Phase III Prospective Randomized Comparison Trial of Depot Octreotide Plus Interferon Alfa-2b Versus Depot Octreotide Plus Bevacizumab in Patients With Advanced Carcinoid Tumors: SWOG S0518

Abstract

Treatment options for neuroendocrine tumors (NETs) remain limited. This trial assessed the progression-free survival (PFS) of bevacizumab or interferon alfa-2b (IFN-a-2b) added to octreotide among patients with advanced NETs. Patients and MethodsSouthwest Oncology Group (SWOG) S0518, a phase III study conducted in a US cooperative group system, enrolled patients with advanced grades 1 and 2 NETs with progressive disease or other poor prognostic features. Patients were randomly assigned to treatment with octreotide LAR 20 mg every 21 days with either bevacizumab 15 mg/kg every 21 days or 5 million units of IFN-a-2b three times per week. The primary end point was centrally assessed PFS. This trial is registered with ClinicalTrials.gov as NCT00569127. ResultsA total of 427 patients was enrolled, of whom 214 were allocated to bevacizumab and 213 to IFNa-2b. The median PFS by central review was 16.6 months (95% CI, 12.9 to 19.6 months) in the bevacizumab arm and was 15.4 months (95% CI, 9.6 to 18.6 months) in the IFN arm (hazard ratio [HR], 0.93; 95% CI, 0.73 to 1.18; P = .55). By site review, the median PFS times were 15.4 months (95% CI, 12.6 to 17.2 months) for bevacizumab and 10.6 months (95% CI, 8.5 to 14.4 months) for interferon (HR, 0.90; 95% CI, 0.72 to 1.12; P = .33). Time to treatment failure was longer with bevacizumab than with IFN (HR, 0.72; 95% CI, 0.58 to 0.89; P = .003). Confirmed radiologic response rates were 12% (95% CI, 8% to 18%) for bevacizumab and 4% (95% CI, 2% to 8%) for IFN. Common adverse events with bevacizumab and octreotide included hypertension (32%), proteinuria (9%), and fatigue (7%); with IFN and octreotide, they included fatigue (27%), neutropenia (12%), and nausea (6%). ConclusionNo significant differences in PFS were observed between the bevacizumab and IFN arms, which suggests that these agents have similar antitumor activity among patients with advanced NETs.

Role of targeted agents in neuroendocrine tumors: Results from a meta-analysis

“…One study was excluded because retracted by the authors. 22 Among these studies, 3 studies 10,12,18 investigated everolimus single agent as experimental arm, 3 studies sunitinib and bevacizumab respectively 11,19,20 and one study the combination of everolimus and bevacizumab. 21 Three studies enrolled patients with pancreatic NET 10,11,21,22 only.…”

“…There were 2 phase II studies 20,21 and 5 phase III studies. [10][11][12]18,19 All studies had a comparator: in 3 10-12 the comparator was placebo, while in 1 was placebo plus octreotide LAR; 18 in 2 studies the comparator was pegylated (PEG)-interferon alfa-2b and interferon respectively 19,20 and everolimus in on trial. 21 The median Jadad score was 5, showing a good quality of the included studies (Table 1).…”

“…11,[19][20][21] RR has been obtained in a total of 59/384 (15.3%) patients for the experimental group and in a total of 17/383 (4.4%) patients in the control group. Using the Mantel-Haenszel method for combining trials, the pooled RR for achieving an objective response with targeted agents vs. placebo or other therapies was 3.33 (95% CI 2.02-5.49; P < 0.00001; I 2 D 0%) (Fig.…”

Systemic Therapy in Incurable Gastroenteropancreatic Neuroendocrine Tumours: A Clinical Practice Guideline

“…Several trials included both pnets and non-pnets in their populations w ithout presenting results by subgroup 9,16,19,20,23,25,[35][36][37]39,40,43,44,46 . Because of heterogeneity and a potential for bias, those trials were not used for making the initial recommendations (pnets and non-pnets both respond differently to treatment, making it difficult to draw any conclusions from those trials).…”

“…The search uncovered eleven relevant randomized prospective studies [9][10][11][12][13][14][15][16][17][18][19] , sixteen nonrandomized prospective studies [20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] , and thirteen retrospective studies [36][37][38][39][40][41][42][43][44][45][46][47][48] . Where multiple reports and abstracts were published for a single trial or study, only the most recent full publication was included, unless other reports contained data that were not available in the most recent publication.…”