Capecitabine in combination with bendamustine in pretreated women with HER2-negative metastatic breast cancer: results of a phase II trial (AGMT MBC-6)
Gabriel Rinnerthaler, Simon Peter Gampenrieder, Andreas Petzer, Michael Hubalek, Edgar Petru, Margit Sandholzer, Johannes Andel, Marija Balic, Thomas Melchardt, Cornelia Hauser-Kronberger, Clemens A Schmitt, Hanno Ulmer, Richard Greil, Gabriel Rinnerthaler, Simon Peter Gampenrieder, Andreas Petzer, Michael Hubalek, Edgar Petru, Margit Sandholzer, Johannes Andel, Marija Balic, Thomas Melchardt, Cornelia Hauser-Kronberger, Clemens A Schmitt, Hanno Ulmer, Richard Greil
Abstract
Background: Bendamustine, a medication approved for the treatment of indolent non-Hodgkin lymphoma, has already shown anticancer activity in metastatic breast cancer (MBC). Here, we present the results of a phase II trial of bendamustine in combination with capecitabine in pre-treated patients with MBC.
Patients and methods: AGMT MBC-6 is a multicentre, open-label, single-arm phase II study in HER2-negative MBC. All patients were pre-treated with anthracyclines and/or taxans and had measurable disease. Patients received per os 1000 mg/m2 capecitabine twice daily on days 1 to 14 in combination with 80 mg/m2 bendamustine intravenously on days 1 and 8 of a 3-week cycle for a maximum of eight cycles, followed by a capecitabine maintenance therapy. The primary endpoint was overall response rate (ORR).
Results: From September 2013 to May 2015, 40 patients were recruited in eight Austrian centres. The median age was 60 years (range 29-77). Twenty-five per cent of patients had triple-negative breast cancer (TNBC) and 93% showed visceral involvement. With 17 partial and one complete remission, ORR was 46%. Median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI) 6.1-10.7]. The most common non-haematological adverse events (AEs) of grade 3 were hand-foot syndrome (13%), fatigue (10%), nausea (8%), and dyspnoea (8%). One grade 4 non-haematological AE (hepatic failure) and three grade 4 haematological AEs (neutropenia) were observed. One patient died of restrictive cardiomyopathy, in which a relationship to capecitabine cannot be excluded, but seems unlikely.
Conclusion: The combination of capecitabine and bendamustine shows promising efficacy and moderate toxicity. Further evaluation of this drug combination is warranted.The clinical trial AGMT MBC-6 was registered at ClinicalTrials.gov, (https://ichgcp.net/clinical-trials-registry/NCT01891227" title="See in ClinicalTrials.gov">NCT01891227).
Keywords: advanced breast cancer; chemotherapy; combination therapy.
Conflict of interest statement
Conflict of interest statement: Conflicts of interest with Mundipharma: Employment or leadership position: none; Consultant or advisory role: Andreas Petzer, Richard Greil; Fees for non-CME services received directly from commercial interest or their agents: none; Contracted research: Richard Greil; Ownership interest: none; Traveler grants: none.
© The Author(s), 2021.
Figures
References
- Corona SP, Sobhani N, Ianza A, et al.. Advances in systemic therapy for metastatic breast cancer: future perspectives. Med Oncol 2017; 34: 119.
- Cardoso F, Senkus E, Costa A, et al.. 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol 2018; 29: 1634–1657.
- Pirvulescu C, von Minckwitz G, Loibl S. Bendamustine in metastatic breast cancer: an old drug in new design. Breast Care 2008; 3: 333–339.
- Jamitzky T, Lange O. Third-line chemotherapy with bendamustin for metastatic breast cancer – a prospective pilot study. Eur J Cancer 1996; 32: 47–47.
- Eichbaum MH, Schuetz F, Khbeis T, et al.. Weekly administration of bendamustine as salvage therapy in metastatic breast cancer: final results of a phase II study. Anticancer Drugs 2007; 18: 963–968.
- Höffken K, Merkle K, Schönfelder M, et al.. Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study. J Cancer Res Clin Oncol 1998; 124: 627–632.
- Reichmann U, Bokemeyer C, Wallwiener D, et al.. Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine. Ann Oncol 2007; 18: 1981–1984.
