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.

Keywords: clinical outcomes; esophageal adenocarcinoma; molecular diagnostics; patient management; proteomics; targeted chemotherapy; targeted therapy.

Figure 1

Paths to treatment in esophageal cancer (EC). Red box is the treatment path of the cohort analyzed in this study.

Figure 2

One disease, 18 different treatments. Neoadjuvant drug regimen used in 123 patients who were referred to Creighton University Medical Center (CUMC) for esophageal resection. Pie chart affirms the variability of first-line esophageal cancer chemotherapy. Red box highlights that only 2 neoadjuvant regimen utilized targeted therapy.

Figure 3

A plea for sanity. Suggested proteomic expression assay panel which could assist in optimizing a first-line therapy for esophageal cancer patients. Unadulterated tumor specimen is crucial for reliable proteomic expression results which can ultimately assist in more robust precision medicine. Please consult with a pathologist on the best ways to achieve expression results on these markers. ERCC1, excision repair cross-complementation group 1; RFC, reduced folate carrier; TUBB3, tubulin beta 3; TOPO2A, type II topoisomerase; TOPO1, topoisomerase-1; TS, thymidylate synthase; HER2, receptor tyrosine-protein kinase erbB-2; EGFR, epidermal growth factor receptor; PD-L1, programmed death-ligand 1; 5-FU, fluorouracil; TKIs, tyrosine kinase inhibitors.

Figure 4

Clinical utility of 9-marker panel: expression matters. Proteomic biomarkers affiliated with improved response to targeted or chemo therapy as well as resistance to various approved chemotherapeutic agents. Knowing the expression status of these biomarkers could improve patient management strategies in esophageal cancer (EC). (A) Markers with potential efficacy predicting response to EC chemotherapy. The left frame demonstrates how high expression of TOPO1 can be effective for topoisomerase inhibitors like irinotecan by forming a complex and disrupting DNA synthesis. TOPO2A and anthracyclines react in a similar way where they form a complex to inactivate DNA synthesis. Both of these mechanisms are dependent upon the formation of a complex resulting in reduced cellular proliferation and an increase in tumor regression. RFC acts like a ferry for the anti-folate drug leucovorin and is dependent on RFC to cross into the cytoplasm of a tumor cell. Once inside the cells, the leucovorin can work as an anti-folate and inhibit cellular proliferation. Greater RFC expression likely increases leucovorin’s access into malignant cells. The right side of the frame demonstrates how low expression of these markers would produce low patient response when treated with these types of drugs. (B) Markers with proven predictive efficacy to EC targeted therapy. When HER2 and EGFR is expressed in a tumor they can be utilized to inhibit cellular growth via targeted therapy. Blocking these proteins with monoclonal antibodies prevents their ability to send growth factor signals which results in tumor regression. Blocking the PD-L1 ligand expressed on a tumor allows for antigen presenting cells (APCs) to come in contact with the tumor uninhibited which causes the activation and infiltration of T-cells directed at the tumor resulting in tumor regression. (C) Markers with proven predictive efficacy for EC chemotherapy. When markers ERCC1, TUBB3 and TS are expressed they act as resistance elements to platinums, taxanes and pyrimidine analogs, respectively. When these markers are not expressed, these classes of drugs can act on tumor cells uninhibited which results in increased tumor regression. The effects of these resistance markers have been tested and validated specifically in EC. ERCC1 excision repair cross-complementation group 1; RFC, reduced folate carrier; TUBB3, tubulin beta 3; TOPO2A, type II topoisomerase; TOPO1, topoisomerase-1; TS, thymidylate synthase; HER2, receptor tyrosine-protein kinase erbB-2; EGFR, epidermal growth factor receptor; PD-L1, programmed death-ligand 1.