Clinical trial NCT03937362: Pre-Surgery If Needed for Oesophageal Cancer
Official title: Accuracy of Detecting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Squamous Cell Carcinoma: the preSINO Trial (Pre-Surgery If Needed for Oesophageal Cancer)
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Esophageal Cancer
Keywords: Esophagectomy
Neoadjuvant chemoradiotherapy
Esophageal cancer
Esophageal squamous cell carcinoma
Active surveillance
Lead sponsor: Shanghai Chest Hospital
Sponsor class: OTHER
Collaborators: name: Chang Gung Memorial Hospital
name: Queen Mary Hospital, Hong Kong
name: Erasmus Medical Center
First posted: 2019-05-03
Enrollment: 200
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

Brief summary: 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).

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).

Eligibility criteria: 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.

Primary outcomes:
measure: Accuracy of clinical response evaluations for detecting substantial residual locoregional disease
timeFrame: 10-12 weeks after completion of neoadjuvant chemoradiotherapy
Secondary outcomes:
measure: Accuracy of clinical response evaluations for detecting any residual locoregional disease
timeFrame: 10-12 weeks after completion of neoadjuvant chemoradiotherapy
Other outcomes:
measure: Accuracy of ctDNA for detecting residual disease after neoadjuvant chemoradiotherapy but prior to surgery
timeFrame: 10-12 weeks after completion of neoadjuvant chemoradiotherapy
measure: Prognostic value of ctDNA for predicting disease-free survival
timeFrame: 1 year after completion of neoadjuvant chemoradiotherapy and surgery
Locations:
city: Shanghai
country: China
facility: Shanghai Chest Hospital
city: Hong Kong
country: Hong Kong
facility: Queen Mary Hospital
city: Rotterdam
country: Netherlands
facility: Erasmus MC Cancer Institute
city: Linkou
country: Taiwan
facility: Chang Gung Memorial Hospital
Study officials:
affiliation: Shanghai Chest Hospital
name: Zhigang Li, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.