Although GBC is a rare disease and the overall incidence has remained stable,2 a trend analysis revealed a recent increase in the incidence of late-stage gallbladder cancer.9 However, the role of metastasis site on survival has not been addressed comprehensively to this day and the management for metastatic GBA patients remains to be explored. To our knowledge, this study is the first comprehensive study concerning the features and management of metastatic GBA on population level.
Based on our results, 788 (51.6%) patients had isolated liver metastases, 80 (5.2%) patients had isolated DL involvement, 45(2.9%) patients had isolated lung metastases, 21 (1.4%) patients had isolated bone metastases, 2 (0.1%) patients had isolated brain metastases and 590 (38.7%) patients had multiorgan metastases. Liver was the most common site of metastases, which is in agreement with previous studies13 and this may be because tumor cells spread to remote organs through the blood and the liver has the most blood vessels.13, 14
Previous studies of the survival on GBA lacked a comprehensive evaluation on the prognostic value of site-specific metastases. Thus, in this study, we made a survival analysis of metastatic GBA patients, and the results showed that median OS and CSS for single metastatic GBA are both 4 months. Median OS and CSS for multi-organ metastatic GBA patients are 4 and 5 months, respectively. There is no statistically significant difference in survival between patients with single site versus multiple sites of metastases (P>0.05), which is similar to the results of previous studies of pancreatic cancer15 and intrahepatic cholangiocarcinoma.16 What’s more, isolated lung metastases and DL involvement are associated with a significantly better prognosis than isolated bone metastases(P<0.05).
Surgery is the only treatment for biliary tract cancer with long term survival. In cases with non-resectable ones (locally advanced, recurrent, or metastatic), the current standard of care favors systemic chemotherapy.17 However, there is little evidence-based consensus about whether and when to use adjuvant therapy due to the limited utilization.18 Some studies have proven that adjuvant therapy provides a survival benefit in node-positive or ≥ T2 disease according to the NCCN guidelines.19-22 Some recommended chemotherapy for stage IV GBA patients with gemcitabine and cisplatin. Nevertheless, clinical response rates to these regimens are low, with <10% long term survival and a complete response only in exceptional cases.23 In our study, chemotherapy was associated with better OS and CSS for metastatic GBA patients. Adjuvant radiotherapy after R0 resection of GBA can improve the overall survival time and reduce the local recurrence rate.20 A retrospective study based on National Cancer Database indicated that for unresectable but non metastatic GBA, radiotherapy combined with chemotherapy can improve survival time than using chemotherapy alone.24 However, this conclusion may need to be verified by further prospective studies. For metastatic GBA, there is no relevant literature suggesting a survival benefit from radiotherapy. The multivariate analysis in our study indicates that radiotherapy is not related to the prognosis of metastatic GBA. Due to the advanced diagnosis and limited choices of adjuvant therapy, researchers have started to find other antineoplastic treatments. Recently, studies on targeted therapy have pointed out that there are many potential mutations in biliary tract cancer such as mutations of P53,25 HER226 and other molecular vulnerabilities, which can be used as therapeutic targets. Although there was a lack of consensus-based evidence for this new therapeutic strategy,27 researchers recommended that it is still of therapeutic significance to conduct a comprehensive genomic profiling of the tumor to identify potentially targetable aberrations and match with appropriate agent.28 Recent immunotherapy has opened up new therapy avenues in biliary tract cancers with pembrolizumab (the PD-1 inhibitor) approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors.29 However, the rate of patients who are MSI-H and dMMR is < 5% of all biliary tract cancer patients.25 So far, strategies incorporating immunotherapy into the treatment of patients with microsatellite stable advanced biliary tract cancers have showed largely disappointing results.29 Thus, routine use of checkpoint inhibitors outside of clinical trials should not be recommended.28 Because of the relative rarity and heterogeneity of GBA subtypes,30 there are few randomized prospective studies to determine the optimal treatment strategy for patients with advanced stage. Although targeted therapy and immunotherapy are in the exploratory stage, the identification of new targets and the development of new molecules are likely to make "Precision Medicine" a newly promising treatment for patients with advanced GBA.
Recently, some studies indicated that it is associated with improved survival outcomes to perform surgery at the primary site for the treatment of metastatic renal cell carcinoma and pancreas cancer.31-33 Since the benefit from surgery was not clear for metastatic GBA patients. We use SEER database to explore the outcomes. For metastatic GBA, which was considered unresectable, patients tend to receive palliative surgery according to the current literature.7 In our study, surgery at primary site improves median survival when tumor spreads to liver or DL. We assume there are cases of patients with metastatic indolent tumor that might be considered for resection and we propose that surgery at primary site may be a choice in certain highly selected patients with liver or DL metastases. However, methods for differentiating them from patients who are not qualified for surgery are needed to further explore. When the cancer spreads to the bone or lungs, it is not helpful to perform surgery.
Multivariate analyses of the entire cohort patients, isolated liver and DL metastasis patients all suggested that performing surgery at primary site, receiving chemotherapy were associated with better OS and CSS. Differences compared to the results of a previous study were that sex , age and marital status did not play roles in survival outcomes.2 We suspect that this finding may be because the advanced cancer was so malignant that it eliminated differences. Although marital status was not a significant predictor for prognosis of GBA patients, interestingly, in a recent study, Dr. Joan DelFattore noted that unmarried patients may be denied potentially lifesaving treatment without objective assessment of their capacity to handle it due to the stereotype that they lack social support, which caused the high mortality of unmarried cancer patients.34
Analyzing the prognostic consequences of metastatic GBA helps us to treat this disease in an outlook view and encourages us to apply systemic therapy. Meanwhile, we believe our results could properly counsel patients and their family about the oncologic outcomes. However, the inherent difficulties in retrospective studies of SEER database remind us to interpret the results cautiously. First, the database lacks information about comorbidities, patients who underwent surgical treatment may have better health conditions and fewer comorbidities. Second, the number of patients who underwent surgery with certain sites was not large enough. Moreover, the information of infiltrations of the liver hilum and pedicle and of the surrounding peritoneum as well as some adjacent sites of metastases such as the stomach, duodenum, pancreas, etc. was not included in the SEER database, which may also be a factor influencing the results. Despite these difficulties, the results are still convincing due to the large sample. Further prospective controlled studies to identify the highly selected subset of patients who may benefit from local treatment of the primary tumor are needed.