Current trends in the management of Gastro-oEsophageal cancers: Updates to the ESSO core curriculum (ESSO-ETC-UGI-WG initiative).

Gastro-oEsophageal Cancers (GECs) are severe diseases whose management is rapidly evolving. The European Society of Surgical Oncology (ESSO) is committed to the generation and spread of knowledge, and promotes the multidisciplinary management of cancer patients through its core curriculum. The present work discusses the approach to GECs, including the management of oligometastatic oesophagogastric cancers (OMEC), the diagnosis and management of peritoneal metastases from gastric cancer (GC), the management of Siewert Type II tumors, the importance of mesogastric excision, the role of robotic surgery, textbook outcomes, organ preserving options, the use of molecular markers and immune check-point inhibitors in the management of patients with GECs, as well as the improvement of current clinical practice guidelines for the management of patients with GECs. The aim of the present review is to provide a concise overview of the state-of-the-art on the management of patients with GECs and, at the same time, to share the latest advancements in the field and to foster the debate between surgical oncologists treating GECs worldwide. We are sure that our work will, at the same time, give an update to the advanced surgical oncologists and help the training surgical oncologists to settle down the foundations for their future practice.

The effectiveness of neoadjuvant chemoradiotherapy in oesophageal adenocarcinoma with presence of extracellular mucin, signet-ring cells, and/or poorly cohesive cells.

Oesophageal adenocarcinomas may show different histopathological patterns, including excessive acellular mucin pools, signet-ring cells (SRCs), and poorly cohesive cells (PCCs). These components have been suggested to correlate with poor outcomes after neoadjuvant chemoradiotherapy (nCRT), which might influence patient management. However, these factors have not been studied independently of each other with adjustment for tumour differentiation grade (i.e. the presence of well-formed glands), which is a possible confounder. We studied the pre- and post-treatment presence of extracellular mucin, SRCs, and/or PCCs in relation to pathological response and prognosis after nCRT in patients with oesophageal or oesophagogastric junction adenocarcinoma. A total of 325 patients were retrospectively identified from institutional databases of two university hospitals. All patients were scheduled for ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) nCRT and oesophagectomy between 2001 and 2019. Percentages of well-formed glands, extracellular mucin, SRCs, and PCCs were scored in pre-treatment biopsies and post-treatment resection specimens. The association between histopathological factors (≥1 and >10%) and tumour regression grade 3-4 (i.e. >10% residual tumour), overall survival, and disease-free survival (DFS) was evaluated, adjusted for tumour differentiation grade amongst other clinicopathological variables. In pre-treatment biopsies, ≥1% extracellular mucin was present in 66 of 325 patients (20%); ≥1% SRCs in 43 of 325 (13%), and ≥1% PCCs in 126 of 325 (39%). We show that pre-treatment histopathological factors were unrelated to tumour regression grade. Pre-treatment presence of >10% PCCs was associated with lower DFS (hazard ratio [HR] 1.73, 95% CI 1.19-2.53). Patients with post-treatment presence of ≥1% SRCs had higher risk of death (HR 1.81, 95% CI 1.10-2.99). In conclusion, pre-treatment presence of extracellular mucin, SRCs, and/or PCCs is unrelated to pathological response. The presence of these factors should not be an argument to refrain from CROSS. At least 10% PCCs pre-treatment and any SRCs post-treatment, irrespective of the tumour differentiation grade, seem indicative of inferior prognosis, but require further validation in larger cohorts.

Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer.

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24-71) (8/17), specificity of 85% (95% CI 42-99) (6/7), positive predictive value (PPV) of 89% (95% CI 51-99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17-67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6-51) (3/14), specificity of 100% (95% CI 56-100) (7/7), PPV of 100% (95% CI 31-100) (3/3), and NPV of 39% (95% CI 18-64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Do pathologists agree with each other on the histological assessment of pT1b oesophageal adenocarcinoma?

