Optimization of detection of residual disease after neoadjuvant therapy in patients with esophageal cancer

Current treatments for locally advanced esophageal cancer consist of neoadjuvant chemotherapy (nCT) or chemoradiotherapy (nCRT) followed by surgery. Nearly one-third of patients obtain a pathologically complete response (pCR) after nCRT. Patients with a complete (clinical) response to nCRT might therefore be candidates for active surveillance, which entails postponement of surgery until recurrence of tumor is detected during clinical response evaluations (CREs). CREs should be performed with accurate diagnostic modalities to timely detect locoregional and distant disease after nCRT. The combination of endoscopy with bite-on-bite biopsies, endoscopic ultrasound with fine-needle aspiration (EUS-FNA) of suspected lymph nodes, and positron emission tomography/computed tomography (PET/CT) has shown 90% sensitivity for detecting substantial (i.e., >10%) residual disease. In this literature review, we address the current state of diagnostic modalities used in CREs and how accuracy for detection of residual tumor after nCRT could be improved. With regard to the currently adopted bite-on-bite biopsy technique, sufficient bite-on-bite biopsies should be taken over larger mucosal areas within the initial tumor site to reduce sampling errors. Detection of positive lymph nodes with EUS-FNA could be improved by sampling all visible lymph nodes. Developments in the field of PET/CT and magnetic resonance imaging (MRI) with simultaneous PET (PET/MRI) have potential to improve CREs by qualitative and quantitative assessment. Other promising techniques require further determination. With wide-area transepithelial sampling (WATS) larger mucosal areas could be sampled compared to regular biopsies, although data in patients treated with nCRT are to be awaited. The detection of positive lymph nodes might be improved by EUS elastography or contrast-enhanced harmonic EUS (CEH-EUS), but these techniques still require further investigation in a setting after nCRT. Finally, image analysis with radiomics, novel biomarkers derived from breath [volatile organic compounds (VOCs)] and liquid biopsies [circulating tumor DNA (ctDNA) as detected in blood samples] might be of complementary value to current diagnostics.