Pathologic Lymph Node Regression After Neoadjuvant Chemotherapy Predicts Recurrence and Survival in Esophageal Adenocarcinoma: A Multicenter Study in the United Kingdom.

PURPOSE: There is limited evidence regarding the prognostic effects of pathologic lymph node (LN) regression after neoadjuvant chemotherapy for esophageal adenocarcinoma, and a definition of LN response is lacking. This study aimed to evaluate how LN regression influences survival after surgery for esophageal adenocarcinoma. METHODS: Multicenter cohort study of patients with esophageal adenocarcinoma treated with neoadjuvant chemotherapy followed by surgical resection at five high-volume centers in the United Kingdom. LNs retrieved at esophagectomy were examined for chemotherapy response and given a LN regression score (LNRS)-LNRS 1, complete response; 2, <10% residual tumor; 3, 10%-50% residual tumor; 4, >50% residual tumor; and 5, no response. Survival analysis was performed using Cox regression adjusting for confounders including primary tumor regression. The discriminatory ability of different LN response classifications to predict survival was evaluated using Akaike information criterion and Harrell C-index. RESULTS: In total, 17,930 LNs from 763 patients were examined. LN response classified as complete LN response (LNRS 1 ≥1 LN, no residual tumor in any LN; n = 62, 8.1%), partial LN response (LNRS 1-3 ≥1 LN, residual tumor ≥1 LN; n = 155, 20.3%), poor/no LN response (LNRS 4-5; n = 303, 39.7%), or LN negative (no tumor/regression; n = 243, 31.8%) demonstrated superior discriminatory ability. Mortality was reduced in patients with complete LN response (hazard ratio [HR], 0.35; 95% CI, 0.22 to 0.56), partial LN response (HR, 0.72; 95% CI, 0.57 to 0.93) or negative LNs (HR, 0.32; 95% CI, 0.25 to 0.42) compared with those with poor/no LN response. Primary tumor regression and LN regression were discordant in 165 patients (21.9%). CONCLUSION: Pathologic LN regression after neoadjuvant chemotherapy was a strong prognostic factor and provides important information beyond pathologic TNM staging and primary tumor regression grading. LN regression should be included as standard in the pathologic reporting of esophagectomy specimens.

Metabolic tumour and nodal response to neoadjuvant chemotherapy on FDG PET-CT as a predictor of pathological response and survival in patients with oesophageal adenocarcinoma.

OBJECTIVES: 2-deoxy-2[18F]Fluoro-D-glucose (FDG) PET-CT has an emerging role in assessing response to neoadjuvant therapy in oesophageal cancer. This study evaluated FDG PET-CT in predicting pathological tumour response (pTR), pathological nodal response (pNR) and survival. METHODS: Cohort study of 75 patients with oesophageal or oesophago-gastric junction (GOJ) adenocarcinoma treated with neoadjuvant chemotherapy then surgery at Guy's and St Thomas' NHS Foundation Trust, London (2017-2020). Standardised uptake value (SUV) metrics on pre- and post-treatment FDG PET-CT in the primary tumour (mTR) and loco-regional lymph nodes (mNR) were derived. Optimum SUVmax thresholds for predicting pathological response were identified using receiver operating characteristic analysis. Predictive accuracy was compared to PERCIST (30% SUVmax reduction) and MUNICON (35%) criteria. Survival was assessed using Cox regression. RESULTS: Optimum tumour SUVmax decrease for predicting pTR was 51.2%. A 50% cut-off predicted pTR with 73.5% sensitivity, 69.2% specificity and greater accuracy than PERCIST or MUNICON (area under the curve [AUC] 0.714, PERCIST 0.631, MUNICON 0.659). Using a 30% SUVmax threshold, mNR predicted pNR with high sensitivity but low specificity (AUC 0.749, sensitivity 92.6%, specificity 57.1%, p = 0.010). pTR, mTR, pNR and mNR were independent predictive factors for survival (pTR hazard ratio [HR] 0.10 95% confidence interval [CI] 0.03-0.34; mTR HR 0.17 95% CI 0.06-0.48; pNR HR 0.17 95% CI 0.06-0.54; mNR HR 0.13 95% CI 0.02-0.66). CONCLUSIONS: Metabolic tumour and nodal response predicted pTR and pNR, respectively, in patients with oesophageal or GOJ adenocarcinoma. However, currently utilised response criteria may not be optimal. pTR, mTR, pNR and mNR were independent predictors of survival. KEY POINTS: • FDG PET-CT has an emerging role in evaluating response to neoadjuvant therapy in patients with oesophageal cancer. • Prospective cohort study demonstrated that metabolic response in the primary tumour and lymph nodes was predictive of pathological response in a cohort of patients with adenocarcinoma of the oesophagus or oesophago-gastric junction treated with neoadjuvant chemotherapy followed by surgical resection. • Patients who demonstrated a response to neoadjuvant chemotherapy in the primary tumour or lymph nodes on FDG PET-CT demonstrated better survival and reduced rates of tumour recurrence.

