Clinicopathological characteristics
A total of 75 patients with mSBA were included in the study and 1 patient was excluded from the study due to insufficient SBA material for the analysis. Clinicopathological characteristics of the 74 remaining patients with mSBA are provided in Table 1. Of the 74 patients, 45 (60.8%) were older than 65 years of age, 49 (66.2%) were men, and 50 patients (67.6%) were PS 0. Primary tumour location was the duodenum in 38 patients (51.3%), jejunum in 27 (36.5%), and ileum in 9 (12.2%). The histological type of mSBA was differentiated-type in 57 patients (77.0%). The proportions of clinicopathological characteristics were comparable between patients with mDJA and those with mIA, except for a lower resection rate of the primary tumour in mDJA. The number of patients receiving each type of first-line chemotherapy is shown in Supplemental Table 3. Of the 74 cases, 16 (21.6%), 39 (52.7%), and 19 (25.7%) were classified into the Bevacizumab+ Platinum, Platinum, and Monotherapy Groups, respectively.
Immunohistochemical expression
Immunohistochemical expression data from the 74 patients with mSBA are shown in Table 2. Specimens were obtained by biopsy in 35 patients (47.3%) and by surgery in 39 patients (52.7%). Expression of VEGF-A was high in 42 patients (56.8%). Expression of CD10, MUC2, MUC5AC, and MUC6 was evaluated as positive in 55 (74.3%), 59 (79.7%), 45 (60.8%), and 29 (39.2%) of the patients, respectively. On the basis of mucinous immunophenotyping, 23 patients (31%) were classified as having I-type, 45 (60.8%) as having GI-type, 5 (6.8%) as having G-type, and 1 (1.4%) as having N-type of mSBA. The percentage of patients with I-type was significantly lower in those with mDJA (24.6%) than in those with mIA (77.8%, P = 0.003), and conversely, GI-type was significantly higher in those with mDJA (66.2%) than in those with mIA (22.2%, P = 0.023).
Efficacy of bevacizumab-containing chemotherapy for patients with mSBA
The efficacy of bevacizumab-containing chemotherapy was investigated by stratifying patients into those with mDJA or mIA. In those with mIA, the OS in the Bevacizumab+ Platinum Group (51 months [19-94]) was significantly longer than that in the Platinum Group (17.5 months [12-23], P = 0.047; Supplemental Figure 2b), as previously reported.[15] We also found that in those with mDJA, both the PFS and OS in the Bevacizumab+ Platinum Group (15 months [1-] and 26 months [5-]) tended to be longer than those in the Platinum Group (7 [5-9] and 17 [8-22], P = 0.075 and P = 0.077; Supplemental Figure 2c and 2d, respectively).
VEGF-A expression as a factor for prolonging PFS and OS in patients with mDJA
When we searched for factors associated with a prolonged PFS and OS in mDJA, univariate analysis followed by multivariate analysis revealed that high VEGF-A expression was a significant factor for prolonging PFS (HR, 0.58, 95% CI, 0.34-0.99; Table 3) and a possible factor for prolonging OS (HR, 0.56, 95%CI, 0.31-1.01; Supplemental Table 4). The clinicopathological characteristics and immunohistochemical expression were not significantly different between patients with high VEGF-A expression and those with low VEGF-A expression (Supplemental Table 5).
We then investigated the PFS and the OS among mDJA patients with high or low VEGF-A expression. The PFS was significantly longer in patients with high VEGF-A expression (median [95% CI] 9 months [4-10]) than in those with low VEGF-A expression (5 months [1-7], P = 0.018; Figure 1a) and the OS tended to be longer in those with high VEGF-A expression (20 months [15-24]) than in those with low VEGF-A expression (7 months [5-14], P = 0.059; Supplemental Figure 3a). In the Bevacizumab+ Platinum Group, the PFS was significantly longer in patients with high VEGF-A expression (26 months [15-]) than in those with low VEGF-A expression (5 months [1-9], P = 0.001; Figure 1b) and the OS tended to be longer in patients with high VEGF-A expression than in those with low VEGF-A expression (P = 0.062; Supplemental Figure 3b). In the Platinum Group, neither the PFS nor the OS differed significantly between patients with high VEGF-A expression (6.5 months [4-10] and 18 months [11-22]) and patients with low VEGF-A expression (7 months [2-7] and 11 months [4-41], P = 0.636 and P = 0.482; Figure 1c and Supplemental Figure 3c).
VEGF-A expression and bevacizumab treatment for patients with mDJA
We next investigated the PFS and OS among the treatment groups by stratifying patients with mDJA into groups with high or low VEGF-A expression. In patients with high VEGF-A expression, the PFS was significantly longer in the Bevacizumab+ Platinum Group (26 months [15-]) than in the Platinum Group (6.5 months [4-10], P = 0.025; Figure 2a). In addition, the OS tended to be longer in the Bevacizumab+ Platinum Group than in the Platinum Group (P = 0.056; Figure 2b). In patients with low VEGF-A expression, neither the PFS nor the OS differed significantly between the Bevacizumab+ Platinum and Platinum Groups (P = 0.519 and P = 0.642; Figure 2c, 2d).
Toxicity
Finally, patients were evaluated in terms of treatment-related toxicity. The proportion of patients with Grade 3 to 4 toxicity did not differ significantly between the Bevacizumab+ Platinum Group (50.0%) and Platinum Group (35.9%, P = 0.375; Table 4). The proportion tended to be smaller (16.7%) in the Monotherapy Group than in the Platinum Group (P = 0.214).