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

Esophageal Cancer Clinical Trial

— PRIDE  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03474341
• Other study ID #: NL62881.041.17
• Secondary ID: Project ID 10291
• Status: Recruiting
• Start date: April 9, 2018
• Est. completion date: January 2022

Study information

• Verified date: November 2020
• Source: UMC Utrecht
• Contact: Gert J Meijer, PhD
• Phone: 0031 88-75 55555
• Email: pride[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 200
• Est. completion date: January 2022
• Est. primary completion date: September 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction (i.e. tumors involving both cardia and esophagus on endoscopy)

• Potentially resectable locally advanced esophageal tumor (cT1b-4a N0-3 M0): based on standard primary staging by EUS and 18F-FDG PET-CT

• Scheduled to receive neoadjuvant chemoradiotherapy according to CROSS-regimen1: weekly administration of carboplatin and paclitaxel for 5 weeks and concurrent radiotherapy (41.4 Gray in 23 fractions, 5 days per week) followed by esophagectomy

• Age > 18 years

Exclusion Criteria:

• Patients who meet exclusion criteria for MRI

• Patients who meet exclusion criteria for intravenous gadolinium-based contrast:

• Glomerular Filtration Rate (GFR) of <30 mL/min/1.73m2

• Nephrogenic Systemic Fibrosis (strict contra-indication for gadolinium-based contrast)

• Known allergy for gadolinium-based contrast

• Patients with a blood plasma glucose concentration >10 mmol/L or poorly controlled diabetes mellitus

• Endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of primary tumor prior to start of neoadjuvant chemoradiotherapy

• Pregnant or breast-feeding patients

Related Conditions & MeSH terms

• Esophageal Adenocarcinoma
• Esophageal Cancer
• Esophageal Neoplasms
• Esophageal Squamous Cell Carcinoma

Intervention

Diagnostic Test:
• MRI
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
• PET-CT
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
• Endoscopy
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
• Blood samples
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

Locations

Country	Name	City	State
Netherlands	Amsterdam University Medical Centers, Academic Medical Center	Amsterdam
Netherlands	Antoni van Leeuwenhoek - Netherlands Cancer Institute (NKI-AVL)	Amsterdam
Netherlands	University Medical Center Groningen (UMCG)	Groningen
Netherlands	University Medical Center Utrecht (UMCU)	Utrecht

Sponsors (5)

Lead Sponsor	Collaborator
UMC Utrecht	Koningin Wilhelmina Fonds, The Netherlands Cancer Institute, University Medical Center Groningen, VU University Medical Center

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Histopathologic response	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	Based on resection specimen (surgery 8-10 weeks after finishing nCRT)
Secondary	Pathological T- and N-stage	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)	Based on resection specimen (surgery 8-10 weeks after finishing nCRT)
Secondary	Disease-free survival.	Disease-free survival based on local follow-up policies (time to locoregional or distal recurrence of esophageal cancer).	Up to 5-year follow-up
Secondary	Overall survival.	Overall survival based on local follow-up policies.	Up to 5-year follow-up