Benefit of Adjuvant Chemoradiotherapy in Resected Gallbladder Carcinoma

To evaluate the benefit of adjuvant treatments, such as chemoradiotherapy (CRT) and chemotherapy (CTx), compared with no adjuvant treatment (No-AT) in resected gallbladder (GB) cancer patients, 151 patients were analyzed: 98 (64.9%) patients received adjuvant treatment with CRT (n = 59, 39.1%) or CTx (n = 39, 25.8%), and the remaining 53 (35.1%) did not (No-AT). The clinicopathological factors, patterns of failure, locoregional recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) were compared among the three groups according to tumor stage. In patients with T2-3N0M0 stage disease, the incidences of locoregional recurrence and distant recurrence and 5-year LRFS, RFS and OS rates were not significantly different among the No-AT, CTx, and CRT groups (p > 0.05 each). In those with T2-3N1-2M0 stage disease, the incidences of locoregional recurrence (11.4%, 78.1%, and 68.4%, respectively) and distant recurrence (42.8%, 73.9% and 66.7%, respectively) in the CRT group were significantly lower than those in the No-AT and CTx groups (p < 0.05), and the CRT group had significantly higher 5-year LRFS (82,1%, 26.8%, and 19.0%), RFS (53.3%, 11.6% and 16.7%) and OS rates (64.0%, 22.7% and 4.3%) than the CTx and No-AT groups (p < 0.05 each). Therefore, adjuvant CRT may improve the LRFS and RFS and subsequently improve OS in lymph node-positive resected GB cancer.

Gallbladder (GB) cancer is characterized by its rarity, advanced stage at diagnosis despite advances in hepatobiliary imaging techniques and poor prognosis due to aggressiveness in the course of disease. Surgical resection is the only potentially curative treatment for GB cancer, but even after complete resection, locoregional and/or distant recurrences frequently become main problems [1][2][3][4][5][6] . Conceptually, additional adjuvant treatment modalities, such as chemoradiotherapy (CRT) and chemotherapy (CTx), are required to decrease both locoregional and distant recurrences and subsequently improve survival in patients with GB cancer undergoing surgical resection 5,[7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] . However, the role of adjuvant treatments and optimal treatment modalities remains controversial. Most previous studies [1][2][3][4][7][8][9]14 regarding adjuvant treatments for GB cancer have included heterogeneous populations that mix GB cancer with extra-and intra-hepatic bile duct cancer as well as patients who have undergone surgical resection with non-curative intent, such as positive resection margin(s) or gross residual tumor. Because of the low incidence of GB cancer, prospective clinical studies to investigate the role and compare the effectiveness of different adjuvant therapeutic modalities, such as CRT and CTx, for GB cancer are difficult to conduct and have rarely been performed. Therefore, further clinical studies to assess the role and compare the effectiveness of different adjuvant modalities in GB cancer patients who have received surgical resection should be needed even with retrospective studies.
The aim of the present study was to evaluate the benefit of adjuvant treatments, such as CRT and CTx, compared with that of surgery alone in resected GB cancer patients.
Univariate analyses for LRFS, RFS and OS are summarized in Table 2 and Fig. 2. In patients at the T2-3N0M0 stage, the CRT group exhibited higher trends in the 5-year LRFS, RFS and OS rates than the CTx and No-AT groups, but these differences were not significant (p > 0.05 each) (Table 2) ( Fig. 2A-C). In patients at the T2-3N1-2M0 stage, the CRT group had significantly higher 5-year LRFS, RFS and OS rates than the CTx and No-AT groups (p > 0.05 each) (Table 2) (Fig. 2D-F), and the CTx group exhibited higher trends in 5-year LRFS, RFS and OS rates than the No-AT group (Table 2) (Fig. 2D-F). In the multivariate analysis, the use of adjuvant therapy was not a significant factor in LRFS, RFS and OS in patients at the T2-3N0M0 stage, but it was a significant factor in LRFS, RFS and OS in patients at the T2-3N1-2M0 stage. N classification and postoperative CA 19-9 level, together with the use of adjuvant therapy, were also significant factors in all LRFS, RFS and OS in the multivariate analysis (p < 0.05 each) ( Table 3). In patients at the T2-3N1-2M0 stage, the postoperative CA 19-9 level was not significantly different among the No-AT, CTx, and CRT groups, but the distribution of the N classification was significantly different among the No-AT, CTx, and CRT groups (Table 1). Thus, to avoid the effect  Table 1). In the subgroup with T2-3N2M0, LRFS and RFS were significantly higher in the CRT group than in the CTx and No-AT groups (p < 0.05 each) (Fig. 3D,E), and the CRT group had a higher OS than the CTx and No-AT groups, respectively. The difference between the CRT and No-AT groups was significant (p < 0.05), but the difference between the CRT and CTx groups was not significant (p > 0.05) (Fig. 3F) (Supplementary Table 1).

