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Paclitaxel

Albumin-Bound Paclitaxel

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Patients (\>18 years) with potentially resectable locally advanced squamous cell- or adenocarcinoma of the esophagus or gastroesophageal junction, receiving nCRT according to the CROSS regimen prior to surgery.

CROSS regimen: weekly carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, delivered 5 days per week on workdays with intensity modulated radiotherapy, including photon and proton therapy)

* Anatomical (T2W) and functional MRI (DWI and DCE) at a 1.5T Siemens or Philips scanner
* DWI series: sagittal (sIVIM) and high-resolution transversal (HR tDWI)
* DCE serie: dynamic20
* In total, three MRI scan series (before, during, after nCRT)
* Measurements: i.a. change in apparent diffusion coefficient (ADC) or area-under-the-gadolinium-concentration time curve (AUC) within tumor delineation over time, radiological (qualitative) assessment of residual disease

* According to European Association of Nuclear Medicine (EANM) Research Ltd guidelines (EARL)
* In total one additional PET-CT (during nCRT) for study purposes. A PET-CT scan at diagnosis and after nCRT are included in the standard diagnostic work-up for esophageal cancer.
* Measurements: i.a. change in TLG (Total Lesion Glycolysis), SUVmax (Standardized Uptake Value) or Ktrans within tumor delineation over time

PET-CT

Additional endoscopy and/or endoscopic ultrasonography (EUS) with biopsies of the primary tumor site and other suspected lesions in the esophagus after completion of nCRT and prior to surgery

Endoscopy

* Blood samples at three different time points (before, during and after nCRT) will be collected
* Blood will be collected in cell-free DNA collection tubes
* Purpose: isolation of ctDNA and subsequent mutation analysis by means of Next Generation Sequencing
* Measurements: the presence of, and changes in, ctDNA during nCRT

Blood samples

Gert J Meijer, PhD

Ingmar L Defize, MD

Hanneke WM van Laarhoven, MD, PhD

Marcel Verheij, MD, PhD

J. (Hans) A. Langendijk, MD, PhD

Gert Meijer, PhD

Rationale: For locally advanced esophageal cancer the standard treatment consists of 5 weeks of neoadjuvant chemoradiotherapy (nCRT) followed by surgery. Surgery is currently performed independent of the response to nCRT and is associated with substantial morbidity. Prior knowledge of the eventual response to nCRT would greatly impact on the optimal care for many esophageal cancer patients for two imperative reasons:

Firstly, it is argued that patients who achieved a pathologic complete response (pCR, 29%) may not have benefitted from surgery. Consequently, proper identification of pathological complete responders prior to surgery could yield an organ-preserving regimen avoiding unnecessary toxicity.

Secondly, non-responders are exposed to the side effects of nCRT without showing any tumor regression. Early identification of the non-responders during nCRT would be beneficial for this group as ineffective therapy could be stopped, and for who altered treatment strategies could be explored.

Objective: To develop a multimodal model that predicts the probability of pathologic complete response to nCRT in esophageal cancer, by integrating diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in conjunction with combined 18F-fluorodeoxyglucose positron emission tomography and computed tomography (18F-FDG PET-CT) scans acquired prior to, during and after administration of nCRT.

Study design: Multi-center observational study

Study population: Patients (\>18 years) with potentially resectable locally advanced squamous cell- or adenocarcinoma of the esophagus or gastroesophageal junction, receiving nCRT prior to surgery.

Intervention: In addition to the standard diagnostic work-up for esophageal cancer that includes a 18F-FDG PET-CT scan at diagnosis and after nCRT, one 18F-FDG PET-CT scans will be performed during nCRT, as well as three MRI scans (before, during and after nCRT) within fixed time intervals. Furthermore, after response imaging after nCRT has been performed, but prior to surgery, patients will undergo (on an opt-out basis) an endoscopy and/or endoscopic ultrasonography (EUS) with biopsies of the primary tumor site, other suspected lesions and suspected lymph nodes. Furthermore, blood samples will be collected at three time points.

Main study parameters/endpoints: An accurate multimodal prediction model for the patients' individual probability of pathologic complete response after nCRT, based on the quantitative parameters derived from a longitudinal series of DW-MRI, DCE-MRI and 18F-FDG PET-CT datasets.

Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer

Histopathologic response of the primary tumor to nCRT according to the tumor regression grade (TRG) scale as determined by expert pathologist.

