Clinical trial NCT03474341: Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer
Official title: Preoperative Image-guided Identification of Response to Neoadjuvant Chemoradiotherapy in Esophageal Cancer
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Esophageal Cancer
Esophageal Adenocarcinoma
Esophageal Squamous Cell Carcinoma
Esophageal Neoplasms
Keywords: Neoadjuvant chemoradiotherapy (nCRT)
Pathologic complete response (pCR)
Magnetic Resonance Imaging (MRI)
PET-CT
Circulating tumor DNA (ctDNA)
endoscopy
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: University Medical Center Groningen
name: The Netherlands Cancer Institute
name: Koningin Wilhelmina Fonds
name: Amsterdam UMC, location VUmc
First posted: 2018-03-22
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with resectable esophageal or gastroesophageal junction adeno- or squamous cell carcinoma, scheduled to receive neoadjuvant chemoradiotherapy according to the CROSS-regimen

Brief 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.


Eligibility criteria: 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

Primary outcomes:
measure: Histopathologic response
timeFrame: Based on resection specimen (surgery 8-10 weeks after finishing nCRT)
Secondary outcomes:
measure: Pathological T- and N-stage
timeFrame: Based on resection specimen (surgery 8-10 weeks after finishing nCRT)
measure: Disease-free survival.
timeFrame: Up to 5-year follow-up
measure: Overall survival.
timeFrame: Up to 5-year follow-up
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centers, Academic Medical Center
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek - Netherlands Cancer Institute (NKI-AVL)
city: Groningen
country: Netherlands
facility: University Medical Center Groningen (UMCG)
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht (UMCU)
Study officials:
affiliation: UMC Utrecht
name: Gert J Meijer, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Antoni van Leeuwenhoek - Netherlands Cancer Institute
name: Marcel Verheij, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Groningen
name: J. (Hans) A. Langendijk, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Amsterdam UMC, location VUmc
name: Hanneke WM van Laarhoven, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Borggreve AS, Mook S, Verheij M, Mul VEM, Bergman JJ, Bartels-Rutten A, Ter Beek LC, Beets-Tan RGH, Bennink RJ, van Berge Henegouwen MI, Brosens LAA, Defize IL, van Dieren JM, Dijkstra H, van Hillegersberg R, Hulshof MC, van Laarhoven HWM, Lam MGEH, van Lier ALHMW, Muijs CT, Nagengast WB, Nederveen AJ, Noordzij W, Plukker JTM, van Rossum PSN, Ruurda JP, van Sandick JW, Weusten BLAM, Voncken FEM, Yakar D, Meijer GJ; PRIDE study group. Preoperative image-guided identification of response to neoadjuvant chemoradiotherapy in esophageal cancer (PRIDE): a multicenter observational study. BMC Cancer. 2018 Oct 20;18(1):1006. doi: 10.1186/s12885-018-4892-6.