RETRACTED: Neoadjuvant Therapy for Esophageal Adenocarcinoma in the Community Setting—Practice and Outcomes

Abstract

There has been an alarming rise in the incidence of esophageal adenocarcinoma which continues to have poor survival rates primarily due to lack of effective chemotherapy and presentation at advanced stages. Over a dozen chemotherapeutic agents are FDA approved for esophageal cancer (EC), and a two or three-drug combination is typically prescribed as first-line therapy for the majority of EC patients, administered either pre or post-operatively with esophageal resection. We have noticed significant variability in adjuvant and neoadjuvant regimens used in the community setting. The aim of this study was to review the various drug regimens used in the neoadjuvant setting for EC patients with adenocarcinoma undergoing resection at a single tertiary referral center in the Midwest. A total of 123 patients (stage II–III) underwent esophageal resection after neoadjuvant treatment at the center. Overall, 18 distinct drug regimens were used in 123 patients including two patients who received targeted therapy. Median survival post-surgery for this group was 11.2 months with no single regimen offering a survival advantage. These results reveal an unclear algorithm of how accepted regimens are prescribed in the community setting as well as a dire need for agents that are more effective. Additionally, it was noted that although proteomic markers have been found to predict drug response to 92% of the FDA-approved drugs in EC (12 of 13), according to pathology reports, molecular diagnostic testing was not used to direct treatment in this cohort. We therefore propose potential strategies to improve clinical outcomes including the use of a robust molecular oncology diagnostic panel and discuss the potential role for targeted chemotherapy and/or immunotherapy in the management of EC patients.

Discovery of Novel and Clinically Relevant Markers in Formalin-Fixed Paraffin-Embedded Esophageal Cancer Specimen

“…Advanced esophageal cancer patients who received chemotherapy had no survival advantage compared to patients who received no treatment course at all ( 7 ). About 95% of EAC patients are prescribed cisplatin in the first-line setting ( 3 ). We discovered that seven proteomic expression trends associated with cisplatin resistance were seen to be either overexpressed or downregulated in the vast majority of EAC tumors analyzed in our study—HMGB1, IL-1RA, LGALS3BP, PRMT1, S100A8, SFN, and TXN ( 11 , 12 , 16 , 17 , 20 , 23 , 27 , 28 , 32 , 33 ).…”

“…We discovered that seven proteomic expression trends associated with cisplatin resistance were seen to be either overexpressed or downregulated in the vast majority of EAC tumors analyzed in our study—HMGB1, IL-1RA, LGALS3BP, PRMT1, S100A8, SFN, and TXN ( 11 , 12 , 16 , 17 , 20 , 23 , 27 , 28 , 32 , 33 ). About 63% of EAC patients receive the chemotherapy drug 5-FU in the first-line setting ( 3 ). We discovered two biomarkers associated with 5-FU resistance in other solid tumor cancers that were upregulated in Barrett’s and EAC tissue (S100P, PRMT1), posing a potential multifaceted resistance to 5-FU in precancerous and cancerous esophageal tissue ( 23 , 28 ).…”

“…Lastly, we found three markers associated with sensitivity to taxanes downregulated in both Barrett’s and EAC tissue, posing a subsequent resistance to this family of chemotherapies. About 37% of patients receive a taxane as part of their first-line regimen ( 3 ). Downregulation of S100A8, IL-IRA, and ANXA1 has been associated with a reduced likelihood of benefit when using taxanes ( 11 , 12 , 17 , 27 ).…”

“…Downregulation of S100A8, IL-IRA, and ANXA1 has been associated with a reduced likelihood of benefit when using taxanes ( 11 , 12 , 17 , 27 ). Again, chemoradiation has been found to have an insufficient clinical effect on EAC patients; therefore, these data potentially explains why FDA-approved chemotherapies for esophageal cancer (i.e., cisplatin, 5-FU, and taxanes) have a limited effect on patient response and OS ( 3 , 40 ). These findings will hopefully prompt a discussion around altering patient management strategies away from the use of cisplatin and other chemotherapies in esophageal cancer care.…”

“…In the last year, our group at Creighton University School of Medicine has reported on the difficulties of the patient management strategies currently utilized in esophageal cancer care ( 1 – 3 ). Indeed, there is an enormous amount of investigation needed in this arena of molecular oncology to better understand the pathogenesis and enhance treatment protocols for esophageal adenocarcinoma (EAC).…”