TRG 1: no residual viable tumor cells, pathologic complete response TRG 2: rare residual cancer cells TRG 3: predominant fibrosis with increased number of residual cancer cells TRG 4: residual cancer outgrowing fibrosis or no regressive change

Pathological T- and N-stage as determined by expert pathologist (based on the American Joint Committee on Cancer \[AJCC\] Tumor Node Metastasis \[TNM\] staging system)

Disease-free survival based on local follow-up policies (time to locoregional or distal recurrence of esophageal cancer).

Overall survival based on local follow-up policies.

University Medical Center Groningen

The Netherlands Cancer Institute

Koningin Wilhelmina Fonds

Amsterdam UMC, location VUmc

UMC Utrecht

PhD, Clinical Physicist at the Department of Radiation Oncology

Standard of care neoadjuvant chemoradiotherapy (nCRT) and esophagectomy

Chemotherapy: Carboplatin (AUC=2)x5 and Paclitaxel (50 mg/m(2))x5 for two cycles. Radiation: a total dose of 40.4 Gray (Gy) will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy.

Chemoradiotherapy

Minimally-invasive esophagectomy (RAMIE) or traditional open approach if necessary.

Esophagectomy

Robert T Ripley

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.

Background:

* The incidence of esophageal cancer continues to increase with an estimated 16,900 new cases and 15,700 deaths in 2016. Esophageal adenocarcinoma (EAC) is the dominant histology in the United States and accounts for the rising incidence; the incidence of esophageal squamous cell cancer (ESCC) remains stable.
* Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is now a standard approach for locally advanced, operable esophageal cancer.
* A survival advantage compared to surgery alone was demonstrated in the phase III Chemo

Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) trial.

* Patients who experience a pathological complete response (pCR) following neoadjuvant therapy are most likely to have long-term survival.
* Presently, accurate assessment of pathologic response requires esophagectomy. Positron-emissions tomography (fludeoxyglucose (FDG-PET)) and endoscopic evaluation with biopsies fail to detect cancer in a significant percentage of patients with residual disease following neoadjuvant therapy.
* Currently there are no validated tissue or serologic biomarkers which can be used to guide surgical management of esophageal cancer patients based on response to nCRT.

Primary Objective:

-To determine whether a metabolomic signature in tumor, blood, or urine or whether BH3 profiling of pre-neoadjuvant tumor biopsies correlates with the outcome of pathological complete response after neoadjuvant chemoradiotherapy for patients with esophageal adenocarcinoma or squamous cell carcinoma.

Eligibility:

-Patients with locally-advanced, histologically confirmed EAC or ESCC who are candidates for nCRT and esophagectomy.

Design:

* Patients will receive standard of care nCRT either at the National Cancer Institute (NCI) or at referring institutions.
* Specimens of plasma, urine, and esophageal tumor with matched normal esophagus will be obtained before neoadjuvant therapy for metabolomic profiling and BH3 profiling.

Blood, urine, normal esophagus, and tumor (if present) will be obtained after neoadjuvant therapy.

* Patients will undergo an esophagectomy as a robotically-assisted, minimally-invasive esophagectomy (RAMIE) or a traditional open approach for contraindications to minimally-invasive approaches or based on institutional expertise.
* Analysis will be performed to determine if pathological complete response (pCR) after chemoradiotherapy (CRT) correlates with pretreatment metabolomic signatures or BH3 profiling in tumor, blood or urine.
* Patients with EAC and ESCC will be evaluated independently.
* The accrual ceiling will be set to 120 patients for the entire study - 80 patients for EAC and 40 patients for ESCC to allow for unevaluable patients. The accrual is expected to be completed in 4 years.

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

Specimens of normal esophagus, esophageal tumors, blood, or urine will be analyzed to determine specific signatures and outcome of pathological complete response after neoadjuvant chemoradiotherapy in patients with esophageal adenocarcinoma or squamous cell carcinoma. Response will be defined by the Mandard Score. Major response with no viable tumor (Grade 1) and \<10% viable tumor (Grade 2) versus non major response of \>10% viable tumor (Grade 3-5) as assessed by final pathology. Grade 1-2 is better survival than Grade 3-5.

Two tumor samples and two normal esophagus samples will be obtained for BH3 profiling of pre-neoadjuvant tumor biopsy and outcome of pathological complete response after neoadjuvant chemoradiotherapy in patients with esophageal adenocarcinoma or squamous cell carcinoma. Response will be defined by the Mandard Score. Major response with no viable tumor (Grade 1) and \<10% viable tumor (Grade 2) versus non major response of \>10% viable tumor (Grade 3-5) as assessed by final pathology. Grade 1-2 is better survival than Grade 3-5.

