Junction Tumors Research Articles

When Gastroplasty Is Not Feasible in Ivor Lewis Esophagectomy: A Single-Center Study of Intrathoracic Esophagojejunostomy.

Objective: The surgical management of tumors of the esophagogastric junction is increasingly performed by minimally invasive Ivor Lewis esophagectomy. However, gastroplasty is not always feasible. The creation of a long loop is an alternative for esophageal reconstruction. The aim of this study was to evaluate the technical feasibility of using a minimally invasive thoracoscopic approach in esophagojejunostomy and to describe the contraindications for gastroplasty. Methods: All patients who had intrathoracic esophagojejunostomy in our center were identified in our database. Since 2016, the preferred approach for intrathoracic esophagojejunostomy is minimally invasive laparoscopy and thoracoscopy, using a long Roux-en-Y jejunal loop with a semimechanical triangular anastomosis technique. Results: Between January 1, 2012 and January 1, 2022, 12 patients who had esophagojejunostomy in our center were included in the study. Among them, 6 had thoracotomy and 6 had total minimally invasive thoracoscopy, representing 3.5% of surgical procedures for esophagogastric junction tumors since 2016. The mean operative time was 416.9 ± 107.47 minutes. No anastomotic leakage was observed in the minimally invasive group versus 2 leakages in the thoracotomy group. The main complication was pneumonia in 3 patients (27.3%). Finally, the main indication for intrathoracic esophagojejunostomy was tumor size with a mean of 4.72 ± 2.35 cm and the patient's surgical history. Conclusion: A total minimally invasive approach using a long jejunal loop with triangular anastomosis could be a feasible and reproducible alternative to gastroplasty to restore continuity in Ivor Lewis esophagectomy when the stomach cannot be used.

Gastric Radiotherapy in the UK – Current Practice and Opinion on Future Directions

Gastric radiotherapy (RT) is more commonly practiced in the US compared to the UK, where postoperative chemoradiotherapy (CRT) is reserved for selected high-risk patients, and preoperative CRT is not standard of care pending the results of phase 3 trials, TOPGEAR and CRITICSII. CRT for inoperable, non-metastatic gastric cancer is also not recommended in the UK, despite being listed in NCCN guidelines. Recent systematic review of definitive gastric CRT (dCRT) conducted by the authors found median overall survival of 11-26.4 months, clinical complete response rates of 8-45% and acceptable rates of ≥G3 toxicity, supporting further research. Given these promising findings and perceived low uptake of gastric RT in the UK, we set out to establish current UK practice, opinion and RT technique to inform the development of a UK gastric RT protocol and future clinical trials. A 19 question survey was developed. Following local ethical approval and pilot by 4 clinical oncologists, the final survey was distributed electronically on 13/12/22 to UK Consultant Clinical Oncologists specializing in esophago-gastric (OG) cancer. Responses were anonymous. Survey was closed 6/2/23 and data analyzed using JISC/spreadsheet software. A total of 43 clinicians completed the survey. For gastric cancer, 28.6%, 7.1% and 9.5% would agree/strongly agree with use of postoperative (postopRT), preoperative (preopRT) or definitive RT (dRT) respectively, compared to 26.2%, 45.2% and 46.6% for type III gastro-esophageal junction tumors. 93% had prescribed palliative gastric RT in the last 3 years compared to 40.5% postopRT, 16.7% dRT and 9.5% preopRT. Main reasons for infrequent use were; rarely indicated within standard UK practice 88.4%, lack of UK gastric RT protocol 53.5%, toxicity concerns 44.2%. 45Gy/25# was most commonly used for preopRT (66%) and postopRT (86%), and 50Gy/25# for dRT (58%). 96% use IMRT/VMAT, 85% CT simulation with IV/oral contrast, 69% gastric filling protocol and 54% 4DCT. When ranked out of 10 (1 = low 10 = high), clinician confidence in accurately delineating gastric volumes mean rank was 4.33 for postopRT, with 9% rating ≥8/10, and 4.52 for dCRT/preopRT with 17% rating ≥8/10. However, 48.8% were experienced in outlining upper abdominal nodes and 62.8% duodenum. 93% would find a detailed outlining protocol useful, 81.4% wanted some form of peer review, 76.7% a nodal atlas, and 74.4% a workshop with an expert. 77.6% would be supportive of a future clinical trial of dCRT, with 23.4% needing more supporting evidence. No-one would not support a future trial in this setting. Gastric RT is not often practiced in the UK, due to lacking evidence and toxicity concerns. Given the growing evidence and supportive OG community, it is time to consider a trial of dCRT in the UK, which must include detailed RT protocols, atlases and educational materials to improve clinician confidence and ensure good RT quality assurance.

