Annals of Oncology Advance Access originally published online on September 14, 2007
Annals of Oncology 2007 18(12):1981-1984; doi:10.1093/annonc/mdm378
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© 2007 European Society for Medical Oncology
breast cancer |
Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine
1 Department of Radiooncology, University of Tuebingen, Tuebingen
2 Department of Oncology and Hematology, University medical center Eppendorf, Hamburg
3 Department of Gynecology and Obstetrics
4 Department of Hematology, Oncology and Immunology, University of Tuebingen, Tuebingen, Germany
5 Breast Center, Kantonsspital St Gallen, St Gallen, Switzerland
* Correspondence to: Dr U. Reichmann, Department of Radiooncology, University of Tuebingen, Hoppe-Seyler-str. 3, 72076 Tuebingen, Germany. Tel: +49-7071-2986142; Fax: +49-7071-295609; E-mail: ursula.reichmann{at}med.uni-tuebingen.de
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Abstract |
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Background: Bendamustine, a bifunctional alkylating agent with anticipated purin-like properties is active in metastatic breast cancer (MBC) patients. This multicenter phase II trial defines the toxicity and activity of bendamustine in heavily pretreated patients.
Patients and methods: Fifty-one patients were included. Patients had a median number of 2 prior chemotherapeutic regimens for MBC (range 0–7) consisting of anthracyclines and taxanes: 26 patients (51%); anthracyclines: nine patients (17.6%); taxanes: seven patients (13.7%); others: five patients (9.8%). Bendamustine was administered four weekly at a dose of 120 mg/m2 on days 1 and 2.
Results: Fifty patients were assessable. Of total, 200 courses were administered. We observed no complete response (CR); 10 patients [20%; 95% confidence interval (CI): 10.0% to 33.7%] achieved a partial response (PR), 14 patients (28%) remained stable for at least 6 months resulting in a clinical benefit rate (CR + PR + stable disease) of 48% (95% CI: 33.7%to 52.6%). Median time to progression was 3.4 months (range 1–51.1). The median duration of remission was 6.6 months (range 1.8–48.7). The treatment was well tolerated with mainly hematologic toxic effects.
Conclusion: Single-agent bendamustine is an active treatment in patients with MBC independent of the previous treatment. The low toxicity profile favors its use as a single agent.
Key words: bendamustine, metastatic breast cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingReferences |
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Bendamustine is a bifunctional alkylating agent with anticipated purin-like properties. It is excreted mainly renally, metabolized in the liver and excreted in small amounts via the bile [1, 2].
Metastatic breast cancer (MBC) combination chemotherapy of bendamustine with doxorubicine and vincristine [3] and 5-fluorouracil and metotrexate [4] has shown high remission rates in the first- and second-line setting. Jamitzky and Lange [5] reported with monotherapy with a dosage of 150 mg/m2, a remission rate of 20% in third-line chemotherapy. These results were confirmed by Höffken et al. [6] with the same dosage.
The aim of this study was to show the clinical efficacy and tolerability of single-agent bendamustine in multimodal pretreated patients (pts) with a dose of 120 mg/m2 to minimize the side-effects.
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patients and methods |
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This was a nonrandomized, multicenter open-label phase II trial.
Primary objective of this trial was to determine the objective response rate [complete response (CR) and partial response (PR)]. Secondary objectives were time to progression (TtP), duration of response and toxicity.
Pts were treated from August 1998 to January 2006 at seven institutions. Pts were eligible if they had histologically proven MBC with at least one unidimensional measurable lesion, World Health Organization (WHO) performance status of two or less and were 18 years or older. All types of prior chemotherapy neo-adjuvant, adjuvant and/or treatment for metastatic disease except bendamustine were permitted, as well as preceding radiotherapy and hormonal therapy. No concurrent treatment with other experimental drugs and anticancer therapy was allowed. Signed informed consent was obtained, and the study was approved by the ethical committee of the University of Tuebingen.
Pretreatment investigations included medical history, physical examination and documentation of baseline symptoms. Hematologic blood counts and biochemical analysis were obtained within 7 days before registration. Radiological assessment included computed tomography scan, chest X-ray and ultrasound or other scans as necessary and were documented within 21 days before registration.
Treatment consisted of 120 mg/m2 bendamustine i.v. on days 1 and 2 every 4 weeks. The drug was administered within 30 min.
Evaluations during treatment comprised physical examination, chemical laboratory and prothrombine time on day 1 of each cycle. Weekly hematologic blood counts were carried out. Radiological examinations were repeated at the end of every second cycle (20 pts every third cycle). Toxicity was evaluated after every cycle and was graded using the WHO criteria. Pts who received at least one cycle of bendamustine were assessable for toxicity analyses.
