Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is significant, with esophageal and gastric cancer representing the ninth and fifth most common cancers, respectively. The approach to diagnosis and staging of these lesions is multimodal and includes a combination of gastrointestinal endoscopy, endoscopic ultrasound, and cross-sectional imaging. Likewise, therapy is multidisciplinary and combines therapeutic endoscopy, surgery, radiotherapy, and systemic chemotherapeutic tools. Future directions for diagnosis of esophageal and gastric malignancies are evolving rapidly and will involve advances in endoscopic and endosonographic techniques including tethered capsules, optical coherence tomography, along with targeted cytologic and serological analyses.

Gastrointestinal (GI) malignancies are some of the most common and devastating malignancies and include colorectal, gastric, esophageal, hepatocellular, and pancreatic carcinomas, among others. Five-year survival rates for many of these malignancies remain low. The majority presents at an advanced stage with limited treatment options and poor overall survival. Treatment is advancing but not at the same speed as other malignancies. Chemotherapy and radiation treatments are still only partially effective in GI malignancies and cause significant side effects. Thus, there is an urgent need for novel strategies in the treatment of GI malignancies. Recently, immunotherapy and checkpoint inhibitors have entered as potential new therapeutic options for patients, and thus, cancer vaccines may play a major role in the future of treatment for these malignancies. Further advances in understanding the interaction between the tumor and immune system have led to the development of novel agents, such as cancer vaccines.

Together, gastric cancer and esophageal cancer (EC) possess two of the highest incidence rates amongst all cancers. They exhibit poor prognoses in which the 5-year survival rate is dismal. In addition to cytotoxic chemotherapy, treatment efforts have been geared toward targeting human epidermal growth factor receptor 2 (HER-2), vascular endothelial growth factor (VEGF), and programmed death ligand-1 (PD-1). Although ample success has been recorded with these agents, gastric and esophageal cancer remain lethal, and further research into potential treatment alternatives is needed. In this article, we will review some of the targets at the forefront of investigation such as claudin, Dickkopf-related protein 1 (DKK-1), fibroblast growth factor receptor (FGFR), and matrix metalloproteinases (MMPs). These innovative target pathways are in the midst of clinical trials to be implemented in the treatment algorithm for this patient population. Ultimately, exploiting the oncogenic tendencies of these potential biomarkers creates an opportunity for precise treatment and improved prognosis for these cancers. Lastly, research aimed toward reversing PD-1 antibodies resistance by combining it with other novel agents or other treatment modalities is underway in order to expand existing treatment options for this patient population.

Cholangiocarcinoma is a malignancy of the bile ducts that is often associated with late diagnosis, poor overall survival, and limited treatment options. The standard of care therapy for cholangiocarcinoma has been cytotoxic chemotherapy with modest improvements in overall survival with the addition of immune checkpoint inhibitors. The discovery of actionable mutations has led to the advent of targeted therapies against FGFR and IDH-1, which has expanded the treatment landscape for this patient population. Significant efforts have been made in the pre-clinical space to explore novel immunotherapeutic approaches, as well as antibody–drug conjugates. This review provides an overview of the current landscape of treatment options, as well as promising future therapeutic targets.

Gastric and esopahgeal cancers account for the six most common causes of cancer death worldwide. Locally advanced resectable cancers have a 5-year life expectancy of 30%. Despite use of chemotherapy, median overall survival for stage IV cancer rarely exceeds 1 year. A subset of gastric cancers such as microsatellite-instable tumor and Epstein-Barr virus-positive tumors have a rich immune infiltrate that makes them more responsive to immune-directed therapies. Tumors can evade T-cell-mediated "immune surveillance" by activating the programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway. Targeting PD-1 and thus de-engaging them from its ligands can help restore immunogenicity. Pembrolizumab is the first immunotherapy to be approved by US FDA for PD-L1 expressing gastric and gastroesopahgeal junction (GEJ) cancers after they have progressed on at least two prior lines of treatment. While PD-L1 positivity does not define tumor's responsiveness to pembrolizumab, PD-L1-positive tumors have better overall response rates. The treatment is usually well tolerated and has a favorable adverse events profile. The exact setting for use of pembrolizumab remains to be determined. Pembrolizumab failed to improve overall survival when administered as second-line treatment for advanced, metastatic gastric and GEJ cancers. There are several ongoing studies with various combinations and different settings not only with pembrolizumab but also with other checkpoint inhibitors.

Gastric and gastroesophageal junction (GEJ) cancer is one of the most common malignancy worldwide. In unresectable or metastatic disease, the prognosis is poor and is generally less than a year. Standard front-line chemotherapy includes two- or three-drug regimens with the addition of trastuzumab in HER2-positive disease. With an increased understanding of the biology of cancer over the past few decades, targeted therapies have made their way into the treatment paradigm of many cancers. They been examined in the first- and second-line settings in the treatment of gastroesophageal cancer though has yielded few viable treatment options. One success is ramucirumab either as monotherapy or in combination with paclitaxel is the preferred choice in second-line therapy. While immunotherapy has been considered a breakthrough in oncology over the past decade, the response rates in gastric and gastroesophageal cancers have been relatively low compared to other cancers, resulting in its limited approval and mostly reserved for second-line therapy or beyond. In this article, we will review the standard first- and second-line treatment regimens. Furthermore, this article will review the use of targeted therapies and immunotherapy in treatment of gastric and gastroesophageal cancers. Lastly, we will touch upon future treatment strategies that are currently under investigation.