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).
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
200
Consisting of: endoscopy with bite-on-bite biopsies
Consisting of: PET-CT, endoscopic bite-on-bite biopsies,EUS with FNA
Shanghai Chest Hospital
Shanghai, China
Queen Mary Hospital
Hong Kong, Hong Kong
Erasmus MC Cancer Institute
Rotterdam, Netherlands
Chang Gung Memorial Hospital
Linkou District, Taiwan
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.
Time frame: 10-12 weeks after completion of neoadjuvant chemoradiotherapy
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+).
Time frame: 10-12 weeks after completion of neoadjuvant chemoradiotherapy
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