Pre-Surgery If Needed for Oesophageal Cancer (preSINO)

Accuracy of Detecting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: the preSINO Trial (Pre-Surgery If Needed for Oesophageal Cancer)

A prospective, multi-centre, diagnostic cohort study investigating the accuracy of positron emission tomography with computed tomography (PET-CT), endoscopic bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) for detecting residual disease after neoadjuvant chemoradiotherapy in patients with potentially resectable esophageal squamous cell carcinoma (SCC).

Study Overview

• Status: Completed
• Conditions: Esophageal Cancer
• Intervention / Treatment: Diagnostic test: First clinical response evaluation (CRE-1); Diagnostic test: Second clinical response evaluation (CRE-2)

Detailed Description

Neoadjuvant chemoradiotherapy (nCRT) followed by esophagectomy is a standard treatment for locally-advanced esophageal cancer. After nCRT, high pathologically complete response (pCR) rates are being achieved in patients with esophageal cancer, especially squamous cell carcinoma (SCC). Surgery for esophageal cancer is risky and is associated with reduced quality of life. It is important to know that with an accurate and safe clinical evaluation strategy, some patients might delay surgery or avoid unnecessary surgery and be safely monitored instead. Therefore, an active surveillance strategy has been proposed for patients with clinically complete response (cCR) after nCRT.

The previous European preSANO trial (Lancet Oncol. 2018 Jul;19(7):965-974, PMID: 29861116) showed that the clinical response evaluations (CRE) were sufficiently accurate to detect residual tumor after nCRT in patients with mainly adenocarcinoma, however, its applicability to SCC, which is characterized by extensive lymph node metastasis, remains unknown.

The objective of this study is to assess the accuracy of response evaluations after nCRT based on the preSANO trial, including positron emission tomography with computed tomography (PET-CT), endoscopic bite-on-bite biopsies and endoscopic ultrasonography (EUS) with fine-needle aspiration (FNA) in patients with potentially operable esophageal SCC. Additionally, this study also explores the value of circulating-tumor DNA (ctDNA) in predicting residual disease.

Locally-advanced operable esophageal SCC patients who are planned to undergo nCRT according to the CROSS regimen and are planned to undergo surgery will be recruited from three high-volume Asian centers. Four to six weeks after completion of nCRT, patients will undergo a first clinical response evaluation (CRE-1) consisting of endoscopic bite-on-bite biopsies. In patients without histological evidence of residual tumor (i.e. without positive biopsies), surgery will be postponed another six weeks. A second clinical response evaluation (CRE-2) will be performed 10-12 weeks after completion of nCRT, consisting of PET-CT, endoscopic bite-on-bite biopsies and EUS with FNA. After CRE-2, all patients without evidence of distant metastases will undergo esophagectomy. Primary endpoint is the accuracy of CRE for detecting TRG3-4 or TRG1-2 with ypN+ residual tumor with a prespecified false-negative rate of 19.5%.

Secondary endpoint includes the accuracy of detecting any residual tumor. Exploratory analyses of ctDNA will be performed in patients with available blood samples.

If the current study shows that major residual disease (>10% residual carcinoma at the primary tumor site and any residual nodal disease) can be accurately (i.e. with sensitivity of 80.5%) detected in patients with esophageal SCC, a prospective trial will be conducted comparing active surveillance with standard esophagectomy in patients with a clinically complete response after nCRT (SINO trial).

• Study Type: Observational
• Enrollment (Actual): 200

Contacts and Locations

Study Locations

• China
  • Shanghai, China
    • Shanghai Chest Hospital
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
• Netherlands
  • Rotterdam, Netherlands
    • Erasmus MC Cancer Institute
• Taiwan
  • Linkou, Taiwan
    • Chang Gung Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Esophageal cancer patients who are planned to undergo nCRT according to the CROSS regimen and who will undergo surgical resection will be recruited from four Asian centres.

Description

Inclusion criteria are:

1. Histologically confirmed esophageal squamous cell carcinoma;
2. Tumor located in the chest;
3. Clinical stage cT1N1-2M0, cT2-4aN0-2M0, according to the 8th Edition of the AJCC TNM classification for Esophageal Cancer;
4. Age > 20 at the date of informed consent;
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of two or less;
6. Considered fit to undergo nCRT followed by surgical resection;
7. Expected survival time more than three months;
8. Written informed consent by the patient.

