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

Sexual and urinary functioning after rectal surgery: a prospective comparative study with a median follow-up of 8.5 years

The purpose of this study was to prospectively compare rectal resection (RR) with colonic resection on sexual, urinary and bowel function and quality of life in both short-term and long-term. Eighty-three patients who underwent RR were compared to 53 patients who underwent a colonic resection leaving the rectum in situ (RIS). A questionnaire assessing sexual, urinary and bowel functioning with a quality of life questionnaire (SF-36) was sent to all participants preoperatively, 3 and 12 months postoperatively and approximately 8 years after the onset of the study. Short-term dysfunction included diminished sexual activity in female RR patients at 3 months and significantly more erectile dysfunction in RR patients 1 year postoperatively. Long-term dysfunction included more frequent and more severe erectile dysfunction in RR patients compared to RIS patients. These short-term and long-term outcomes did not influence overall quality of life. The incidence of urinary dysfunction was comparable between both groups. Bowel functioning was significantly better in the RIS group compared to the RR group 3 months and 1 year postoperatively. Patients who underwent RR experienced up to 1 year postoperatively more sexual and bowel function problems than RIS patients. However, short-term and long-term dysfunction did not influence overall quality of life. Erectile dysfunction in male RR patients persisted in time, whereas other aspects of sexual, urinary and bowel function after RR and colonic resection are similar after a median follow-up of 8.5 year

Characteristics Predicting Short-Term and Long-Term Health-Related Quality of Life in Patients with Esophageal Cancer After Neoadjuvant Chemoradiotherapy and Esophagectomy

Background: Esophagectomy is associated with lasting effect on health-related quality of life (HRQOL). Patients desire detailed information on the expected impact of treatment on their postoperative HRQOL. The aim of the present study is to identify clinicopathological characteristics predictive for changes in short-term and long-term HRQOL after neoadjuvant chemoradiotherapy (nCRT) and surgery. Methods: HRQOL was measured using EORTC-QLQ-C30 and QLQ-OES24 questionnaires prior to nCRT, three, six, nine and twelve months postoperatively and at a minimum of six years postoperatively. Based on previous experience and available literature, several subgroups were predefined for different clinicopathological characteristics: baseline global HRQOL, WHO performance status, histology, tumor stage and tumor location. The primary endpoints of the present study were the change compared to baseline in the HRQOL dimensions physical functioning and eating problems. Secondary endpoints were global HRQOL, fatigue and emotional problems. Results:In total, 134 (76%) of 177 patients who received HRQOL questionnaires, responded at baseline. Patients who reported a high baseline global HRQOL had a more severe deterioration in eating problems (+14.5 to + 18.0), global HRQOL (-16.0 to -28.0) and fatigue (+10.5 to +14.9) up to six years postoperatively compared to patients who reported a low baseline global HRQOL. Patients who had stage 2 tumor (UICC 6th edition) had a more severe deterioration in eating problems (+14.6 to +19.0) and global HRQOL (-10.1 to -17.1) than patients who had stage 3 tumor. Conclusions: The results suggest that patients with locally advanced esophageal cancer in favorable condition at baseline decline more in terms of various HRQOL outcomes.</p

Pattern of recurrence in patients with a pathologically complete response after neoadjuvant chemoradiotherapy and surgery for oesophageal cancer

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) and surgery is a widely used treatment for locally advanced resectable oesophageal cancer, with 20-50 per cent of patients having a pathological complete response (pCR). Disease, however, still recurs in 20-30 per cent of these patients. The aim of this study was to assess the pattern of recurrence in patients with a pCR after nCRT and surgery. METHODS: All patients with a pCR after nCRT and surgery included in the phase II and III CROSS (ChemoRadiotherapy for Oesophageal followed by Surgery Study) trials (April 2001 to December 2008) and after the CROSS trials (September 2009 to October 2017) were identified. The site of recurrence was compared with the applied radiation and surgical fields. Outcomes were median time to recurrence, and overall and progression-free survival. RESULTS: A total of 141 patients with a median follow-up of 100 (i.q.r. 64-134) months were included. Some 29 of 141 patients (20,6 per cent) developed recurrence. Of these, four had isolated locoregional recurrence, 15 had distant recurrence only, and ten had both locoregional and distant recurrence. Among the 14 patients with locoregional recurrences, five had recurrence within the radiation field, seven outside the radiation field, and two at the border. Median time to recurrence was 24 (10-62) months. The 5-year overall survival rate was 74 per cent and the recurrence-free survival rate was 70 per cent. CONCLUSION: Despite good overall survival, recurrence still occurred in 21 per cent of patients. Most recurrences were distant, outside the radiation and surgical fields