- von Minckwitz G, Chernozemsky I, Sirakova L, et al.. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs 2005; 16: 871–877.
- Cameron DA, Gabra H, Leonard RC. Continuous 5-fluorouracil in the treatment of breast cancer. Br J Cancer 1994; 70: 120–124.
- Bunnell CA, Winer EP. Oral 5-FU analogues in the treatment of breast cancer. Oncology (Williston Park) 1998; 12: 39–43.
- Lechleider RJ, Kaminskas E, Jiang X, et al.. Ixabepilone in combination with capecitabine and as monotherapy for treatment of advanced breast cancer refractory to previous chemotherapies. Clin Cancer Res 2008; 14: 4378–4384.
- Sparano JA, Vrdoljak E, Rixe O, et al.. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010; 28: 3256–3263.
- Miller KD, Chap LI, Holmes FA, et al.. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–799.
- Friedkin M, Roberts D. The enzymatic synthesis of nucleosides. I. Thymidine phosphorylase in mammalian tissue. J Biol Chem 1954; 207: 245–256.
- Toi M, Atiqur Rahman M, Bando H, et al.. Thymidine phosphorylase (platelet-derived endothelial-cell growth factor) in cancer biology and treatment. Lancet Oncol 2005; 6: 158–166.
- Andreetta C, Puppin C, Minisini A, et al.. Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer. Ann Oncol 2009; 20: 265–271.
- Brockmann B, Kirchhof I, Geschke E, et al.. [Therapeutic results and toxic side effects of the combination cytostasan, adriamycin and vincristine as second-line therapy of metastatic breast cancer]. Arch Geschwulstforsch 1989; 59: 341–346.
- Schmidt P, Heck HK, Preiss J. Bendamustin/mitoxantrone in the treatment of advanced breast cancer. ECCO 1999; 35: S324.
- Loibl S, Doering G, Müller L, et al.. Multicenter phase II study with weekly bendamustine and paclitaxel as first- or later-line therapy in patients with metastatic breast cancer: RiTa II trial. Breast Care 2011; 6: 457–461.
- Alsaloumi L, Shawagfeh S, Abdi A, et al.. Efficacy and safety of capecitabine alone or in combination in advanced metastatic breast cancer patients previously treated with anthracycline and taxane: a systematic review and meta-analysis. Oncol Res Treat 2020; 43: 694–702.
- Bajetta E, Procopio G, Celio L, et al.. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol 2005; 23: 2155–2161.
- Eisenhauer EA, Therasse P, Bogaerts J, et al.. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228–247.
- NCI. CTCAE version 4.03. (accessed 16 May 2017).
- Fayers P, Aaronson N, Bjordal K. EORTC QLQ-C30 scoring manual, 3rd ed. Brussels: European Organisation for Research and Treatment of Cancer, 2001.
- Sprangers MA, Groenvold M, Arraras JI, et al.. The European Organization for Research and Treatment of Cancer breast cancer-specific quality-of-life questionnaire module: first results from a three-country field study. J Clin Oncol 1996; 14: 2756–2768.
- Tsuda H, Akiyama F, Kurosumi M, et al.. Reproducible immunohistochemical criteria based on multiple raters’ judgments for expression of thymidine phosphorylase in breast cancer tissue. Breast Cancer Res Treat 2004; 86: 215–223.
- Blum JL, Jones SE, Buzdar AU, et al.. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999; 17: 485–485.
- Blum JL, Dieras V, Lo Russo PM, et al.. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92: 1759–1768.
- Talbot DC, Moiseyenko V, Van Belle S, et al.. Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines. Br J Cancer 2002; 86: 1367–1372.
- Reichardt P, Von Minckwitz G, Thuss-Patience PC, et al.. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 2003; 14: 1227–1233.
- Fumoleau P, Largillier R, Clippe C, et al.. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40: 536–542.
- Dear RF, McGeechan K, Jenkins MC, et al.. Combination versus sequential single agent chemotherapy for metastatic breast cancer. Cochrane Database Syst Rev 2013; 2013: CD008792.
- Choi EK, Kim IR, Chang O, et al.. Impact of chemotherapy-induced alopecia distress on body image, psychosocial well-being, and depression in breast cancer patients. Psychooncology 2014; 23: 1103–1110.
Source: PubMed