In 2008, the FDA approved bendamustine hydrochloride (TREANDA, Cephalon, Inc., North Wales, PA), an intravenously administered alkylating agent, for the treatment of patients with chronic lymphocytic leukemia and indolent B-cell non-Hodgkin lymphoma that progressed during or within 6 months of treatment with rituximab or a rituximab-containing regimen.
Bendamustine is a cytotoxic alkylating agent that contains a purine and an amino acid antagonist; it is a bifunctional mechlorethamine derivative that also contains a purine-like benzimidazole ring.1 The effects of bendamustine are caused by the cross-linking of double- and single-stranded DNA, which disrupts DNA synthesis and induces apoptosis. The exact mechanism of action of bendamustine remains unknown.1,2
In solid tumors, bendamustine has been used alone or in combination with other chemotherapy agents and has had promising results in patients with various tumor types, including head and neck cancer, germ cell tumors, small cell lung cancer, and breast cancer.2-9 In a study comparing bendamustine, methotrexate, and fluorouracil (n=25) with cyclophosphamide, methotrexate, and fluorouracil (n=24)10 in patients with metastatic breast cancer, the bendamustine combination regimen was associated with an overall response rate of 52% and a median duration of remission of 15.2 months, compared with 46% and 6.2 months in the cyclophosphamide group.10 In another study, bendamustine was used as salvage therapy in 36 patients with advanced breast cancer; the overall response rate was 27%.11 In a study combining bendamustine with radiation therapy in 13 patients with recurrent squamous cell carcinoma of the head and neck, 62% of patients had a partial response.3 In patients with small cell lung cancer treated with single-agent bendamustine5 or bendamustine combined with carboplatin,4 the overall response rates were 29% and 73%, respectively.
Bevacizumab is a recombinant humanized antibody directed against vascular endothelial growth factor (VEGF). It is approved for the treatment of patients with colon, lung, kidney, breast (outside the United States), and brain (glioblastoma multiforme, only in the United States) tumors.
Based on the promising results of the studies of bendamustine in solid tumors, an investigator-initiated study of the combination of bendamustine and bevacizumab was conducted in patients with advanced cancer. The rationale for this first-ever clinical trial combining bevacizumab and bendamustine was that adding an anti-VEGF agent to bendamustine would result in a combination of 2 drugs with different mechanisms of antitumor activity and non-cross-toxicity, which would improve the antitumor activity of either drug alone in patients with advanced cancer. The primary objectives were to assess the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and tolerability of bendamustine and bevacizumab in patients with advanced cancers, and the secondary objective was to assess the antitumor efficacy of this regimen.
Bottke D, Bathe K, Wiegel T et al.. Phase I trial of radiochemotherapy with bendamustine in patients with recurrent squamous cell carcinoma of the head and neck. Strahlenther Onkol 2007;183:128–132.
Koster W, Heider A, Niederle N et al.. Phase II trial with carboplatin and bendamustine in patients with extensive stage small-cell lung cancer. J Thorac Oncol 2:312–316. 2007
Schmittel A, Knodler M, Hortig P et al.. Phase II trial of second-line bendamustine chemotherapy in relapsed small cell lung cancer patients. Lung Cancer 2007;55:109–113.
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.
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. von Minckwitz G Chernozemsky I Sirakova L 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.
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. Therasse P Arbuck SG Eisenhauer EA New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205– 216.
Tsimberidou AM, Fu S, Ng C et al.. A phase 1 study of hepatic arterial infusion of oxaliplatin in combination with systemic 5-fluorouracil, leucovorin, and bevacizumab in patients with advanced solid tumors metastatic to the liver. Cancer 2010;116:4086–4094.
Schoffski P, Hagedorn T, Grunwald V et al.. Repeated administration of short infusions of bendamustine: a phase I study in patients with advanced progressive solid tumours. J Cancer Res Clin Oncol 2000;126:41–47.
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.
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