Gallbladder cancer is a rare type of biliary tract cancer, with only 12,610 cases diagnosed annually in the United States. Gallbladder cancer is nevertheless a deadly disease, with 4,400 deaths projected for 2025 and an overall survival of 20% at five years for all stages combined. Survival is strongly influenced by stage, however, with early localized disease having a 69% five-year survival and patients with lymph node disease having a drop in survival to 28% at five years. Unfortunately, the survival for patients with distant (metastatic) disease is 3% at five years.1
General approach to management
As an overview, the standard management for resectable gallbladder cancers is a) complete staging, b) upfront oncologic surgery, and c) systemic chemotherapy (if pathologic staging is T1b or greater). Biopsy of gallbladder cancers should be avoided due to a high risk of peritoneal seeding. However, for locally unresectable or metastatic disease, biopsy is necessary to start neoadjuvant or palliative treatment. Oncologic surgical resection for gallbladder cancer is a cholecystectomy with en bloc central liver resection, a portal lymphadenectomy, and resection of the cystic duct stump, if necessary, to achieve negative margins.
Because presentation can occur in a variety of clinical settings, the precise application of this management can change subtly. These clinical algorithms are outlined in great detail in the NCCN Guidelines; however, in brief:
Incidental gallbladder cancer
Gallbladder cancer is often diagnosed as an incidental finding in cholecystectomy specimens performed for other indications (Incidental Gallbladder Cancer, IGBC). Estimates of the incidence of IGBC range from 0.3%-3% of cholecystectomy specimens, and one large institutional series found that up to 47% of gallbladder cancers were diagnosed as IGBCs.2 If the lesion is stage T1a, no suspicious lymph nodes are noted on imaging or pathology, and the cystic duct stump is negative for tumor, the patient can be observed. If, however, a higher stage is noted on pathology or there are any positive margins (liver or cystic duct stump), then an oncologic operation is indicated.
Incidental gallbladder mass on imaging
Alternatively, patients may also present with gallbladder masses or polyps discovered incidentally on imaging done for other reasons. Gallbladder masses and any polyps (greater than 1cm) should be referred to a surgical oncologist and removed with an oncologic operation (described above) at the initial sitting.
Patients who present with symptoms
Patients may also present with symptoms of right upper abdominal pain, bloating after meals, jaundice, or other more vague symptoms like loss of appetite and weight loss. In these cases, cross-sectional imaging usually identifies a gallbladder mass and sometimes an associated liver mass. Some patients with more challenging diagnostic paths will present with right upper abdominal complaints and are found to have a liver abscess associated with gallbladder inflammation. When the liver is biopsied during placement of a drain, they are found to have gallbladder cancer with local spread to the liver and necrosis of the liver mass.
These patients can be more challenging to manage and usually require a multidisciplinary approach. Nevertheless, after appropriate drainage and abx, if the anatomy appears resectable and no metastatic disease is suspected, the patient can proceed with upfront surgical resection. However, the disease in these cases is often borderline in its resectability, or there may be suspicious non-regional lymph nodes, or the tumor board simply feels that the patient might benefit from neoadjuvant therapy. In these cases, systemic chemo or chemoradiation might be offered first, followed by surgery.
Adjuvant postoperative treatment
Patients with resected gallbladder cancer who have a T stage of T1b or greater (muscle invasive) or who have positive lymph nodes are offered adjuvant Capecitabine.3 If the patient has a positive margin that is not amenable to surgical revision, then chemoradiation can be offered, usually in the setting of a multidisciplinary tumor board.
Palliative systemic chemotherapy
For patients with locally unresectable disease or metastatic disease, systemic chemotherapy with immunotherapy has become the new first-line standard of care with these recent practice-changing studies. Gemcitabine-Cisplatin (Gem-Cis) with Durvalumab (vs. Gem-Cis placebo) increased median survival significantly from 11.5 mo to 12.8 mo and 2-year overall survival from 10% to 25% in the TOPAZ-1 trial.4 Gem-Cis with Pembrolizumab (vs. Gem-Cis placebo) increased median survival from 10.9 mo to 12.7 mo and two-year overall survival from 18% to 25% in the KEYNOTE-966 trial.5
Molecular testing of tumor tissue for all patients with advanced gallbladder cancer is recommended. There have been several FDA approvals for targeted therapies in biliary tract cancers. Tumors that express IDH-1 BRAF, or NTRK mutations, FGFR aberrations, MSI-H phenotype, and most recently, HER2 overexpression benefit from systemic therapies that are more effective and have better toxicity profile than second-line chemotherapy. Clinical trials, when available, remain the preferred treatment option for all stages and lines of therapy. For advanced-stage patients, nutrition and palliative care are also vital parts of comprehensive patient care.
Conclusion
Gallbladder cancer is a rare and deadly cancer with several presenting clinical settings. It is important to consult a surgical oncologist upfront for suspected gallbladder cancer to help guide the management, and it is important to consult a medical oncologist to make sure you are receiving the most up-to-date post-surgery chemo and immunotherapies. Despite the challenging statistics surrounding gallbladder cancer, there remains reason for optimism if treated early and aggressively.
Learn more about gallbladder cancer treatment at Northside Hospital Cancer Institute.
References:
- American Cancer Society. SEER Database Statistics. Accessed February 12, 2025. https://seer.cancer.gov/statfacts.
- Duffy, A., M. Capanu, G. K. Abou-Alfa, D. Huitzil, W. Jarnagin, Y. Fong, M. D'Angelica, R. P. DeMatteo, L. H. Blumgart, and E. M. O'Reilly. 2008. "Gallbladder Cancer (GBC): 10-Year Experience at Memorial Sloan-Kettering Cancer Centre (MSKCC)." Journal of Surgical Oncology 98 (6): 485–89.
- Primrose, John N., et al. 2019. "Capecitabine Compared with Observation in Resected Biliary Tract Cancer (BILCAP): A Randomized, Controlled, Multicentre, Phase 3 Study." The Lancet Oncology 20 (5): 663–73.
- Oh, Do-Youn, Ji-Won Kim, Hye Jin Kang, et al. 2022. "Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer." NEJM Evidence 1 (8). https://doi.org/10.1056/EVIDoa2200015.
- Kelley, Robin Kate, Sameek Roychowdhury, Amir A. Rahmani, et al. 2023. "Pembrolizumab in Combination with Gemcitabine and Cisplatin Compared with Gemcitabine and Cisplatin Alone for Patients with Advanced Biliary Tract Cancer (KEYNOTE-966): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial." The Lancet 401 (10391): 1853–65. https://doi.org/10.1016/S0140-6736(23)00727-4.
