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Microsatellite status should be assessed in all upper and lower gastrointestinal (GI) cancers. If an upper GI cancer is microsatellite instable (MSI), clinicians should consider treatment with an immune checkpoint inhibitor (ICI) or a combination of ICIs instead of chemotherapy. Immunotherapy is also active in lower GI cancers, where treatment is driven by microsatellite status. For upper GI cancers, the benefit has mostly been shown in the neoadjuvant and metastatic settings. In colorectal cancer, most of the benefit has been established in metastatic disease, although the use of immunotherapy in the neoadjuvant and adjuvant settings is an active area of research. In rectal cancer, a response benefit has been established for ICI as neoadjuvant therapy, although survival outcomes have not matured.

Gastric and esophageal cancers continue to be a significant health problem. The incidence of proximal gastric and distal esophageal cancers has been increasing, especially in white men. Gastric and esophageal cancers have high rates of locoregional and distant failure, resulting in poor overall survival. Therefore, patients with gastric and esophageal cancer may benefit from combined modality therapy. Adjuvant chemoradiation has been shown to improve survival in gastric and gastroesophageal cancers in a phase III trial. In esophageal cancer, most randomized trials have not shown a survival benefit for preoperative chemotherapy or chemoradiation, although these approaches are widely used. This article reviews the role of staging, surgery, and adjuvant and preoperative therapies in the management of localized gastric and esophageal cancers.

Use of definitive chemoradiation as primary therapy for locoregional squamous cell carcinoma of the anal canal has been the standard approach in the United States since the 1980s. Over the past several years, phase III studies have shown that combination mitomycin C (MMC) and 5-fluorouracil (5-FU) concurrent with radiotherapy had better outcomes than radiotherapy alone or 5-FU with radiotherapy. Two recent phase III studies using diverse treatment strategies showed that cisplatin and 5-FU were not superior to 5-FU and MMC; in one of the trials, use of cisplatin-based chemoradiation resulted in a higher rate of colostomy compared with mitomycin-based chemoradiation. MMC and 5-FU concurrent with radiotherapy remains standard care. Further improvement is likely depending on an increased understanding of the molecular biology of anal carcinoma and the addition of relevant biologic agents to chemoradiation to overcome chemoradiation resistance.

The 7th edition of the AJCC Cancer Staging Manual has attempted to harmonize gastric and esophageal cancers, including management of gastroesophageal junction (GEJ)-type tumors. The treatment of complex tumor types is best guided by a staging classification that reliably groups patients according to prognosis and therapy. This article reviews and discusses these changes with the goal of elucidating key features of the staging system and outlining how these changes relate to the NCCN Clinical Practice Guidelines in Oncology with regard to the care and treatment of patients. The 7th edition of the AJCC Cancer Staging Manual has certainly improved harmonization of gastric and distal esophageal/GEJ-type adenocarcinomas, although issues persist, particularly regarding the optimal neoadjuvant treatment for the management of GEJ carcinomas.

The clinical spectrum of esophageal cancer has changed dramatically over the past couple of decades. Most notably, a profound rise in esophageal adenocarcinoma and decrease in the incidence of squamous carcinomas have occurred. An understanding of the factors that influence survival for patients with localized esophageal cancer has evolved concomitantly with these changes in epidemiology. Significant advancement in endoscopic and radiographic staging allows for more selective use of treatment modalities. The treatment of localized esophageal cancer mandates a multidisciplinary approach, with treatment tailored to disease extent, location, histology, and an accurate assessment of pretreatment staging. Despite these improvements in the staging and use of multimodality therapy, only modest improvements in patient survival have been observed. This article summarizes these modern approaches to localized cancer of the esophagus.