Effect of peri-operative chemotherapy regimen on survival in the treatment of locally advanced oesophago-gastric adenocarcinoma - A comparison of the FLOT and 'MAGIC' regimens.

BACKGROUND: Peri-operative chemotherapy improves survival in patients with locally advanced oesophago-gastric adenocarcinoma. Two regimens with proven survival benefits are epirubicin, cisplatin plus capecitabine or fluorouracil (Medical Research Council Adjuvant Gastric Infusional Chemotherapy, MAGIC) and fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT). This study aimed to compare the effect of these regimens on survival (primary aim) and pathological response, surgical complications, adverse events and chemotherapy completion rates. METHODS: Cohort study including 946 patients treated with FLOT (n = 257) or MAGIC (n = 689) who underwent surgical resection for oesophageal (n = 743) or gastric (n = 203) adenocarcinoma between 2002 and 2021 at St Thomas' Hospital or The Royal Marsden Hospital, London, UK. Survival analysis was performed using multivariable Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, clinical T-stage, clinical N-stage, tumour grade and presence of signet ring cells. RESULTS: Patients treated with FLOT had better overall survival (HR = 0.69, 95% CI 0.50-0.94) and disease-free survival (HR = 0.75, 95% CI 0.58-0.98) than MAGIC. Patients treated with FLOT were more likely to have a complete pathological response (9.5% FLOT versus 5.5% MAGIC, p = 0.027) and were less likely to have a positive resection margin (19.1% FLOT versus 32.2% MAGIC, p < 0.001). The stratified analysis revealed similar results for oesophageal and gastric tumours. Rates of surgical complications, chemotherapy-associated adverse events and completion were similarly distributed between treatment groups. CONCLUSIONS: Patients with oesophageal or gastric adenocarcinoma treated with peri-operative FLOT had better survival and pathological response than those treated with peri-operative MAGIC. Rates of surgical complications, adverse events and chemotherapy completion were comparable.

Predicting response to neoadjuvant chemotherapy in patients with oesophageal adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy is often used prior to surgical resection for oesophageal adenocarcinoma but remains ineffective in a high proportion of patients. The histological Mandard tumour regression grade is used to determine chemoresponse but is not available at the time of treatment decision-making. The aim of this cohort study was to identify factors that predict chemotherapy response prior to surgery. METHODS: A prospectively collected database of patients undergoing surgical resection for oesophageal adenocarcinoma from a high-volume UK institution was used. Patients were subcategorised using pathological tumour response into 'responders' (Mandard grade 1-3) and 'non-responders' (Mandard grade 4 and 5). Multivariable logistic regression analysis was performed to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for responder status adjusting for a variety of parameters. Receiver operating characteristic (ROC) curves were calculated. RESULTS: Among 315 patients included, 102 (32%) were responders and 213 (68%) non-responders. A decrease in radiological tumour volume (OR 1.92 95%CI 1.02-3.62; p = 0.05), a 'partial response' RECIST score (OR 7.16 95%CI 1.49-34.36; p = 0.01), a clinically improved dysphagia score (OR 2.79 95%CI 1.05-7.04; p = 0.04) and lymphovascular invasion (OR 0.06 95%CI 0.02-0.13; p = 0.000) influenced responder status. ROC curve analysis for responder status utilising all available parameters had an area under the curve (AUC) of 0.86. CONCLUSION: This study has highlighted the potential for using pre-defined factors to identify those patients who have responded to neoadjuvant chemotherapy, prior to surgical resection, potentially facilitating a more individualised therapeutic approach.