Background: In early (T1) oesophageal adenocarcinoma (OAC), the histological profile of an endoscopic resection specimen plays a pivotal role in the prediction of lymph node metastasis and the potential need for oesophagectomy with lymphadenectomy. Objective: To evaluate the inter-observer agreement of the histological assessment of submucosal (pT1b) OAC. Methods: Surgical and endoscopic resection specimens with pT1b OAC were independently reviewed by three gastrointestinal pathologists. Agreement was determined by intraclass correlation coefficient for continuous variables, and Fleiss' kappa (κ) for categorical variables. Bland-Altman plots of the submucosal invasion depth were made. Results: Eighty-five resection specimens with pT1b OAC were evaluated. The agreement was good for differentiation grade (κ=0.77, 95% confidence interval (CI) 0.68-0.87), excellent for lymphovascular invasion (κ=0.88, 95% CI 0.76-1.00) and moderate for submucosal invasion depth using the Paris and Pragmatic classifications (κ=0.60, 95% CI 0.49-0.72 and κ=0.42, 95% CI 0.33-0.51, respectively). Systematic mean differences between pathologists were detected for the measurement of submucosal invasion depth, ranging from 297 µm to 602 µm. Conclusions: A substantial discordance was found between pathologists for the measurement of submucosal invasion depth in pT1b OAC. Differences may lead to an over- or underestimation of the lymph node metastasis risk, with grave implications for the treatment strategy. Review by a second gastrointestinal pathologist is recommended to improve differentiating between a favourable and an unfavourable histological profile.

Four cancer cases after esophageal atresia repair: Time to start screening the upper gastrointestinal tract.

Esophageal atresia (EA) is one of the most common congenital digestive malformations and requires surgical correction early in life. Dedicated centers have reported survival rates up to 95%. The most frequent comorbidities after EA repair are dysphagia (72%) and gastroesophageal reflux (GER) (67%). Chronic GER after EA repair might lead to mucosal damage, esophageal stricturing, Barrett's esophagus and eventually esophageal adenocarcinoma. Several long-term follow-up studies found an increased risk of Barrett's esophagus and esophageal carcinoma in EA patients, both at a relatively young age. Given these findings, the recent ESPGHAN-NASPGHAN guideline recommends routine endoscopy in adults born with EA. We report a series of four EA patients who developed a carcinoma of the gastrointestinal tract: three esophageal carcinoma and one colorectal carcinoma in a colonic interposition. These cases emphasize the importance of lifelong screening of the upper gastrointestinal tract in EA patients.

Submucosal invasion and risk of lymph node invasion in early Barrett's cancer: potential impact of different classification systems on patient management.

BACKGROUND: Due to the high mortality and morbidity rates of esophagectomy, endoscopic mucosal resection (EMR) is increasingly used for the curative treatment of early low risk Barrett's adenocarcinoma. OBJECTIVE: This retrospective cohort study aimed to assess the prevalence of lymph node metastases (LNM) in submucosal (T1b) esophageal adenocarcinomas (EAC) in relation to the absolute depth of submucosal tumor invasion and demonstrate the efficacy of EMR for low risk (well and moderately differentiated without lymphovascular invasion) EAC with sm1 invasion (submucosal invasion ≤500 µm) according to the Paris classification. METHODS: The pathology reports of patients undergoing endoscopic resection and surgery from January 1994 until December 2013 at one center were reviewed and 54 patients with submucosal invasion were included. LNM were evaluated in surgical specimens and by follow up examinations in case of EMR. RESULTS: No LNM were observed in 10 patients with sm1 adenocarcinomas that underwent endoscopic resection. Three of them underwent supplementary endoscopic eradication therapy with a median follow up of 27 months for patients with sm1 tumors. In the surgical series two patients (29%) with sm1 invasion according to the pragmatic classification (subdivision of the submucosa into three equal thirds), staged as sm2-3 in the Paris classification, had LNM. The rate of LNM for surgical patients with low risk sm1 tumors was 10% according to the pragmatic classification and 0% according to Paris classification. CONCLUSION: Different classifications of the tumor invasion depth lead to different LNM risks and treatment strategies for sm1 adenocarcinomas. Patients with low risk sm1 adenocarcinomas appear to be suitable candidates for EMR.