Discussion
As in other malignancies, disease recurrence after radical resection for GB cancer inevitably leads to death. However, little information is available regarding the patterns of disease recurrence in resected GB cancer patients. Several previous studies have reported a 31.9-66.3% disease recurrence rate: 33.9-79.2%, 52.6-79.8% and 18.9-50% disease recurrence occurred at locoregional sites, distant sites, and both, respectively 1-6 , and the most common sites of disease recurrence were regional lymph nodes (27.8-47.3%), the liver (22.2-36.8%), and the local area (20.8-28.3%) 1,2,5 . These data suggested that locoregional and distant recurrences in patients with resected GB cancer were common and that adjuvant treatment should be considered in resected GB cancer patients to reduce both locoregional and distant recurrence. In the present study, disease recurrence rates in resected GB cancer patients at the T2-3N0M0 and T2-3N1-2M0 stages were still relatively high (27.5% and 68.3%, respectively). Although the incidences of locoregional recurrence and distant recurrence in resected GB cancer patients with T2-3N0M0 stage disease were not significantly different among the No-AT, CTx, and CRT groups (p > 0.05), the incidences of locoregional recurrence and distant recurrence were significantly different among the No-AT, CTx, and CRT groups in patients at the T2-3N1-2M0 stage (p < 0.05) (Fig. 1). These findings suggest that CRT reduces both locoregional and distant recurrence and subsequently improves survival. However, the incidence of distant recurrence was still high (42.8%) in resected GB cancer even after CRT, and the addition of CTx to CRT might be considered to further reduce distant recurrence.
Through randomized phase III trials evaluating the adjuvant CTx using 5-FU and mitomycin C for pancreatobiliary cancer, which included patients with stage IV and/or received surgical resection with non-curative intent, Takada et al. 16 , showed that the 5-year OS rate in the subgroup with GB cancer (n = 112) was significantly superior in patients who received adjuvant CTx than those who did not (26% vs. 14.4%, p < 0.05). A recent phase III trial 24 for resected biliary cancer that included 79 GB cancer cases showed that adjuvant capecitabine significantly improved the median survival time (53 months vs. 36 months, p = 0.028) compared with that in the per-protocol population, but it did not significantly improve survival in the intention-to-treat population. However, these studies did not compare CTx with CRT in patients with resected GB cancer. Another recent multi-institutional study 11   surgical resection with curative intent showed that adjuvant treatments, such as CTx and CRT, improved the disease-free survival and OS, and its benefit was pronounced in patients with adverse prognostic features, such as advanced tumor stage, lymph node metastasis and a microscopic positive surgical margin. In addition, in an analysis of resected GB cancer from the Surveillance, Epidemiology, End Results (SEER) database, Wang et al. 15 showed that adjuvant therapy yielded a survival benefit in ≥T2 and lymph node-positive patients and that CRT provided a greater advantage than CTx alone. Similar to the above studies, the present study showed that compared with CTx and No-AT, CRT did not significantly improve the LRFS, RFS and OS in resected GB cancer patients with lymph node-negative T2-3 disease, but did significantly improve the LRFS, RFS and OS in resected GB cancer patients with lymph node-positive disease (p < 0.05 each) ( Table 2) (Fig. 2D-F). This study had inherent limitations stemming from single institutional retrospective data with heterogeneity of treatments, such as heterogeneous chemotherapeutic regimens, completeness of surgery, etc., and thus possible selection bias was not thoroughly assessed. Nevertheless, to date, the present investigation was a relatively large study (n = 151) in GB cancer patients who received curative-intent surgical resection for investigating the benefit of CRT compared with CTx alone and observation. We compared the clinicopathological factors, patterns of failure, LRFS, RFS, and OS among three groups (CRT, CTx, No-AT) according to tumor stage, i.e., T2-3N0M0 (n = 69) and T2-3N1-2M0 (n = 82), and showed that compared with CTx and No-AT, CRT yielded significant benefits in LRFS, RFS and OS in resected GB patients with T2-3N1-2M0 stage disease. Although, in resected GB cancer patients at the T2-3N0M0 stage, adjuvant treatments, such as CRT and CTx, did not show a significant improvement in LRFS, RFS and OS compared with that yielded by No-AT, further investigation to develop effective adjuvant treatment strategies should be conducted due to the relatively high rate (25-33.5%) of disease recurrence.
The present study showed that the disease recurrence in resected GB cancer at the T2-3N0M0 and T2-3N0M0 stage was as high as 26.7% and 91.3%, respectively, in patients who did not undergo adjuvant treatment, suggesting that effective adjuvant treatment might be needed for these patients. In addition, our data showed that adjuvant CRT could significantly improve the LRFS, RFS and OS in resected GB cancer patients with T2-3N1-2M0 stage disease and suggest that further large-scale studies for investigating the optimal adjuvant treatment strategies, such as CRT, CTx using new chemotherapeutic regimens, and combination of CRT and CTx, are needed.