The role of surgery after prolonged primary chemotherapy for advanced oesophageal adenocarcinoma.

BACKGROUND: Most patients presenting with oesophageal cancer do so with advanced disease not suitable for surgery. However, there are examples of encouraging survival following surgery in highly selected patients who respond well to chemotherapy. METHODS: This was a retrospective cohort study of patients who presented with advanced but nonvisceral metastatic oesophageal cancer. Consecutive patients on a prolonged primary chemotherapy pathway who underwent surgical resection following a favourable response to chemotherapy were included. Survival and recurrence rates were analysed using Cox regression, providing hazard ratios (HRs) with 95% confidence intervals (CIs). RESULTS: A total of 57 patients included in the cohort operated between 2007 and 2015, the overall median survival was 44 months and the 5-year survival was 42%. Prechemotherapy cN0/cN1 (HR: 0.27, 95% CI: 0.12-0.62) conferred an independent survival advantage compared to cN2 and cN3 disease. Poor differentiation (HR: 2.46, 95% CI: 1.11-5.42), R1 resection (HR: 2.43, 95% CI: 1.14-5.19) and advanced nodal status (HR: 3.28, 95% CI: 1.44-7.47) predicted worse survival on univariable analysis. Poor differentiation (HR: 3.93, 95% CI: 1.62-9.56) was independently associated with poor survival when adjusted for other variables. CONCLUSION: Patients who present with advanced inoperable oesophageal cancer who have a favourable response to chemotherapy represent a limited group of patients who may benefit from surgery.

Does a high Mandard score really define a poor response to chemotherapy in oesophageal adenocarcinoma?

BACKGROUND: A high Mandard score implies a non-response to chemotherapy in oesophageal adenocarcinoma. However, some patients exhibit tumour volume reduction and a nodal response despite a high score. This study examines survival and recurrence patterns in these patients. METHODS: Clinicopathological factors were analysed using multivariable Cox regression assessing time to death and recurrence. Computed tomography-estimated tumour volume change was examined in a subgroup of consecutive patients. RESULTS: Five hundred and fifty-five patients were included. Median survival was 55 months (Mandard 1-3) and 21 months (Mandard 4 and 5). In the Mandard 4 and 5 group (332 patients), comparison between complete nodal responders and persistent nodal disease showed improved survival (90 vs 18 months), recurrence rates (locoregional 14.75 vs 28.74%, systemic 24.59 vs 48.42%) and circumferential resection margin positivity (22.95 vs 68.11%). Complete nodal response independently predicted improved survival (hazard ratio 0.34 (0.16-0.74). Post-chemotherapy tumour volume reduction was greater in patients with a complete nodal response (-16.3 vs -7.7 cm3, p = 0.033) with no significant difference between Mandard groups. CONCLUSION: Patients with a complete nodal response to chemotherapy have significantly improved outcomes despite a poor Mandard score. High Mandard score does not correspond with a non-response to chemotherapy in all cases and patients with nodal downstaging may still benefit from adjuvant chemotherapy.

Analysis of outcomes of a transoral circular stapled anastomosis following major upper gastrointestinal cancer resection.