Delay in Diagnostic Workup and Treatment of Esophageal Cancer

Introduction: Esophageal cancer should preferably be detected and treated at an early stage, but this may be prohibited by late onset of symptoms and delays in referral, diagnostic workup, and treatment. The aim of this study was to investigate the impact of these delays on outcome in patients with esophageal cancer. Methods: For 491 patients undergoing esophagectomy for cancer between 1991 and 2007, patients' short- and long-term outcome were analyzed according to different time intervals between onset of symptoms, diagnosis, and surgical treatment. Results: Length of prehospital delay (from onset of symptoms until endoscopic diagnosis) did not affect patient's short- or long-term outcome. A shorter hospital delay between establishing the diagnosis of esophageal cancer on endoscopy and surgery was associated with lower overall morbidity and in-hospital mortality. Patients of ASA classes I and II experienced a shorter hospital delay than patients of ASA classes III and IV. Length of hospital delay between endoscopic diagnosis and surgery did not affect pathological tumor-node-metastasis stage or R0-resection rate. Longer hospital delay did not result in worse survival: Overall survival after esophagectomy for cancer was not significantly different between patients with hospital delay 8 weeks (24. 7%, 21. 7%, and 32. 3%, respectively; p = 0. 12). Conclusion: A longer hospital delay (between endoscopic diagnosis and surgery) resulted in worse patient's short-term outcome (higher overall morbidity and mortality rates) but not in a worse long-term outcome (overall survival). This may be explained by a more time-consuming diagnostic workup in patients with a poorer physical status and not by tumor progression

External validation of ¹⁸F-FDG PET-based radiomic models on identification of residual oesophageal cancer after neoadjuvant chemoradiotherapy

Objectives Detection of residual oesophageal cancer after neoadjuvant chemoradiotherapy (nCRT) is important to guide treatment decisions regarding standard oesophagectomy or active surveillance. The aim was to validate previously developed 18F-FDG PET-based radiomic models to detect residual local tumour and to repeat model development (i.e. 'model extension') in case of poor generalisability. Methods This was a retrospective cohort study in patients collected from a prospective multicentre study in four Dutch institutes. Patients underwent nCRT followed by oesophagectomy between 2013 and 2019. Outcome was tumour regression grade (TRG) 1 (0% tumour) versus TRG 2-3-4 (≥1% tumour). Scans were acquired according to standardised protocols. Discrimination and calibration were assessed for the published models with optimism-corrected AUCs &gt;0.77. For model extension, the development and external validation cohorts were combined. Results Baseline characteristics of the 189 patients included [median age 66 years (interquartile range 60-71), 158/189 male (84%), 40/189 TRG 1 (21%) and 149/189 (79%) TRG 2-3-4] were comparable to the development cohort. The model including cT stage plus the feature 'sum entropy' had best discriminative performance in external validation (AUC 0.64, 95% confidence interval 0.55-0.73), with a calibration slope and intercept of 0.16 and 0.48 respectively. An extended bootstrapped LASSO model yielded an AUC of 0.65 for TRG 2-3-4 detection. Conclusion The high predictive performance of the published radiomic models could not be replicated. The extended model had moderate discriminative ability. The investigated radiomic models appeared inaccurate to detect local residual oesophageal tumour and cannot be used as an adjunct tool for clinical decision-making in patients.</p