Prospective Study of Bevacizumab Plus Temozolomide in Patients With Advanced Neuroendocrine Tumors

Abstract

A B S T R A C T PurposeBoth tyrosine kinase inhibitors targeting the vascular endothelial growth factor (VEGF) receptor and bevacizumab, a monoclonal antibody targeting VEGF, have antitumor activity in neuroendocrine tumors (NETs). Temozolomide, an oral analog of dacarbazine, also has activity against NETs when administered alone or in combination with other agents. We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs. Patients and MethodsThirty-four patients (56% with carcinoid, 44% with pancreatic NETs) were treated with temozolomide 150 mg/m 2 orally per day on days 1 through 7 and days 15 through 21, together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle. All patients received prophylaxis against Pneumocystis carinii and varicella zoster. Patients were followed for toxicity, biochemical and radiologic response, and survival. ResultsThe combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities, including lymphopenia (53%) and thrombocytopenia (18%). Although the overall radiographic response rate was 15% (five of 34), response rates differed between patients with pancreatic NETs (33%; five of 15) and those with carcinoid tumors (zero of 19). The median progression-free survival was 11.0 months (14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors). The median overall survival was 33.3 months (41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors). ConclusionTemozolomide and bevacizumab can be safely administered together in patients with advanced NETs, and the combination regimen appears promising for patients with pancreatic NETs. Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted.

Endocrine vasculatures are preferable targets of an antitumor ineffective low dose of anti-VEGF therapy

“…Unlike endocrine organs, tumors use multiple angiogenic factors to stimulate neovascularization and inhibition of the VEGF-VEGFR signaling may not always produce profound antiangiogenic effects. In this regard, tumors originating from endocrine organs and neuroendocrine tumors are probably more susceptible to antiangiogenic therapy (33,34).…”

The Role of Capecitabine/Temozolomide in Metastatic Neuroendocrine Tumors

“…The use of steptozocin-based therapies has been the mainstay of treatment for both pancreatic and nonpancreatic NETs [10,11].This regimen is sometimes limited by its toxicity. More recently, the oral alkylating agent temozolomide has become a treatment option and has been used as both a single agent and also in combinations, such as thalidomide/ temozolomide, bevacizumab/temozolomide, and capecitabine/ temozolomide (CAPTEM) [12][13][14][15][16].…”

A Case Report of a Poorly Differentiated Neuroendocrine Carcinoma Diagnosed in the Bone Marrow

“…Newer agents, such as sorafenib, bevacizumab and EGF inhibitors, are currently being tested in various clinical trials [10][11][12][13]. Furthermore, novel targets such as Bcl-2 deserve further investigation given the Bcl-2 over expression in poorly differentiated and particularly small cell neuroendocrine tumors.…”