Summary of Esophageal cancer treatment

Epidemiology & Etiology:

• Approximately 60% of cases of distal esophageal or gastroesophageal adenocarcinomas have evidence of Barrett’s esophagus.
• High-grade dysplasia is an indication for more aggressive management, including surgical resection.
• Tumor markers, such as TP53, may be predictors of potential progression to malignant disease.
• There is an inverse association between Helicobacter pylori (H. pylori) infection and adenocarcinomas of the lower esophagus, presumably a result of the reduced acidity associated with atrophic gastritis.9  
• Infection with human papillomavirus (HPV) has been correlated with an increased incidence of squamous cell cancers of the upper esophagus.10

Diagnosis:

• endoscopic ultrasound (EUS), have become more important in the evaluation and staging of esophageal cancer.11
• EUS, in the hands of a skillful sonographer, can accurately assess the depth of penetration in as many as 90% of tumors and determine involvement of mediastinal lymph nodes in nearly all patients.
• In addition, EUS allows the biopsy of suspicious lymph nodes to confirm the presence of lymph node metastases.
• Particularly in the era of preoperative chemotherapy and radiation, obtaining accurate staging with the use of EUS and CT has become a standard component when evaluating patients with esophageal cancer.
• Positron emission tomography (PET), preferably as a PET/CT scan, has become part of the routine pretreatment diagnostic work-up for patients with esophageal cancers. PET allows for the determination of lymph node status and the detection of occult sites of distant metastatic spread, and, therefore, may spare the patient the morbidity of an aggressive local-regional treatment approach.12,13

Treatment:

• Survival is poor for patients who have been treated with surgery only, with fewer than 10% to 15% of patients surviving 5 years.
• Use of chemotherapy alone did not result in a significant improvement in outcome.
• Similarly, radiation therapy alone for the treatment of esophageal cancer failed to yield a positive survival benefit.
• Squamous cancers (mainly found in the middle and upper esophagus) appear to be more sensitive to chemoradiotherapy than adenocarcinomas and exhibit different tumor biology. Therefore, esophagectomy after chemoradiotherapy might not improve overall outcome after chemoradiotherapy in these patients.24. This is especially important for cancers of the cervical esophagus, which can provide a surgical challenge. However, patients with a good performance status and in good physical condition for a surgical approach should still undergo surgery after chemoradiotherapy, rather than receiving chemoradiotherapy alone.
• (MAGIC) trial, which compared perioperative chemotherapy using epirubicin, cisplatin, and continuously infused 5-FU (ECF) with surgery alone for patients with gastric and gastroesophageal cancers, yielded a significant improvement in overall survival for patients who received perioperative chemotherapy. 26% of patients in this trial had esophageal and gastroesophageal junction cancers.
• Thus, perioperative chemotherapy with a combination regimen such as ECF should be considered for patients with gastroesophageal junction cancers who are not optimal candidates for chemoradiotherapy.
• A meta-analysis, which included 18 randomized controlled trials with approximately 3,000 patients, found that trimodality therapy significantly improved 2-year survival (hazard ratio [HR] 0.81; p = 0.002; 13% absolute difference) and reduced locoregional recurrence when compared with surgery alone.27,28
• Most recently, data from a Dutch phase III trial confirmed the superiority of a neoadjuvant chemoradiotherapy approach compared with surgery alone in patients with localized esophageal cancer.20 In this study, 363 patients were randomly assigned to receive chemoradiotherapy with a carboplatin/paclitaxel regimen and a relatively low radiation dose of 41.4 Gy followed by surgery or surgery alone. The neoadjuvant treatment led to a pathologic CR rate of 32.6%. The overall survival was significantly better (p = 0.011) in the group of patients treated with chemoradiotherapy (HR 0.67, 95% CI 0.50, 0.92). Median survival was 49 months in the neoadjuvant arm compared with 26 months in the surgery-alone arm. One-, 2- and 3-year survival rates were 82%, 67%, and 59% in the trimodality arm and 70%, 52%, and 48% in the surgery-alone arm. Importantly, the results appeared to be more convincing in squamous cell cancers than in adenocarcinomas.
• In most clinical trials with single-agent therapy, the response rate has ranged from 10% to 40%. Combination regimens have yielded response rates as high as 50%.
• Initial results of a phase III trial that investigated the role of bevacizumab in advanced gastroesophageal and gastric cancers have been disappointing.34
• EGFR monoclonal antibodies added to chemotherapy even exhibit a detrimental effect on outcome.35
• Data from a second-line phase III trial comparing the VEGF receptor (VEGFR)-2 monoclonal antibody ramucirumab against best supportive care have shown improved survival in advanced gastroesophageal cancers.35,36
• Trastuzumab, the humanized monoclonal antibody against HER2, added to standard chemotherapy in HER2-overexpressing gastric and gastroesophageal cancers improved overall and progression-free survival as well as response rates compared with chemotherapy alone.37