Detecting Residual Disease After Neoadjuvant Chemoradiotherapy for Oesophageal Squamous Cell Carcinoma: Prospective Multicentre PRESINO Trial

Medicine Oncology
Oesophageal squamous cell carcinoma Neoadjuvant chemoradiotherapy Residual disease Prospective study Multicentre trial Tumour recurrence Liquid biopsy

Oesophageal Squamous Cell Carcinoma (OSCC) is one of the most common malignant tumours globally, with a particularly high incidence in East Asia. Neoadjuvant Chemoradiotherapy (NCRT) is the standard treatment for locally advanced oesophageal cancer, aiming to reduce tumour volume and improve surgical resection rates. However, some patients may achieve Clinical Complete Response (CCR) after NCRT, raising the question of whether oesophagectomy is still necessary. While oesophagectomy effectively removes tumours, it is associated with high complication and mortality rates. Therefore, active surveillance may be a viable alternative strategy for patients who achieve CCR after NCRT.

The premise of active surveillance is the ability to accurately detect residual disease after NCRT. Currently, commonly used clinical detection methods include bite-on-bite biopsies, Endoscopic Ultrasound Fine-Needle Aspiration (EUS-FNA), and PET-CT (Positron Emission Tomography-Computed Tomography). Although these methods have shown high accuracy in adenocarcinoma, their effectiveness in OSCC has not been fully validated. Additionally, Circulating Tumour DNA (ctDNA), as an emerging liquid biopsy technology, has shown potential in reflecting Molecular Residual Disease (MRD) and disease surveillance. Therefore, the PRESINO trial aimed to evaluate the accuracy of Clinical Response Evaluations (CRES) after NCRT in OSCC patients and explore the clinical application value of ctDNA in residual disease detection and recurrence prediction.

Source of the Paper

The PRESINO trial was conducted by a team of researchers from Shanghai Chest Hospital, Queen Mary Hospital, Chang Gung Memorial Hospital, and Erasmus University Medical Center. The primary authors include Yang Yang, Zhichao Liu, Ian Wong, among others, with the corresponding author being Zhigang Li from Shanghai Chest Hospital. The study was published in 2025 in the British Journal of Surgery (BJS) under the title “Detecting Residual Disease After Neoadjuvant Chemoradiotherapy for Oesophageal Squamous Cell Carcinoma: Prospective Multicentre PRESINO Trial.”

Study Process and Results

Study Design

The PRESINO trial was a prospective, multicentre, diagnostic cohort study designed to evaluate the accuracy of CRES after NCRT in OSCC patients. The study enrolled 309 patients with locally advanced OSCC, all of whom received NCRT and underwent the first Clinical Response Evaluation (CRE-1) 4–6 weeks after completing NCRT. CRE-1 included endoscopy with at least four bite-on-bite biopsies. If residual disease was detected, patients underwent immediate surgery; if no residual disease was detected, surgery was postponed, and a second Clinical Response Evaluation (CRE-2) was performed 10–12 weeks after NCRT. CRE-2 included PET-CT, bite-on-bite biopsies, and EUS-FNA. All patients without distant metastases underwent surgery.

Pathological Assessment

The resected specimens were reviewed by experienced pathologists at each centre according to standard protocols. Tumour cells were considered vital if their cytomorphological integrity was intact. The Chirieac Tumour Regression Grade (TRG) system was used to classify pathological responses into four grades: no residual tumour cells (TRG1), 1–10% residual tumour cells (TRG2), 11–50% residual tumour cells (TRG3), and more than 50% residual tumour cells (TRG4).

Primary Endpoint

The primary endpoint of the study was the diagnostic accuracy for detecting TRG3–4 or TRG1–2 with lymph node-positive (ypN+) residual disease, with a prespecified False-Negative Rate (FNR) of 19.5%. Secondary endpoints included sensitivity, specificity, negative predictive value, and positive predictive value for detecting any residual disease.

Results

Among the 242 patients included in the final analysis, 143 (59.1%) had positive results at CRE-1 or CRE-2. Of the 133 patients with TRG3–4 or TRG1–2 with ypN+ residual disease, 18 had false-negative CRES results, yielding an FNR of 13.5% (95% confidence interval: 8.7–20.4), which was lower than the prespecified 19.5% (p=0.041). The sensitivity, specificity, negative predictive value, and positive predictive value for detecting any residual disease were 81.7%, 93.2%, 68.7%, and 96.5%, respectively.

PET-CT Analysis

Among the 268 patients included in the PET-CT analysis, 4.9% (13 patients) were found to have distant metastases before surgery. Of these, five patients were detected at CRE-1 and eight at CRE-2. Metastatic sites included the lung (5 cases), liver (3 cases), bone (2 cases), brain (1 case), both liver and bone (1 case), and supraclavicular lymph nodes (1 case).

ctDNA Analysis

Among the 132 patients included in the ctDNA analysis, 99.2% had detectable ctDNA in pre-NCRT plasma samples. After NCRT, 75 patients were ctDNA-positive at CRE-1 or CRE-2, while 57 were ctDNA-negative. Of the 74 patients with TRG3–4 or TRG1–2 with ypN+ residual disease, 16 were ctDNA-negative, resulting in an FNR of 21.6%. When ctDNA was combined with bite-on-bite biopsies and EUS-FNA, the FNR decreased from 14.9% to 5.4%. After a minimum follow-up of 12 months, the systemic recurrence rate was 28.0% in ctDNA-positive patients compared to 5.3% in ctDNA-negative patients.

Conclusions and Significance

The PRESINO trial confirmed that bite-on-bite biopsies and EUS-FNA are highly accurate in detecting residual disease after NCRT in OSCC, with an FNR of 13.5%, which was lower than the prespecified 19.5%. PET-CT was valuable in detecting distant metastases before surgery, allowing 4.9% of patients to avoid unnecessary surgery. Additionally, ctDNA showed potential in predicting systemic recurrence during CRES after NCRT, with ctDNA-positive patients having a significantly higher risk of systemic recurrence. These results provide a scientific basis for the future SINO trial, which will compare overall survival between active surveillance and immediate surgery in patients with CCR after NCRT.

Highlights of the Study

  1. Accuracy Validation: The PRESINO trial is the first to validate the accuracy of bite-on-bite biopsies and EUS-FNA in detecting residual disease after NCRT in OSCC patients, filling a gap in this field.
  2. ctDNA Application: The study explored the application of ctDNA in disease surveillance after NCRT, demonstrating its ability to predict systemic recurrence and providing new insights into the use of liquid biopsy in oesophageal cancer.
  3. Multicentre Collaboration: The study was conducted in collaboration with multiple high-volume medical centres in Asia and Europe, ensuring the broad applicability and reliability of the results.

Other Valuable Information

The study also noted that post-NCRT oesophagitis may lead to false-positive PET-CT results, limiting its utility in detecting local disease. Furthermore, the long-term prognostic value of ctDNA analysis requires further investigation, particularly in its potential application for distant recurrence and overall survival.

The PRESINO trial not only provides a scientific basis for the individualised treatment of OSCC patients but also lays a solid foundation for future active surveillance strategies in oesophageal cancer.