Prognostic Implications of Various Surgical Procedures and Postoperative Margin Status in Gastroesophageal Junction Tumors.

Esophagogastric junction (EGJ) carcinomas often require access to two compartments of the body for good margin and lymphadenectomy. Whether it is required to do so in all patients is debatable. We analyzed outcomes of patients who underwent surgeries for EGJ carcinomas in terms of margin status and survival. This is a retrospective analysis of a prospectively maintained database of patients with EGJ adenocarcinomas operated between January 2014 and December 2016. Type of surgery performed and its impact on margin status and survival were assessed. Follow-up was for a minimum of 5 years. Ninety-four patients with EGJ carcinomas were operated on during the study period. Eight (8.51%) had involved proximal margin, and 2 of these had positive distal margin also. None had distal margin alone involved. Seventeen (18.09%) and 5 (5.32%) had a close proximal and distal margin, respectively. Radial margin was close/involved in 6 (6.38%) patients. Five-year overall survival and disease-free survival for the cohort was 38% and 30.8%, respectively. Proximal gastrectomy had a higher proximal margin positivity. Positive proximal or distal margin and a close/involved radial margin were detrimental to disease free survival and overall survival. Proximal gastrectomy is associated with a higher likelihood of proximal margin positivity. Positive margin leads to lower survival. Whether involvement of margins is just a surrogate marker of aggressive tumor or is an error in assessing extent tumor needs to be studied. Large-scale prospective studies in this regard are desirable.

Radiation Oncologists' Approach to Rectosigmoid Junction Tumors in Turkey: The Turkish Society for Radiation Oncology Gastrointestinal Group Survey Study (TROD 02-007).

The objective was to determine the preferences and perspectives regarding preoperative evaluation and treatment strategies for rectosigmoid junction cancer among radiation oncologists using a questionnaire survey. Since defining the correct origin of the neoplasm is essential in tailoring the most appropriate treatment scheme in the rectosigmoid junction region, we surveyed Turkish radiation oncologists about clinical decisions in rectosigmoid junction cancer patients via a 20-point questionnaire. Based on responses from 130 radiation oncologists surveyed across the country, 119 (91.5%) used the anterior peritoneal reflection as the landmark, while 111 (85.4%) used the distance from the anal verge to the boundary between the rectum and sigmoid. This indicates that most of the participants decided to consider both pretreatment evaluation methods. Although distance at colonoscopy can be very variable, when the discrepancy was observed between these methods, 66 (50.8%) participants made the final decision according to the distance from the anal verge in our questionnaire. The conclusion from the questionnaire is that there is difficulty in interpreting magnetic resonance imaging findings, and there is a need for anatomic landmarks relevant to the limit between the rectum and sigmoid so that clinicians can confidently facilitate the diagnosis. There is a wide variation in the diagnosis and decision-making of rectosigmoid junction cancer among radiation oncologists in Turkey, according to our survey, because of several definitions of the rectosigmoid junction boundaries. Considerable attention is required to clarify whether the first preoperative treatment or surgery for rectosigmoid junction cancer.

Addition of trastuzumab to perioperative chemotherapy in HER2-positive gastroesophageal adenocarcinoma patients: A multicenter retrospective observational AGEO study

BackgroundApproximately 10–20% of patients with gastroesophageal adenocarcinoma (GE-ADK) have HER2-positive tumors. The addition of trastuzumab to chemotherapy improves OS in patients with advanced disease. We investigated the effect of perioperative trastuzumab on survival outcomes. MethodsThis French, multicenter, retrospective observational study included HER2-positive GE-ADK patients treated between January 2015 and December 2020. The primary endpoint was DFS at 18 months. Secondary endpoints were pathological complete response rate (pCR), R0 resection rate, OS, and toxicity. ResultsForty-eight patients were included, and they received a median of 6 cycles of preoperative treatment, with grade III/IV adverse events occurring in 23%. Pathologic complete response (pCR) and major pCR according to Mandard system were achieved in 5/48 (10%) and 20/48 (42%) patients, respectively. Loss of HER2 expression was observed in 18/48 (38%) patients. Postoperative complications rate according to the Clavien Dindo classification (≥3) was 37.5%. After a median follow-up of 29 months, the 18-month DFS was 80.4% (95% CI 68.9–93.8) and the 2-year OS rate was 89.0%. Subgroup analysis showed a longer DFS for gastric tumor than gastro-esophageal junction tumor. ConclusionsThis study suggests that perioperative chemotherapy with trastuzumab in patients with HER2-positive GE-ADK is feasible and safe with encouraging survival.

