Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

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Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Immunotherapies such as checkpoint-blocking antibodies and adoptive cell transfer are emerging as treatments for a growing number of cancers. Despite clinical activity of immunotherapies across a range of cancer types, the majority of patients fail to respond to these treatments and resistance mechanisms remain incompletely defined. Responses to immunotherapy preferentially occur in tumors with a preexisting antitumor T-cell response that can most robustly be measured via expression of dendritic cell and CD8+ T cell-associated genes. The tumor subset with high expression of this signature has been described as the T cell-"inflamed" phenotype. Segregating tumors by expression of the inflamed signature may help predict immunotherapy responsiveness. Understanding mechanisms of resistance in both the T cell-inflamed and noninflamed subsets of tumors will be critical in overcoming treatment failure and expanding the proportion of patients responding to current immunotherapies. To maximize the impact of immunotherapy drug development, pretreatment stratification of targets associated with either the T cell-inflamed or noninflamed tumor microenvironment should be employed. Similarly, biomarkers predictive of responsiveness to specific immunomodulatory therapies should guide therapy selection in a growing landscape of treatment options. Combination strategies may ultimately require converting non-T cell-inflamed tumors into T cell-inflamed tumors as a means to sensitize tumors to therapies dependent on T-cell killing. Cancer Immunol Res; 6(9); 990-1000. ©2018 AACR.

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T Cell–Inflamed versus Non-T Cell–Inflamed Tumors: A Conceptual Framework for Cancer Immunotherapy Drug Development and Combination Therapy Selection

Gastric cancer remains a major unmet clinical problem with over 1 million new cases worldwide. It is the fourth most commonly occurring cancer in men and the seventh most commonly occurring cancer in women. A major fraction of gastric cancer has been linked to variety of pathogenic infections including but not limited to Helicobacter pylori (H. pylori) or Epstein Barr virus (EBV). Strategies are being pursued to prevent gastric cancer development such as H. pylori eradication, which has helped to prevent significant proportion of gastric cancer. Today, treatments have helped to manage this disease and the 5-year survival for stage IA and IB tumors treated with surgery are between 60 and 80%. However, patients with stage III tumors undergoing surgery have a dismal 5-year survival rate between 18 and 50% depending on the dataset. These figures indicate the need for more effective molecularly driven treatment strategies. This review discusses the molecular profile of gastric tumors, the success, and challenges with available therapeutic targets along with newer biomarkers and emerging targets.

Gastric cancer: a comprehensive review of current and future treatment strategies

Esophageal cancer is one of the most aggressive gastrointestinal cancers. This review focuses on eight topics within the multidisciplinary approach for esophageal cancer. As esophagectomy is highly invasive and likely to impair quality of life, the development of less invasive strategies is expected. Endoscopic resection (ER) of early esophageal cancer is a less invasive treatment for early esophageal cancer. A recent phase II trial revealed that combined ER and chemoradiotherapy (CRT) is efficacious as an esophagus-preserving treatment for cT1bN0 squamous cell carcinoma (SCC). Esophagectomy and definitive CRT are equally effective for patients with clinical stage I SCC in terms of long-term outcome. For locally advanced resectable cancers, multidisciplinary treatment strategies have been established through several clinical trials of neoadjuvant or perioperative treatment. Minimally invasive esophagectomy may improve the outcomes of patients and CRT is a curative-intent alternative to esophagectomy. CRT with 50.4 Gy radiotherapy combined with salvage surgery is a promising option to preserve the esophagus. Induction chemotherapy followed by esophagectomy may improve the outcomes of patients with locally advanced unresectable tumors. Immune checkpoint inhibitors are effective for esophageal cancer, and their introduction to clinical practice is awaited.

https://link.springer.com/content/pdf/10.1007/s00595-019-01878-7.pdf

Recent progress in multidisciplinary treatment for patients with esophageal cancer

Liquid biopsies are providing new opportunities for detection of residual disease in cell-free DNA (cfDNA) after surgery but may be confounded through identification of alterations arising from clonal hematopoiesis. Here, we identify circulating tumor-derived DNA (ctDNA) alterations through ultrasensitive targeted sequencing analyses of matched cfDNA and white blood cells from the same patient. We apply this approach to analyze samples from patients in the CRITICS trial, a phase III randomized controlled study of perioperative treatment in patients with operable gastric cancer. After filtering alterations from matched white blood cells, the presence of ctDNA predicts recurrence when analyzed within nine weeks after preoperative treatment and after surgery in patients eligible for multimodal treatment. These analyses provide a facile method for distinguishing ctDNA from other cfDNA alterations and highlight the utility of ctDNA as a predictive biomarker of patient outcome to perioperative cancer therapy and surgical resection in patients with gastric cancer.

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White blood cell and cell-free DNA analyses for detection of residual disease in gastric cancer

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4)

Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer

Salah-Eddin al Batran

Papers

Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4)

Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer