Bevacizumab plus octreotide and metronomic capecitabine in patients with metastatic well-to-moderately differentiated neuroendocrine tumors: the XELBEVOCT study

Alfredo Berruti, Nicola Fazio, Anna Ferrero, Maria Pia Brizzi, Marco Volante, Elisabetta Nobili, Lucia Tozzi, Lisa Bodei, Mirella Torta, Antonio D'Avolio, Adriano Massimiliano Priola, Nadia Birocco, Vito Amoroso, Guido Biasco, Mauro Papotti, Luigi Dogliotti, Alfredo Berruti, Nicola Fazio, Anna Ferrero, Maria Pia Brizzi, Marco Volante, Elisabetta Nobili, Lucia Tozzi, Lisa Bodei, Mirella Torta, Antonio D'Avolio, Adriano Massimiliano Priola, Nadia Birocco, Vito Amoroso, Guido Biasco, Mauro Papotti, Luigi Dogliotti

Abstract

Background: We assessed the activity and toxicity of the XELBEVOCT regimen in patients with metastatic well-to-moderately differentiated neuroendocrine neoplasms (WMD-NEN). Ancillary studies evaluated hypertension, proteinuria, and vascular endothelial growth factor (VEGF) polymorphisms in predicting progression-free survival (PFS) and the predictive role of serum vitamin D in progression-free survival and proteinuria onset.

Methods: This prospective phase 2 study included 45 patients with WMD-NEN arising from various primary sites. The treatment regimen was octreotide long-acting release (LAR), 20 mg monthly, metronomic capecitabine, 2000 mg/daily, and intravenous bevacizumab, 5 mg/kg every 2 weeks, without interruption for 9 months. Bevacizumab was continued until disease progression.

Results: Partial response was obtained in 8 patients (17.8%, 95% confidence interval [CI], 6.4%-28.2%); tumor response was more frequent in pancreatic than in non-pancreatic malignancies. The median PFS was 14.9 months; median overall survival was not attained. Biochemical and symptomatic responses were observed in 52.9% and 82.3% of cases, respectively. The treatment was well tolerated. Grade 3 toxicities included hand and foot syndrome (11.1%), proteinuria (4.4%), and renal toxicity (2.2%). Proteinuria (all grades) was correlated with longer PFS (p = 0.017). There was an inverse relationship between proteinuria and vitamin D levels. VEGF polymorphisms were not associated with patient outcome.

Conclusion: The XELBEVOCT regimen is active and well tolerated in patients with metastatic WMD-NEN. Proteinuria correlated with hypovitaminosis D status and was the best predictive factor of treatment efficacy.

Trial registration: Trial registration number NCT01203306.

Figures

Figure 1
Figure 1
Waterfall diagram of changes in tumor size in all patients.
Figure 2
Figure 2
Effect of hypertension (a) and proteinuria (b) on time to progression.
Figure 3
Figure 3
Influence of hypovitaminosis D on time to progression.

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