BACKGROUND: Esophageal anastomoses performed following esophagectomy and total gastrectomy are technically challenging with a significant risk of anastomotic leak. A safe, reliable, and easy anastomotic technique is required to improve patient outcomes and reduce morbidity. METHOD: This paper analyses 328 consecutive patients who underwent transoral circular stapled esophageal anastomosis (ORVIL™) from a prospectively collected single-center database between December 2011 and February 2019. RESULTS: Two hundred and twenty-seven esophagectomies and 101 gastrectomies were performed using OrVil™ anastomoses. The mean patient age was 63.7 years. Of 328 consecutive OrVil™-based anastomoses, there were 10 clinically significant anastomotic leaks requiring radiological or operative intervention (3.05%). Twenty-eight (8.54%) patients developed anastomotic stricture, all of which were successfully treated with endoscopic balloon dilatation (a median of 1 dilatation was required per patient). CONCLUSION: The OrVil™ anastomotic technique is reliable and safe to perform. This is the largest reported series of the OrVil™ anastomotic technique to date. Leak rates and anastomotic dilations were similar to other reported series. Based on our experience, we consider the use of the OrVil™ device for reconstruction after major upper GI resection to be safe and reliable.

Adjuvant therapy following neoadjuvant chemotherapy and surgery for oesophageal adenocarcinoma in patients with clear resection margins.

BACKGROUND: The role of adjuvant therapy in patients with oesophagogastric adenocarcinoma treated by neoadjuvant chemotherapy (NAC) and surgery is contentious. In UK practice, surgical resection margin status is often used to classify patients into receiving adjuvant treatment. This study aimed to assess any survival benefit of adjuvant therapy in patients with clear resection margins. METHODS: This was a retrospective collaborative cohort study combining two prospectively collected UK institutional databases of patients with oesophageal adenocarcinoma. Multivariable Cox regression and propensity matched analyses were used to compare overall and recurrence-free survival according to the adjuvant treatment. RESULTS: Of 374 patients with clear resection margins, 221 patients (59%) had no adjuvant treatment, 137 patients (37%) had adjuvant chemotherapy and 16 patients (4%) had adjuvant chemoradiotherapy. For patients who had received NAC (290, 76%), when adjuvant chemotherapy was compared to no adjuvant treatment, hazard ratios (HRs) favoured adjuvant chemotherapy but did not reach independent significance (overall survival [OS] HR 0.65 95% confidence interval [CI] 0.40-1.06; p .0.087). Responders to NAC (Mandard 1-3) were seemingly more likely to demonstrate a survival benefit from adjuvant chemotherapy (HR 0.42 95% CI 0.15-1.11; p .1.081). CONCLUSIONS: Although no independent survival benefit was observed, the point estimates favoured adjuvant treatment, predominantly in patients with chemo-responsive tumours.

Staging FDG PET-CT changes management in patients with gastric adenocarcinoma who are eligible for radical treatment.

AIM: 18-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT) is valuable in the management of patients with oesophageal cancer, but a role in gastric cancer staging is debated. Our aim was to review the role of FDG PET-CT in a large gastric cancer cohort in a tertiary UK centre. METHODS: We retrospectively reviewed data from 330 patients presenting with gastric adenocarcinoma between March 2014 and December 2016 of whom 105 underwent pre-treatment staging FDG PET-CT scans. FDG PET-CT scans were graded qualitatively and quantitatively (SUVmax) and compared with staging diagnostic CT and operative pathology results (n = 30) in those undergoing resection. RESULTS: Of the 105 patients (74 M, median age 73 years) 86% of primary tumours were metabolically active (uptake greater than normal stomach) on FDG PET-CT [41/44 (93%) of the intestinal histological subtype (SUVmax 14.1 ± 1.3) compared to 36/46 (78%) of non-intestinal types (SUVmax 9.0 ± 0.9), p = 0.005]. FDG PET-CT upstaged nodal or metastastic staging of 20 patients (19%; 13 intestinal, 6 non-intestinal, 1 not reported), with 17 showing distant metastases not evident on other imaging. On histological analysis, available in 30 patients, FDG PET-CT showed low sensitivity (40%) but higher specificity (73%) for nodal involvement. CONCLUSION: FDG PET-CT provides new information in a clinically useful proportion of patients, which leads to changes in treatment strategy, most frequently by detecting previously unidentified metastases, particularly in those with intestinal-type tumours.