A phase I/II dose escalation and expansion trial to evaluate safety and preliminary efficacy of BNT141 in patients with claudin-18.2-positive solid tumors.

TPS2670 Background: Claudin-18.2 (CLDN18.2), whose expression is normally restricted to short-lived gastric epithelial cells, is ectopically expressed in tumors with unmet needs such as gastric, gastroesophageal junction (GEJ), pancreatic, ovarian, and biliary tract tumors. CLDN18.2 has thus emerged as a promising target for therapeutic antibody development. BNT141 is a novel RNA-based therapeutic that comprises two pseudouridine-modified mRNAs encapsulated in lipid nanoparticles. Upon intravenous injection, BNT141 is preferentially taken up by the liver where RNAs are translated and released into the circulation as fully assembled anti-CLDN18.2 antibodies. The resulting antibody is sequence identical to IMAB362, a CLDN18.2-targeted antibody that provided clinical benefit as an add-on to chemotherapy in the Phase III SPOTLIGHT trial (Shitara et al. J Clin Oncol. 2023). RNA-encoded antibodies can be developed more rapidly compared with recombinant antibodies and have the potential for favorable PK/PD properties and improved tolerability. Methods: This is a Phase I/II, open-label, multisite, dose escalation and expansion trial to examine safety, efficacy, and PK/PD of BNT141 in patients with CLDN18.2+ tumors (NCT04683939). The trial comprises 3 parts: dose escalation with BNT141 as monotherapy, dose escalation with BNT141 in combination with nab-paclitaxel and gemcitabine, and dose expansion. For monotherapy dose escalation, patients with CLDN18.2+ gastric, GEJ, pancreatic, mucinous ovarian, and biliary tract cancers who have exhausted or are ineligible for the current standard of care are eligible. CLDN18.2 positivity is defined as intermediate/strong staining intensity in ≥50% of tumor cells evaluated using a validated immunohistochemistry assay. Doses of BNT141 are escalated in up to 8 planned dose levels (DLs) until the maximum tolerated dose (MTD) is reached. For combination dose escalation, patients with advanced CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma who are eligible for treatment with nab-paclitaxel/gemcitabine will be included. Combination therapy will start at the first safe DL where the target antibody concentration is reached during monotherapy. Combination dose escalation will continue in parallel with the monotherapy part and will define the recommended Phase II dose (RP2D). For both parts, up to 10 additional patients may be enrolled at the MTD level to collect further safety and PK/PD data. For dose expansion, 2 cohorts of patients with CLDN18.2+ pancreatic adenocarcinoma or cholangiocarcinoma will receive combination therapy (nab-paclitaxel/gemcitabine) together with BNT141 at the defined RP2D. The study was initiated in January 2022 and recruitment is ongoing in the USA and Canada. Sites in Spain, Portugal, Germany, Denmark, Netherlands and the UK will be opened in 2023. Clinical trial information: NCT04683939 .

A phase 1, first-in-human, open label, escalation and expansion study of ORM-5029, a highly potent GSPT1 degrader targeting HER2, in patients with HER2-expressing advanced solid tumors.

