Gallbladder cancer is a rare malignant tumour of the digestive system, but its incidence has increased in recent years, with a higher incidence in women than in men[9]. For early-stage gallbladder cancer, achieving R0 resection is the key to planning for surgical treatment, while for advanced disease, comprehensive multidisciplinary management is emphasised. Index cholecystectomy may lead to RC, and no assessment of lymph node status, reassessment of tumour staging and removal of the residual disease have a positive effect on improving patient outcomes[2, 10]. Although extended resection is recommended for selected IGC patients without the disseminated disease, optimal management of IGC remains a critical issue[4, 6, 7, 11, 12]. The main reason is that residual disease detection represents a poor outcome regardless of anatomical location.
An international multicentre study in 2015 showed that patients with T2h had higher vascular invasion, neural invasion, and lymph node metastasis than patients with T2p, and T2h were often associated with worse prognosis[13]. The gallbladder adjacent to the hepatic side has no serosal layer, there are as many as 20 (2–20) gallbladder veins, and the tumour easily metastasises to the liver bed through the gallbladder veins[14]. RC was found in 31.4% of patients after index cholecystectomy, with the liver being the most common residual site. In addition, patients with RC had higher rates of lymph node positivity and lower differentiation tumours. These are the possible reasons for the poor prognosis of RC patients.
Although surgical resection has an irreplaceable role in managing IGC, surgical treatment alone is unlikely to be sufficient in patients with RC or stage III-IV disease, and systemic treatment has an important emerging role[15, 16]. However, systematic reviews and meta-analyses pointed out that there is no strong evidence that adjuvant therapy is effective in GBC patients undergoing radical resection and only has some benefit in patients with positive lymph node disease, and positive surgical margins, or advanced disease[17, 18]. A recent cohort study of 6391 GBC patients who underwent definitive surgery from the US National Database (NCBD) showed that 49.2% received adjuvant chemotherapy and 1.6% received neoadjuvant chemotherapy[19]. Further propensity score matching analysis suggested that GBC patients who received adjuvant chemotherapy had a longer median OS than those who received surgery alone (22 vs. 18 months, HR = 0.78, 95% CI: 0.63–0.96), and lymph node-positive patients benefited from neoadjuvant therapy (median OS: 30 vs. 14 months, P = 0.002).
Our analysis of prognostic factors in 102 IGC patients who underwent re-excision showed that lymph node-positive status and RC were independent risk factors for poor OS and DFS. Even with R0 resection, patients with lymph node positivity and/or RC were associated with low median OS and DFS. Recurrent disease is the main reason for the poor prognosis; 84% of GBC patients experience recurrence within the first 18 months after radical resection, of which 53% only have a local recurrence, 26% only have a distant recurrence, 21% have a local and distant recurrence, and the liver is the most common site, followed by carcinomatosis and lymph nodes[20]. In a subgroup analysis, we found that adjuvant chemotherapy significantly improved OS for IGC patients with lymph node metastases and/or residual disease after R0 resection. Therefore, we recommend routine adjuvant therapy for T3 IGC patients with residual disease or lymphatic metastasis.
In conclusion, index cholecystectomy does not attain the goal of curative treatment of T3 IGC, and all patients undergoing index cholecystectomy should be systematically evaluated to determine the need for reoperation. If the underlying conditions permit, extended resection should be actively performed for all resectable IGC, and R0 resection should be as extensive as possible to attain better OS and DFS. Residual disease and lymphatic metastasis after index cholecystectomy are the main reasons for the poor prognosis of IGC, and adjuvant therapy should be actively used in these patients.