Long-term outcome and quality of life after supercharged jejunal interposition for oesophageal replacement.

BACKGROUND: The consequences of major conduit necrosis following oesophagectomy are devastating. Jejunal interposition with vascular supercharging is an alternative reconstructive method if colon is unavailable. Aims of this study were to review the long-term outcome and quality of life of patients undergoing this surgery in our tertiary unit. METHODS: Patients undergoing oesophageal reconstruction with supercharged jejunum were identified and retrospective review of hospital notes performed. Each patient was then interviewed for follow up data and quality of life assessment using the EORTC QLQ-C30 questionnaire. RESULTS: Six patients (5 men) (median age 59 years (range 34-72) underwent supercharged pedicled jejunal (SPJ) interposition from May 2005-August 2010. Indications for surgery were loss of both gastric and colonic conduits following surgery for oesophageal cancer (n = 4), loss of gastric conduit and previous colectomy (n = 1) and lastly, gastric and colonic infarction in a strangulated paraoesophageal hernia (n = 1). Median time to reconstruction was 12 months [6-15 range]. There were no in-hospital deaths. Median postoperative stay was 46 days [13-118]. Three patients required surgical re-intervention for leak, sepsis and reflux, respectively. Median follow up was 6.5 years [range 7-102 months]. One patient died seven months following surgery due to respiratory complications. On follow up, 5 patients have an enteral diet without supplemental nutrition, maintaining weight and good quality of life scores. CONCLUSIONS: Supercharged jejunal interposition is a suitable alternative conduit for delayed oesophageal replacement in patients with otherwise limited reconstructive options. Good functional outcomes can be achieved despite formidable technical challenges in this group.

An unusual cause of dysphagia: transabdominal Roux-en-Y cyst-jejunostomy in the surgical management of a symptomatic mediastinal cyst.

We present a 52-year-old gentleman with an unusual cause of progressive dysphagia, namely due to extrinsic lower oesophageal compression from a cystic mass of the posterior mediastinum. Cystic masses in adults are uncommon, and there is a wide differential diagnosis. This includes neoplastic, such as germ cell tumour (cystic teratoma), and non-neoplastic aetiologies. The later include foregut duplication cysts, lymphatic malformations, infective (hydatid), simple mediastinal cysts or pseudocysts. Management is principally surgical with complete excision, or alternatively, in cases of benign cysts, marsupialization or decompression. In our patient, a simple mediastinal cyst was diagnosed and this case is the first description of a totally transabdominal approach to mediastinal cyst decompression by a Roux-en-Y cyst-jejunostomy.

Thoracoscopic-assisted four-phase esophagectomy with four-field lymph node dissection for esophageal cancer: case report and description of a new technique.

Complete (R0) resection and extent of lymphadenectomy are important prognostic factors for survival in patients undergoing surgery for esophageal carcinoma. We describe the first case of combined open and thoracoscopic esophagectomy with extended lymphadenectomy including abdominal, cervical, right, and left mediastinal (four-field, four-phase) nodal clearance in a 37-year-old woman with squamous cell carcinoma of the esophagus. This report provides a tailored strategy to achieve a high level of tumor clearance and complete resection. The approach described challenges the limitations of standard radical nodal clearance and may encourage surgeons to consider more extensive resections.

Two-phase laparoscopic-assisted oesophago-gastrectomy: a single-unit experience of 111 consecutive cases and outcomes.