Small bites versus large bites for closure of abdominal midline incisions (STITCH): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Incisional hernia is a frequent complication of midline laparotomy and is associated with high morbidity, decreased quality of life, and high costs. We aimed to compare the large bites suture technique with the small bites technique for fascial closure of midline laparotomy incisions. METHODS: We did this prospective, multicentre, double-blind, randomised controlled trial at surgical and gynaecological departments in ten hospitals in the Netherlands. Patients aged 18 years or older who were scheduled to undergo elective abdominal surgery with midline laparotomy were randomly assigned (1:1), via a computer-generated randomisation sequence, to receive small tissue bites of 5 mm every 5 mm or large bites of 1 cm every 1 cm. Randomisation was stratified by centre and between surgeons and residents with a minimisation procedure to ensure balanced allocation. Patients and study investigators were masked to group allocation. The primary outcome was the occurrence of incisional hernia; we postulated a reduced incidence in the small bites group. We analysed patients by intention to treat. This trial is registered at Clinicaltrials.gov, number NCT01132209 and with the Nederlands Trial Register, number NTR2052. FINDINGS: Between Oct 20, 2009, and March 12, 2012, we randomly assigned 560 patients to the large bites group (n=284) or the small bites group (n=276). Follow-up ended on Aug 30, 2013; 545 (97%) patients completed follow-up and were included in the primary outcome analysis. Patients in the small bites group had fascial closures sutured with more stitches than those in the large bites group (mean number of stitches 45 [SD 12] vs 25 [10]; p<0·0001), a higher ratio of suture length to wound length (5·0 [1·5] vs 4·3 [1·4]; p<0·0001) and a longer closure time (14 [6] vs 10 [4] min; p<0·0001). At 1 year follow-up, 57 (21%) of 277 patients in the large bites group and 35 (13%) of 268 patients in the small bites group had incisional hernia (p=0·0220, covariate adjusted odds ratio 0·52, 95% CI 0·31-0·87; p=0·0131). Rates of adverse events did not differ significantly between groups. INTERPRETATION: Our findings show that the small bites suture technique is more effective than the traditional large bites technique for prevention of incisional hernia in midline incisions and is not associated with a higher rate of adverse events. The small bites technique should become the standard closure technique for midline incisions. FUNDING: Erasmus University Medical Center and Ethicon.

Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol.