Evaluation of metabolomic profiles and Bcl-2 homology domain-3 (BH-3) profiling in resectable esophageal adenocarcinomas (EAC) and esophageal squamous cell carcinoma (ESCC) treated with neoadjuvant chemoradiotherapy (nCRT)

Specimens of tumor, blood, or urine will be obtained to determine metabolomic signatures or BH3 profiling in tumor, blood, or urine of EAC and ESCC with major responses (Mandard score of 1 and 2) versus minimal response (Mandard score 3-5). Grade 1-2 is better survival than Grade 3-5.

One tumor sample and one normal esophagus sample will be obtained. p53 mutational analysis will be performed to determine mutational status and the metabolomic profiles .

Disease-free survival is defined as the appearance of any new lesion that is likely metastatic or locally-recurrent esophageal cancer and will be assessed from the time of esophagectomy until development of metastatic disease or death, whichever comes first

Overall survival is defined as the time from treatment start date until date of death or date last known alive.

National Cancer Institute (NCI)

Deputy Clinical Director

There were no adverse events recorded for the participants on this trial during the time frame noted above.

Standard of care neoadjuvant chemoradiotherapy (nCRT) and esophagectomy

Chemoradiotherapy: Chemotherapy: Carboplatin (AUC=2)x5 and Paclitaxel (50 mg/m(2))x5 for two cycles. Radiation: a total dose of 40.4 Gray (Gy) will be given in 23 fractions of 1.8 Gy, 5 fractions per week, starting the first day of the first cycle of chemotherapy.

Esophagectomy: Minimally-invasive esophagectomy (RAMIE) or traditional open approach if necessary.

Neoadjuvant Chemoradiotherapy and Esophagectomy

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Caryn Steakley

Neither patient enrolled in the trial underwent resection based on post neoadjuvant therapy assessment of resectability. These patients were initially deemed potentially resectable prior to neoadjuvant therapy, but their course deviated from the initial plans. Therefore, the primary endpoint cannot be assessed.

Metabolomic Signature in Tumor, Blood, or Urine and Outcome of Pathological Complete Response After Neoadjuvant Chemoradiotherapy in Patients With Esophageal Adenocarcinoma or Squamous Cell Carcinoma

BH3 Profiling of Pre-neoadjuvant Tumor Biopsy and Outcome of Pathological Complete Response After Neoadjuvant Chemoradiotherapy in Patients With Esophageal Adenocarcinoma or Squamous Cell Carcinoma

This outcome measure was not done. Neither patient enrolled in the trial underwent resection based on post neoadjuvant therapy assessment of resectability. These patients were initially deemed potentially resectable prior to neoadjuvant therapy, but their course deviated from the initial plans.

Metabolomic Profiles and B-cell Lymphoma (Bcl-2) Homology Domain-3 (BH-3) Profiling in Resectable Esophageal Adenocarcinomas (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Treated With Neoadjuvant Chemoradiotherapy (nCRT)

Metabolomic Signatures or BH3 Profiling in Tumor, Blood, or Urine of Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) With Major Responses (Mandard Score of 1 and 2) Versus Minimal Response (Mandard Score 3-5)

Tumor Protein 53 (p53) Mutational Status and the Metabolomic Profiles

This outcome measure was not done because one patient was deemed to be unsafe/unfit for surgery by the doctor. And the second patient was taken off-study prior to surgery because the principal investigator left the National Institutes of Health and closed the trial.

Disease-free Survival in Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Patients Undergoing Neoadjuvant Chemoradiotherapy (nCRT) and Esophagectomy

Overall Survival (OS) in Esophageal Adenocarcinoma (EAC) and Esophageal Squamous Cell Carcinoma (ESCC) Patients Undergoing Neoadjuvant Chemoradiotherapy (nCRT) and Esophagectomy

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer	NCT03474341	Esophageal Canc... Esophageal Aden... Esophageal Squa... Esophageal Neop...	MRI PET-CT Endoscopy Blood samples	18 Years -	UMC Utrecht
Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer	NCT03474341	Esophageal Canc... Esophageal Aden... Esophageal Squa... Esophageal Neop...	MRI PET-CT Endoscopy Blood samples	18 Years -	UMC Utrecht
Metabolomic and BH3 Profiling of Esophageal Cancers: Identification of Novel Assessment Methods of Treatment Response for Precision Therapy	NCT03223662	Esophageal Canc... Esophageal Aden... Esophageal Squa... Esophageal Neop... Squamous Cell C...	Chemoradiothera... Esophagectomy	18 Years - 99 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for neoadjuvant chemoradiotherapy (ncrt)