BACKGROUND: Minimal access surgery for oesophago-gastric cancer is topical and demanding, and approaches vary significantly. There is little data on the hybrid technique of laparoscopic-assisted two-phase oesophago-gastrectomy (LA2OG). Here we aim to review our experience, which exceeds 10 years, of this technique for oesophageal malignancy. METHODS: From June 1998 to May 2009, 111 patients underwent LA2OG. Patients included 84 men and 27 women with mean age 65 years (range 35-85 years). Retrospective analysis of indications, outcome, staging, complications and survival was performed. RESULTS: The majority of resections (96%) were performed for gastro-oesophageal junction or distal oesophageal pathology. Indications included adenocarcinoma (84.7%), squamous cell carcinoma (7.2%) and high-grade dysplasia (5.4%). Of patients, 67.6% received neoadjuvant chemotherapy. The median time for the laparoscopic phase was 207 min (range 105-600 min), and 420 min (range 210-780 min) overall. Estimated blood loss was 330 ml (range 100-1,200 ml). Median critical care and post-operative stays were 3 and 14 days, respectively. Over time, the radicality of surgery increased. From 1998 to 2001 median lymph node yield was 5, from 2002 to 2005 it was 12 nodes, and from 2006 to 2009 it was 28 nodes (p < 0.001). The overall complication rate was 38.7%, minor in 24.3%, with anastomotic leak rate of 5.5%. Median survival was 38.5 ± 5.4 months. Thirty-day and in-hospital mortality were 1.8 and 2.7%, respectively. CONCLUSIONS: Two-stage laparoscopic-assisted oesophago-gastrectomy is a safe staged method of developing minimal access surgery for oesophago-gastric cancer. This study provides a useful reference for comparison with other minimally invasive methods.

Impaired carotid and femoral viscoelastic properties and elevated intima-media thickness in peripheral vascular disease.

BACKGROUND: We undertook a study to determine whether peripheral vascular disease of the lower extremity (PVD) per se affects the arterial viscoelastic properties and intima-media thickness (IMT) of the carotid and femoral arteries. METHODS: Thirty-five patients with PVD, 35 age- and gender-matched control subjects were examined with ultrasound scan wall tracking system, with the simultaneous measurement of blood pressure for carotid and femoral IMT and viscoelastic properties. RESULTS: Subjects with PVD have significantly impaired carotid elastic properties including compliance (mean (SD): 6.50 (2.39) vs 9.93 (4.07) %mmHg(-1)x10(-2), P<0.001), Petersen's elastic modulus (1.77 (0.69) vs 1.19 (0.63) mmHg x 10(3), P=0.001) and stiffness index (17.92 (7.21) vs 12.10 (6.17), P=0.001) when compared to non-PVD controls. They also have significantly altered femoral elastic properties including Petersen's elastic modulus (5.94 (4.98) vs 3.64 (3.27) mmHg x 10(3), P=0.025) and stiffness index (58.42 (47.76) vs 36.96 (33.43), P=0.033). The carotid (0.85 (0.35) vs 0.59 (0.23) mm, P<0.001) and femoral (1.05 (0.39) vs 0.69 (0.31) mm, P<0.001) IMTs are also significantly elevated in PVD patients. After adjustment for the presumed cardiovascular load assessed on the basis of a cumulative total vascular risk score, as well as age, systolic and diastolic pressure, the carotid viscoelastic indices and the carotid and femoral IMTs remained highly significant. However, the difference in femoral elastic variables was no longer evident. CONCLUSION: PVD per se affects the femoral and carotid wall mechanics and morphology similarly to other cardiovascular risk factors and events. These parameters may provide further information for cardiovascular risk assessment in addition to the classical risk factors and the Framingham equation. Indeed, some guidelines have suggested that additional factors such as the carotid scan may influence the clinician's decision to intervene with therapy.