BACKGROUND: Results from the recent CROSS trial showed that neoadjuvant chemoradiotherapy (nCRT) significantly increased survival as compared to surgery alone in patients with potentially curable esophageal cancer. Furthermore, in the nCRT arm 49% of patients with a squamous cell carcinoma (SCC) and 23% of patients with an adenocarcinoma (AC) had a pathologically complete response in the resection specimen. These results provide a rationale to reconsider and study the timing and necessity of esophagectomy in (all) patients after application of the CROSS regimen. OBJECTIVE: We propose a "surgery as needed" approach after completion of nCRT. In this approach, patients will undergo active surveillance after completion of nCRT. Surgical resection would be offered only to those patients in whom residual disease or a locoregional recurrence is highly suspected or proven. However, before a surgery as needed approach in oesophageal cancer patients (SANO) can be tested in a randomized controlled trial, we aim to determine the accuracy of detecting the presence or absence of residual disease after nCRT (preSANO trial). METHODS: This study is set up as a prospective, single arm, multicenter, diagnostic trial. Operable patients with potentially curable SCC or AC of the esophagus or esophagogastric junction will be included. Approximately 4-6 weeks after completion of nCRT all included patients will undergo a first clinical response evaluation (CRE-I) including endoscopy with (random) conventional mucosal biopsies of the primary tumor site and of any other suspected lesions in the esophagus and radial endo-ultrasonography (EUS) for measurement of tumor thickness and area. Patients in whom no locoregional or disseminated disease can be proven by cytohistology will be offered a postponed surgical resection 6-8 weeks after CRE-I (ie, approximately 12-14 weeks after completion of nCRT). In the week preceding the postponed surgical resection, a second clinical response evaluation (CRE-II) will be planned that will include a whole body PET-CT, followed again by endoscopy with (random) conventional mucosal biopsies of the primary tumor site and any other suspected lesions in the esophagus, radial EUS for measurement of tumor thickness and area, and linear EUS plus fine needle aspiration of PET-positive lesions and/or suspected lymph nodes. The main study parameter is the correlation between the clinical response assessment during CRE-I and CRE-II and the final pathological response in the resection specimen. RESULTS: The first patient was enrolled on July 23, 2013, and results are expected in January 2016. CONCLUSIONS: If this preSANO trial shows that the presence or absence of residual tumor can be predicted reliably 6 or 12 weeks after completion of nCRT, a randomized trial comparing nCRT plus standard surgery versus chemoradiotherapy plus "surgery as needed" will be conducted (SANO trial). TRIAL REGISTRATION: Netherlands Trial Register: NTR4834; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=4834 (archived by Webcite at http://www.webcitation.org/6Ze7mn67B).

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: long-term results of a randomized controlled trial.

BACKGROUND: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. METHODS: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. RESULTS: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. CONCLUSIONS: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC.

Accuracy of identification of tissue types in endoscopic esophageal mucosal biopsies used for molecular biology studies.

OBJECTIVES: To determine if histopathologic assessment of esophageal biopsies harvested for research study is justified due to the heterogeneity of tissues in the esophagus, and the consequent histopathologic mis-matches with the clinical histopathology of biopsies taken at the same level. METHODS: Since 2004, patients undergoing upper endoscopy for a variety of clinical conditions were invited to provide additional esophageal biopsies; those were collected for research purpose at the same level as biopsies collected for clinical histopathology. Research biopsies were cut in two parts: one part was submitted to research histopathology and the other stored for molecular analysis. Results of clinical histopathology for each patient were summarized per biopsy level and compared to results obtained from research biopsies at the corresponding level. RESULTS: A total of 377 level summaries were obtained from 137 patients. Clinical histopathology summaries classified 123 levels (32.6%) as squamous epithelium, 84 levels (22.3%) as metaplastic columnar-lined epithelium, 135 levels (35.8%) as columnar-lined epithelium with intestinal metaplasia, 30 levels (8%) as dysplasia, and 5 levels (1.3%) as adenocarcinoma. Research histopathology matched to clinical summaries on 120 of 123 (97.5%) levels for squamous epithelium, 52 of 84 (61.9%) for metaplastic columnar-lined epithelium, and 94 of 135 (69.5%) for columnar-lined epithelium with intestinal metaplasia. There were no matches for dysplasia between the groups; however, they agreed on all five cases of AC. On 59 (70.2%) metaplastic columnar-lined epithelium levels and on 62 (46%) columnar-lined epithelium with intestinal metaplasia levels, tissue heterogeneity was observed in clinical histopathology, with portions of squamous epithelium within the samples. Matches with pure tissue samples in both clinical and research histopathology levels were observed on 22 (26.2%) levels of metaplastic columnar-lined epithelium and in 55 (40.7%) levels of columnar-lined epithelium with intestinal metaplasia. CONCLUSIONS: The high proportion of mismatches and tissue heterogeneity observed, especially among columnar-lined epithelium with intestinal metaplasia and dysplasia, points to the necessity of determining the histopathology of the research samples to avoid sampling errors during molecular studies.