Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022

SIMPLE SUMMARY: Gallbladder cancer is distinct type of biliart tract cancer that is rare, aggressive and with limited treatment options aside from surgical resection. As of now in year 2022, systemic chemotherapy remains as the mainstay treatment option for patients with advanced staged gallbladder cancer. Despite decades of scientific research, new treatment options have been struggling to succeed. Furthermore, almost all clinical studies on gallbladder cancer have included other tyes of biliary tract cancers, raising the need to specifically inspect the outcomes of these clinical trial regimens on gallbladder cancer. In this article, we summarized all seminal literature and the most recent advances in scientific discoveries and clinical trials on gallbladder cancer. We provide a succinct update on current understanding, treatment landscape and therapeutic challenges in gallbladder cancer, as well as future prospects in the management of this disease. ABSTRACT: Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- and intra-hepatic cholangiocarcinoma. The advent of next-generation sequencing (NGS) clearly shows that GBC is genetically different from cholangiocarcinoma. Although GBC is a relatively rare cancer, it is highly aggressive and carries a grave prognosis. To date, complete surgical resection remains the only path for cure but is limited to patients with early-stage disease. The majority of the patients are diagnosed at an advanced, inoperable stage when systemic treatment is administered as an attempt to enable surgery or for palliation. Gemcitabine and platinum-based chemotherapies have been the main treatment modality for unresectable, locally advanced, and metastatic gallbladder cancer. However, over the past decade, the treatment paradigm has evolved. These include the introduction of newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation of targeted therapeutics towards driver mutations of genes including HER2, FGFR, BRAF, as well as approaches to unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due to the rarity of BTC in general, most clinical trials included both GBC and cholangiocarcinomas. Here, we provide a review on the pathogenesis of GBC, past and current systemic treatment options focusing specifically on GBC, clinical trials tailored towards its genetic mutations, and emerging treatment strategies based on promising recent clinical studies.