Metabolomic and BH3 Profiling of Esophageal Cancers: Identification of Novel Assessment Methods of Treatment Response for Precision Therapy

Background: The number of patients with esophageal cancer keeps rising. For many patients, a combination of surgery, chemotherapy, and radiation is necessary to completely treat the disease. Usually, patients receive chemotherapy and radiation at the same time followed by surgery to remove the part of the esophagus with the tumor (Neoadjuvant chemoradiotherapy (nCRT)). Researchers want to learn how to make this treatment more effective. Objective: To see if biopsies before treatment can show which patients will do the best with a combination of chemotherapy, radiation, and surgery. Eligibility: Adults at least 18 years old with esophageal adenocarcinoma or squamous cell carcinoma who should be treated with chemotherapy, radiation, and surgery. Design: Patients will undergo standard testing that is routine for all patients with this disease. These tests include: Medical history Physical exam with activity and nutritional assessment Standard lab tests Imaging studies including a computerized axial tomography (CAT) scan and positron-emission tomography (PET) scan Breathing test into a machine to measure size and function of lungs. Biopsy for a small sample of tumor is removed by esophagogastroduodenoscopy (EGD): A tube inserted into the mouth under anesthesia Endoscopic ultrasound is performed in some but not all patients. Patients will have nCRT at the clinic or with their local doctor. In 6 -12 weeks after nCRT, patients will undergo surgery with: 1. A robotically-assisted, minimally-invasive esophagectomy 2. Or, a traditional, open approach. After surgery, patients are usually in the hospital for 2 weeks and have a feeding tube for at least 2 weeks and potentially longer until they are eating enough to not lose weight. Patients will return for follow-up visits with labs and CAT scans every 6 months for the first two years then every year afterwards.

Sex

All

Minimum age

18 Years

Maximum age

99 Years

* INCLUSION CRITERIA:
* Patients must have histologically confirmed esophageal adenocarcinoma (EAC) or esophageal squamous cell carcinoma (ESCC).
* Disease should be deemed resectable by pre-operative computed tomography (CT) and/or positron-emission tomography (PET) scans and the patient should be operable based on surgeon assessment.
* Patients willing to complete neoadjuvant chemoradiotherapy (nCRT) per standard of care followed by esophagectomy. Patients will be treated under protocol 04-C0165.
* 18 years of age or older.
* Able to understand and sign the Informed Consent Document.
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2.
* Patients must have organ and marrow function that is not prohibitive of surgical resection as defined below:

leukocytes greater than or equal to 3,000/mcL

absolute neutrophil count greater than or equal to 1,500/mcL

platelets greater than or equal to 50,000/mcL

* nCRT used in this study is potentially dangerous for developing human fetus. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration and 6 months post chemoradiotherapy. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
* Women must have a negative urine pregnancy test OR be post-menopausal for at least 2 years OR patient has had a hysterectomy

EXCLUSION CRITERIA:

* Patients in which nCRT followed by surgery is not the appropriate management:

  * Early stage disease that requires local therapy without chemoradiotherapy (CRT).
  * Patients with metastatic disease.
* Patients in which biopsy prior to starting nCRT is not obtainable.
* Patients who previously received neoadjuvant chemotherapy
* Concomitant medical problems in the opinion of physician that would place the patient at unacceptable risk for a major surgical procedure.
* Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, heart failure, hepatic disease that prohibits administration of neoadjuvant therapy or surgery.
* Women who are pregnant or breastfeeding because of the potentially dangerous effects of the chemotherapy on the fetus or infant.
* Patients with a diagnosis of another malignancy that is either active or in remission less than five years. Basal cell and squamous cell carcinoma of the skin are not contraindications to this protocol

• BACKGROUNDPiessen G, Messager M, Mirabel X, Briez N, Robb WB, Adenis A, Mariette C. Is there a role for surgery for patients with a complete clinical response after chemoradiation for esophageal cancer? An intention-to-treat case-control study. Ann Surg. 2013 Nov;258(5):793-9; discussion 799-800. doi: 10.1097/SLA.0000000000000228. PMID 24096755
• BACKGROUNDStiles BM, Salzler G, Jorgensen A, Nasar A, Paul S, Lee PC, Port JL, Altorki NK. Complete metabolic response is not uniformly predictive of complete pathologic response after induction therapy for esophageal cancer. Ann Thorac Surg. 2013 Nov;96(5):1820-5. doi: 10.1016/j.athoracsur.2013.05.027. Epub 2013 Jul 26. PMID 23895888
• BACKGROUNDShaikh T, Ruth K, Scott WJ, Burtness BA, Cohen SJ, Konski AA, Cooper HS, Astsaturov I, Meyer JE. Increased time from neoadjuvant chemoradiation to surgery is associated with higher pathologic complete response rates in esophageal cancer. Ann Thorac Surg. 2015 Jan;99(1):270-6. doi: 10.1016/j.athoracsur.2014.08.033. Epub 2014 Nov 18. PMID 25440267
• DERIVEDTaylor Ripley R, Surman DR, Diggs LP, Trepel JB, Lee MJ, Ryan J, Davis JL, Steinberg SM, Hernandez JM, Hoang C, Kenney CM, Bond CD, Kunst TF, Letai A, Schrump DS. Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy. BMC Gastroenterol. 2018 Jun 22;18(1):94. doi: 10.1186/s12876-018-0823-x. PMID 29933761