Systemic Therapy of Gallbladder Cancer

Review of First Line, Maintenance, Neoadjuvant and Second Line Therapy Specific to Gallbladder Cancer

Alexander A. Azizi; Angela Lamarca; Juan W. Valle


Chin Clin Oncol. 2019;8(4) 

In This Article

Abstract and Introduction


Gallbladder cancer is the most common malignant cancer of the biliary tract and is distinct from other forms of biliary tract cancer in several of its risk factors and molecular aberrations. Locally advanced, unresectable and metastatic gallbladder cancer is associated with a poor prognosis and systemic chemotherapy is the main form of treatment available to these patients. This review is focused on the available evidence supporting the use of first-line chemotherapy specifically for gallbladder cancer. Numerous non-randomised studies have been published and certain forms of monotherapy and combination therapy can both lead to response rates (RRs) of approximately 40% and may prove to affect overall survival, most notably a recent phase II study of triplet therapy with gemcitabine, cisplatin and nab-paclitaxel. There are however relatively few randomised phases II and III studies on which to base recommendations, but they do demonstrate significant survival advantages of gemcitabine-containing combination therapies over best supportive care and chemotherapeutic monotherapy. The ABC-02 trial established the combination of gemcitabine and cisplatin as standard therapy in 2010, but more recent phase III studies reported as conference papers may support alternative, gemcitabine-containing doublet chemotherapy regimens such as gemcitabine in combination with oxaliplatin or S1. This manuscript also highlights the available data from studies examining maintenance chemotherapy, biomarkers, neoadjuvant therapy and second line studies in gallbladder cancer; unfortunately, there is insufficient evidence to make recommendations in these regards. The prognosis for unresectable and metastatic gallbladder cancer remains poor, and biomarkers for stratifying patients to particular first line therapies are not defined. This might be improved by gallbladder cancer specific analysis and reporting, and making histological primary specific data available publicly for further analysis.


Gallbladder cancer the sixth most common cancer of the gastrointestinal tract and the most common malignant cancer of the biliary system.[1,2] It is mostly associated with late diagnosis, an aggressive disease course and poor prognosis.[1]

There is marked international variation in incidence; the top five countries are in South America and East Asia: Bolivia, Chile, Thailand, South Korea and Nepal [age-standardised rate (ASR) per 100,000 of 14.0, 9.3, 7.4, 6.8 and 6.7 respectively].[3] There is also great variation within countries, for example, the indigenous populations of North and South America have an increased risk of gallbladder cancer, as do the people of Northern India. Recent reports calculate an ASR of 7.16 per 100,000 for Northern India's Gwalior district, however historical data suggests that the ASR could be even higher (21.5 per 100,000) for women in Delhi.[1,4,5] The United States of America (US), India and the United Kingdom (UK) have much lower rates of gallbladder cancer (with an ASR of 1.5–2.0 per 100,000).[6,7]

The predominant histological type of gallbladder cancer is adenocarcinoma (approaching 98%) and two thirds of these are moderately or poorly differentiated.[8–10] The remaining histological variants are papillary, mucinous, squamous and adenosquamous alongside extra-pulmonary small cell and neuroendocrine tumours.[8] Risk factors for gallbladder cancer include age, female sex, ethnicity, gallstones, gallbladder polyps, chronic cholecystitis, chronic infection with Salmonella typhi, an abnormal pancreatobiliary duct junction, obesity and diabetes.[11,12] Many of these are distinct from the risk factors for cancers arising elsewhere in the biliary tract.[11] Gallbladder cancer development is associated with several molecular aberrations, some of which are distinct to gallbladder cancer, such as EGFR, ERBB3, PTEN, ARID2, MLL2, MLL3, TERT promotor mutations, and others, such as TP53, BRCA1, BRCA2, PIK3CA mutations, which are common to all forms of biliary tract cancer.[13,14]

Gallbladder cancer is staged in accordance with the TNM categories of the American Joint Committee on Cancer (AJCC) Union for International Cancer Control (UICC) 8th edition.[15,16] The primary tumour might invade the lamina propria (T1a) or the muscular layer (T1b) of the gallbladder wall. The primary tumour might invade further into the perimuscular connective tissue without involvement of the serosa (T2a) or into the perimuscular connective tissue on the hepatic side with no extension into the liver (T2b), further into the liver, into the serosa or an adjacent organ (T3) or into the main portal vein, hepatic artery or several extrahepatic organs or structures (T4). Disease is further categorised by regional lymph node spread: no regional lymph node metastasis (N0), metastases to one or three regional lymph nodes (N1) or metastases to four or more regional lymph nodes (N2), and by distant metastasis: no distant metastatic spread (M0) or distant metastases (M1). If there is no regional or distant spread (N0M0) then gallbladder cancer is staged according to the primary tumour: T1, T2a, T2b, T3 disease is categorised as stage I, IIA, IIB and IIIA respectively. Stage IIIB disease corresponds to T1–3 with N1 M0 disease, stage IVa to T4 N0–1 M0 and stage IVB to T1–4 with N2 or M1 disease.

Surgery can be attempted in patients with up to stage IVa disease, but gallbladder cancer is usually diagnosed at an unresectable locally advanced or metastatic stage.[6,9] Gallbladder cancer is usually diagnosed as either an incidental finding in patients with cholelithiasis who are treated with cholecystectomy, in patients investigated for localising symptoms such as jaundice or right upper quadrant pain, or with systemic symptoms such as anorexia or weight loss.[6,9] Even if extensive surgical resection is performed, gallbladder cancer frequently recurs and is associated with a poor prognosis of less than 4–5 months without systemic therapy.[6,9] Therefore, many gallbladder cancer patients will be candidates for and could benefit from systemic chemotherapy, which is the focus of this article.