TPS1114 Background: Targeted protein degradation (TPD) molecules have expanded the therapeutic options through their catalytic mechanism of action (MOA) and ability to degrade “undruggable” proteins. To increase the efficacy versus tolerability window of protein degradation and improve drug delivery, ORM-5029 uses a Dual-Precision TPD (TPD2) approach combining the catalytic mechanism of TPDs with the precision of tumor-targeting therapeutic antibodies. ORM-5029 is a first-in-class human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) comprised of SMol006, a highly potent GSPT1 degrader, conjugated to pertuzumab, a clinically validated antibody. HER2 is overexpressed in cancers such as breast, ovarian and gastric, and associated with early-onset aggressive disease. ORM-5029 is in development for treatment of HER2-expressing solid tumors. The MOA is mediated by targeted uptake of the ADC, release of the TPD payload, and cell death by GSPT1 degradation. ORM-5029 showed robust in vitro and in vivo efficacy in multiple HER2-expressing models with comparable activity to trastuzumab deruxtecan and strong activity in trastuzumab emtansine-refractory models. Methods: This phase 1 first-in-human study evaluates the safety, tolerability, and efficacy of ORM-5029 administered by intravenous infusion in patients (pts) with HER2-expressing advanced solid tumors (NCT05511844). The escalation, guided by the Bayesian Optimal Interval design, explores cohorts of ORM-5029 to identify the maximum tolerated dose (MTD) and/or expansion dose level (EDL). Each cohort will enroll ≥3 breast cancer pts with at least HER2 1+ (HER2 low) or greater by immunohistochemistry or positive by in situ hybridization. Expansion cohort A (HER2+ breast cancer) may enroll in parallel to escalation evaluating doses showing pharmacodynamic activity or efficacy. Up to 10 pts may be enrolled at each dose explored in cohort A. Enrollment into expansion cohort B (up to 21 pts) and cohort C (up to 22 pts) will begin once the EDL has been determined to further assess the safety, tolerability and efficacy of ORM-5029 using a Simon’s optimal 2-stage design. Cohort B will enroll pts with HER2+ breast cancer refractory or intolerant to standard treatment after ≥2 HER2 therapies in the metastatic setting. Cohort C will enroll pts with advanced solid tumors that are refractory or intolerable to standard treatment or for which no standard treatment is available, including HER2+ gastric or gastroesophageal junction adenocarcinoma or tumors with HER2 expression, amplification or mutations (e.g., colorectal, bile duct, ovarian, bladder, non-small cell lung). Study enrollment began in October 2022 in the United States. Escalation cohort 1 was completed without DLT; enrollment in cohort 2 began as of December 2022. Clinical trial information: NCT05511844 .

Leptomeningeal carcinomatosis and brain metastases in gastroesophageal carcinoma: A real-world analysis of outcomes, clinical and pathologic characteristics.

2029 Background: Brain metastasis (BM) and Leptomeningeal Carcinomatosis (LC) are uncommon complications in gastroesophageal carcinoma (GEC) patients (pts). These patients have a poor prognosis and are challenging to study. We described the clinicopathologic features and outcomes in the largest real-world cohort of CNS metastasis in GEC pts. Methods: We conducted a single-center retrospective study of GEC pts treated at the Princess Margaret Cancer Centre from 2007 to 2021 who developed BM. Clinicopathologic characteristics and treatment modalities were reviewed. Survival was calculated from the date of BM or LC diagnosis until date of death/last follow-up using the Kaplan-Meier method. A multivariable Cox proportional hazards regression model was used to examine the association of baseline covariates and survival. Results: Of 3283 consecutive pts with GEC, 101 (3.08%) were diagnosed with BM and 20 with LC (0.61%). Most pts with BM were male (75.3%), non-Asian (93%), with a primary gastroesophageal junction tumor (47%) and adenocarcinoma histology (86%). Among pts with known HER2 status (N= 48), 60% were HER2 positive (defined as IHC 3+ or IHC 2+/FISH+). All patients with LC had adenocarcinoma histology; most were signet-ring subtype (85%), poorly differentiated (80%) histology and only 15% (2/13) were HER2 positive. Median survival was 0.8; 3.8; and 7.7 months (mo) in BM pts treated with palliative care only, radiation only and surgery followed by radiation, respectively (p< 0.001). In LC, median survival was 0.7 mo in pts who had palliative care only (7/20) and 2.7 mo for those (13/20) who had whole brain radiation therapy (WBRT) (p .008). Multivariate analysis showed a higher probability of death in patients with number of BM ≥4 (p 0.02) and predicted superior survival in patients who received radiation and surgery followed by radiation (p 0.02). Conclusions: This is the most comprehensive summary of clinicopathologic characteristics and survival in patients with GEC and BM and LC disease to date. Biomarker analysis reveals an enriched frequency of HER2 expression in BM, while this is uncommon in pts with LC. BM pts who were treated with surgery followed by radiation had a significantly improved OS. WBRT benefited patients with LC over palliative care alone. These findings add to our understanding for the management of this understudied population with poor survival. [Table: see text]