Exclusion criteria are:

1. Patient with a second primary tumor;
2. Previous major surgery in the chest or upper abdomen;
3. Tumor not 18F-FDG-avid at baseline PET-CT;
4. Suspected positive lymph nodes that cannot be covered by an uninterrupted radiation field that also includes the primary tumor area;
5. Primary (early) lesion already removed by EMR/ESD;
6. Previous history of chemotherapy and/or radiation therapy;
7. Cervical esophageal cancer.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Clinical Response Evaluation; Patients with operable esophageal squamous cell carcinoma who are planned to undergo neoadjuvant chemoradiotherapy according to the CROSS regimen (intravenous carboplatin AUC 2 mg/mL/min and intravenous paclitaxel 50 mg/m2 on days 1, 8, 15, 22 and 29 with concurrent 41.4 Gy radiotherapy given in 23 fractions of 1.8 Gy on 5 days per week) followed by surgery. Patients will undergo a first clinical response evaluation (CRE-1) 4-6 week after completion of nCRT. In patients without histological evidence of residual tumor surgery will be postponed another 6 weeks. A second clinical response evaluation (CRE-2) will be performed 10-12 weeks after completion of nCRT. Immediately after CRE-2 all patients without evidence of distant metastases will undergo esophagectomy.

Diagnostic test: First clinical response evaluation (CRE-1); Consisting of: endoscopy with bite-on-bite biopsies; Diagnostic test: Second clinical response evaluation (CRE-2); Consisting of: PET-CT, endoscopic bite-on-bite biopsies,EUS with FNA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of clinical response evaluations for detecting substantial residual locoregional disease	The diagnostic performance in terms of sensitivity and specificity of both CRE-1 and CRE-2 for detecting TRG 3-4 residual tumor (more than 10% residual carcinoma) or TRG 1-2 residual tumor (less than 10% residual carcinoma) with residual nodal disease (ypN+) in the surgical resection specimen.	10-12 weeks after completion of neoadjuvant chemoradiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of clinical response evaluations for detecting any residual locoregional disease	The diagnostic performance in terms of sensitivity and specificity of both CRE-1 and CRE-2 for detecting pathologically non-complete response in both the primary tumor and the regional lymph nodes (TRG2-4 or ypN+).	10-12 weeks after completion of neoadjuvant chemoradiotherapy

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Accuracy of ctDNA for detecting residual disease after neoadjuvant chemoradiotherapy but prior to surgery	The ctDNA status during CRE-1 and CRE-2 time points will be assessed using a tumor-informed personalized-panel based on next-generation sequencing. The diagnostic performance in terms of sensitivity and false-nageative of the combination of biopsy and ctDNA for detecting residual tumor in the surgical resection specimen	10-12 weeks after completion of neoadjuvant chemoradiotherapy
Prognostic value of ctDNA for predicting disease-free survival	The postoperative ctDNA status will be assessed using a tumor-informed personalized-panel based on next-generation sequencing. Patients will be stratified according to their ctDNA status. Disease-free survival is defined as the time from the completion of treatment to recurrence or death from any cause. Survival prognostic analyses will adjust for clinical factors and TNM staging using Cox regression.	1 year after completion of neoadjuvant chemoradiotherapy and surgery

Collaborators and Investigators

• Sponsor: Shanghai Chest Hospital
• Collaborators: Chang Gung Memorial Hospital; Erasmus Medical Center; Queen Mary Hospital, Hong Kong
• Investigators: Principal Investigator: Zhigang Li, MD, PhD, Shanghai Chest Hospital

Publications and helpful links

General Publications

• Zhang X, Eyck BM, Yang Y, Liu J, Chao YK, Hou MM, Hung TM, Pang Q, Yu ZT, Jiang H, Law S, Wong I, Lam KO, van der Wilk BJ, van der Gaast A, Spaander MCW, Valkema R, Lagarde SM, Wijnhoven BPL, van Lanschot JJB, Li Z. Accuracy of detecting residual disease after neoadjuvant chemoradiotherapy for esophageal squamous cell carcinoma (preSINO trial): a prospective multicenter diagnostic cohort study. BMC Cancer. 2020 Mar 6;20(1):194. doi: 10.1186/s12885-020-6669-y.

Study record dates

Study Major Dates

• Study Start (Actual): August 8, 2019
• Primary Completion (Actual): May 31, 2023
• Study Completion (Actual): May 31, 2024

Study Registration Dates

• First Submitted: May 1, 2019
• First Submitted That Met QC Criteria: May 1, 2019
• First Posted (Actual): May 3, 2019

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 26, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Active surveillance; Esophageal cancer; Esophageal squamous cell carcinoma; Esophagectomy; Neoadjuvant chemoradiotherapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Esophageal Diseases; Carcinoma; Neoplasms, Squamous Cell; Carcinoma, Squamous Cell; Esophageal Squamous Cell Carcinoma; Esophageal Neoplasms
• Other Study ID Numbers: Chest201902

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No