Treatment was to be discontinued on pts' request or in case of serious unmanageable toxic effects. Responses were determined according to Response Evaluation Criteria in Solid Tumors [7]. Duration of therapy depended on the best response obtained. For CR, treatment was planned to be continued for a maximum of two cycles after CR was confirmed (maximum eight cycles). In case of PR, treatment was continued until progression or for at least two further cycles after documentation of an ongoing PR. In case of stabilization of the disease, treatment was given for a maximum of eight cycles. Treatment was stopped as soon as disease progression was clinically or radiologically documented. The administration of bendamustine was delayed in pts with hematologic or other toxic effects greater than WHO grade 2.
Treatment was continued when leucocytes were 
3000/µl and thrombocytes 100 000/µl. If these criteria were not met, there was a weekly evaluation until recovery. If the hematological toxicity during the preceding course was greater than grade 1 and the therapy had to be delayed, the dose could be reduced to 80%, alternatively only day 1 of the two days schedule was administered. For non-hematological toxicity, treatment was discontinued until grade 1 toxicity was reached. If treatment was delayed for >4 weeks, the patient was excluded from the study.
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results |
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Overall 51 pts were recruited in seven centers. The characteristics of these pts are outlined in Table 1. In total, 200 courses of bendamustine were given, the median number per patient was 3 (range 1–8). All pts were eligible for toxicity (Table 2). Grade 3/4 adverse events occurred very rarely and we observed only two febrile neutropenias. Alopecia was mild and no toxic death occurred.
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Five pts discontinued the treatment, three due to hematological toxicity (one grade 4 thrombocytopenia, two prolonged myelosuppressions grade 2), two refused further chemotherapy without toxicity reasons. In 26 pts, the study was terminated because of disease progression. Ten pts had a prolonged interval of bendamustine application (two for 1 week, seven for 2 weeks, one for 4 weeks), in seven pts because of hematotoxicity and three due to other reasons. In seven pts, the dose of bendamustine was reduced, in three pts only day 1 was given for one or two courses and four pts had a reduction to 80% of the planned dose. Two pts had supportive treatment with erythropoetin and two with granulocyte colony-stimulating factor.
In 50 assessable pts, we observed 10 PRs without any CR summing up to an overall response rate of 20%, a stabilization of the disease could be seen in 14 pts (28%), primary progression was observed in 26 pts (52.0%). The median TtP was 3.4 months (range 0.34–51.1), the median duration of PR was 6.6 months (range 1.8–48.7). The rate of PRs in pts pretreated with anthracyclines was 21.3%, in those pretreated with taxanes 21.6% and after previous therapy with anthracyclines and taxanes 21.6%. There was obviously no significant difference in response according to the previously given regimens.
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discussion |
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In MBC, there were so far only a few earlier reports that have shown that bendamustine has some activity in these pts [3–6, 8, 9]. Therefore, we started our phase II study to investigate the activity and toxicity profile of bendamustine in pts pretreated with the most effective drugs such as anthracyclines and taxanes. Since most of the high-risk pts have already been treated in the adjuvant setting with these agents, further substances with proven activity and a favorable toxicity profile are desirable in the treatment of MBC. Bendamustine might be a promising drug in this setting. In order to minimize toxicity and allow regular application of the regimen in pretreated pts, we reduced the dose of bendamustine to 120 mg/m2 in contrast to 150 mg/m2 used by Höffken et al. [6] in their study. And indeed the results of our phase II study indicate a reduced hematologic toxicity with the lower dose of bendamustine and also less frequent grade 4 side-effects were seen with our regimen compared with Höffken et al. (one grade 4 thrombocytopenia in comparison with six severe toxic effects). Bendamustine was an active drug with a dose of 120 mg/m2 and the comparison with the Höeffken study does not point to relevant differences (response rate 20% versus 27%, median TtP 3.3 versus 2 months). However, since patient populations vary in different phase II studies, results are not exactly comparable and findings must be interpreted carefully.
Preclinical investigations [10, 11] showed that bendamustine is active against anthracycline-resistant cells and may even be more active than other alkylating agents, so it was assumed that the mode of action is different. Our analysis shows that the effect of bendamustine was independent from the agents used before. We saw no cross-resistance to anthracyclines or taxanes and the response rate was similar if the pts were pretreated with anthracyclines, taxanes or both. Even if pts were pretreated in the metastastic setting with other alkylating agents such as cyclophosphamide, bendamustine was an effective therapy (response rate 33%). The number of previous regimes had no effect on the activity of bendamustine. In the two pts who had received seven different lines chemotherapy before entering the study, activity of bendamustine was seen (one PR and one NC).
We conclude that bendamustine is an additional useful agent in the treatment of MBC. Our data warrant further investigations of this drug either as monotherapy or in combination with other agents.
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This study was supported by ribosepharm, Germany.
Received for publication April 23, 2007. Revision received June 24, 2007. Accepted for publication July 3, 2007.
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References |
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