients (13.3%). However, only three septic episodes were observed (3.3%). Alopecia was almost universal. Most of the patients (72%) did not have nausea or vomiting at all and only grade 1 nausea or vomiting was declared (28%). Neuropathy grade 1 or 2 occurred in over half of the patients (N=52, 58.5%) and more severe, grade 3, in 10 patients (10%). Pain was in many cases considered to be disease-related, especially when almost half of our patients had bone metastasis. However, severe grade 3 arthalgia/myalgia occurred only in one patient (Table III).
Patients' characteristics.
Time-to-progression and survival time from the first cycle.
Worst toxicities during the treatment including all treatment cycles.
Reasons for stopping the treatment were disease progression in 43%, side-effects in 17%, patient's request in 10%, according the protocol limits in 6% and for other reasons in 6%, patient death in 1% and a combination of several reasons in 10%.
Discussion
Several single or combinations of chemotherapy as first-line treatment have been used in advanced breast cancer. The response rates reported vary from 0% to 50%-60%, the average being around 30% (7, 8, 14, 15, 17-19). Thus our response rate (55%) with weekly paclitaxel is among the best series reported, especially when over half of our patients were administered paclitaxel as second- or third-line therapy for advanced breast cancer. In addition, most of our patients had visceral metastases and over half had liver metastases. One third had stable disease due to the known difficulties of evaluating response in the bones. Ten patients (12%) achieved a complete response. The median survival time was almost two years, which is considered to be quite favourable, especially with single-agent chemotherapy after failure either to hormonal or first-line chemotherapy. In our first-line trial with either docetaxel-alone or docetaxel alternating with gemcitabine, the median time-to-treatment failure was almost the same, six months (19). Our results are in line with the meta-analysis by Mauri et al. where paclitaxel in a weekly regimen gave overall survival advantages compared with the standard every-three-weeks regimen (19).
In most patients the treatment was well-tolerated. Neutropenia without severe infections was common. Other grade 3-4 toxicities occurred in fewer than 8% of patients. Due to the good tolerability and responses, the median number of cycles given was five. No hypersensitivity reaction occurred. However, in the literature only 1.5% of patients with pre-medication exhibited hypersensitivity reactions (14, 18). No severe cardiotoxicity was observed. Weekly paclitaxel is, thus, much better tolerated than paclitaxel combined with epirubicin. The combination of paclitaxel and doxorubicin seems highly cardiotoxic; some authors have reported an incidence of congestive heart failure of approximately 20% (21, 22). Our toxicity profile was as favourable as that in a recent meta-analysis, where weekly paclitaxel was compared to 3-weeks paclitaxel as treatment of different solid tumor types (23).
In HER2-negative breast cancer studies, combing weekly paclitaxel with anti-angiogenic agents such as bevazicumab, did not increase overall survival and these agents are very expensive (24). The most promising results with chemotherapy have been obtained in metastatic HER2-positive patients with breast cancer with combinations of the HER2-targeted new agents: trastuzumab, pertuzumab, trastuzumab emtansine and lapatinib (9-11, 25-27) and more studies with taxane-based therapy are ongoing with these agents in HER2-positive breast cancer, both in adjuvant and metastatic settings. In our study, weekly paclitaxel proved to be well-tolerated and active after even anthracycline-based chemotherapy and as a second- or third-line chemotherapy for advanced breast cancer, with acceptable toxicity.
Progression-free survival from the start of weekly paclitaxel treatment.
Overall survival after the start of weekly paclitaxel treatment.
- Received April 9, 2013.
- Revision received April 25, 2013.
- Accepted April 26, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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