Aspects of neoadjuvant therapy in the curative treatment of cancer in the esophagus or gastroesophageal junction

Sammanfattning: Malignant esophageal tumors are among the most severe cancers. Only about 30% of the patients are suitable for curative treatment at diagnosis. The treatment is extremely demanding and unfortunately has disappointing results. The staging of disease and the treatment for cancer of the esophagus and gastroesophageal junction need to be improved. It is currently well established that neoadjuvant therapy, either with chemotherapy or with combined chemo- and radiotherapy, followed by surgery, offers a better chance for a cure in stage II and III esophageal and gastroesophageal junction cancer, than surgery alone. Data directly comparing neoadjuvant chemotherapy and chemoradiotherapy are scarce and it is debatable which of these neoadjuvant treatment concepts offers the best chance for long-term survival. This thesis aims to improve the knowledge about neoadjuvant treatment in the curative treatment of esophageal cancer. Papers I and III were based on the Neoadjuvant Chemotherapy versus Chemoradiotherapy in Resectable Cancer of the Esophagus and Gastric Cardia (NeoRes) trial, which was performed in Norway and Sweden during the period 2006– 2013. Patients with resectable squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction were randomized to either preoperative chemotherapy or preoperative combined chemoradiotherapy followed by surgical resection. Paper I showed an increased risk for severe postoperative complications after chemoradiotherapy compared to chemotherapy. In paper III we found that neoadjuvant chemoradiotherapy significantly increases the proportion of complete histological response, increases the occurrence of N0 lymph-node status, and increases the R0 resection rate, but there was no difference in overall survival compared to neoadjuvant chemotherapy. Paper II is a retrospective cohort study of patients with cancer of the esophagus or gastro- esophageal junction, who was reconstructed with cervical anastomosis. The planned radiation dose to the site of the cervical anastomosis on the gastric fundus was estimated for each patient. This study suggests that nCRT exposes the future anastomotic site to doses of radiation that may impair healing of the subsequent cervical anastomosis. Our data further suggest that nCRT may increase the severity of cervical anastomotic complications. Paper IV is a prospective population-based cohort study including all patients who underwent an esophagectomy operation due to cancer in Sweden, excluding T1N0, recorded in the Swedish National Register for Esophageal and Gastric Cancer, 2006-2014. The results showed that neoadjuvant chemoradiotherapy increases local tumor control, represented by increased R0 resection rates and pathological node-negative disease both compared to surgery alone and chemotherapy. For patients with the histological subtype squamous cell carcinoma, neoadjuvant treatment increases long-term survival but also increases the risk of postoperative morbidity and mortality compared to surgery alone. Neither of the two neoadjuvant treatment options seem to improve survival in adenocarcinomas, compared to surgery alone, in an unselected population of patients.