ESMO update: upper gastrointestinal cancer

SummaryAt the European Society for Medical Oncology (ESMO) 2022 annual meeting, several pertinent studies in the field of upper gastrointestinal cancer were presented. The most practice-changing study appeared to be the Destiny-Gastric02 study evaluating trastuzumab–deruxtecan as a second-line treatment option in patients with Her2-positive gastric and gastroesophageal junction cancer. The median overall survival was 12.1 months with a confirmed overall response rate of 41.8%. 55.7% of patients experienced grade ≥ 3 events with nausea, vomiting, and fatigue being the most frequently observed. This study led to the approval of trastuzumab–deruxtecan as second-line therapy in patients with Her2-positive gastric and gastroesophageal junction tumors who have experienced disease progression after first-line trastuzumab-containing therapy.

Abstract CT234: A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors

Abstract Background: Despite recent therapeutic developments for patients with advanced, metastatic, unresectable HER2+ solid tumors, significant unmet medical needs still exist, especially in tumors other than breast and gastric. The T cell antigen coupler (TAC) technology is a novel approach to modifying T cells, allowing them to recognize and treat HER2+ solid tumors. The TAC receptor redirects T cells to tumor cells, and upon tumor cell recognition, co-opts the natural T cell receptor (TCR) to yield safer anti-tumor responses versus chimeric antigen receptor (CAR) T cells. In preclinical studies, TAC T cells led to complete tumor clearance in mouse models of human cancer, without any TAC-related toxicities. In the ongoing clinical trial (NCT04727151), TAC01-HER2 treatment of HER2+ solid tumors is hypothesized to result in safe and effective anti-tumor responses. Subjects undergo leukapheresis, bridging therapy (if needed) while their TAC01-HER2 are engineered, lymphodepletion chemotherapy (LDC), and finally TAC01-HER2 infusion. Trial Design and Early Results: In phase I dose escalation, the primary objective is to evaluate the safety of TAC01-HER2 at increasing doses of 0.3, 0.8, 3, and 8 × 106 cells/kg in HER2+ solid tumors (1+, 2+ or 3+ as identified by immunohistochemistry) in adult subjects who have progressed after ≥2 lines of systemic therapy. Dose limiting toxicities (DLTs) are assessed up to 28 days from cell infusion. In Phase II, dose expansion groups will further evaluate the safety, efficacy, and pharmacokinetics of the optimal TAC01-HER2 dose in HER2+ breast and other solid tumor types. As of 12 Dec 2022, 12 patients have been treated in Cohorts 1-4 with breast, colorectal, gall bladder, gastro-esophageal junction, gastric and ovarian tumors. No DLTs or neurotoxicity events have been reported. All patients treated so far at Cohorts 3 and 4 (3 × 106 and 8 × 106 cells/kg, respectively) experienced Grade ≤2 CRS which were resolved with standard of care treatments. Eight subjects have reported a total of 15 serious adverse events, all unrelated to TAC01-HER2 except for a Grade 1 and a Grade 2 CRS, both resolved with standard of care. Most adverse events were related to LDC or the underlying neoplasm. At Cohort 2, a partial response was observed in a subject with refractory metastatic gastric adenocarcinoma (3+ HER2) at 1st scan, with a 36.5% reduction in measurable disease and clinical benefit was maintained for 6 months. A 71% disease control rate was observed at Cohorts 2 and 3 at 1st scan (0.8 × 106 and 3 × 106 cells/kg, respectively)). Dose escalation of TAC01-HER2 is ongoing, with the first subject treated at Cohort 4. These results in a heavily pre-treated cancer population show manageable safety and promising clinical activity with a novel T cell therapy that may have broad clinical applicability in HER+ cancers. Citation Format: Ecaterina Elena Dumbrava, Daniel Olson, Samuel Saibil, Brooke Pieke, Mridula A. George, Riemke Bouvier, Miriam Gavriliuc, Kelly Gruber, Kara Moss, Nathan Ternus, Maria Apostolopoulou, Deyaa Adib, Benjamin L. Schlechter. A phase I/II trial investigating safety and efficacy of autologous TAC01-HER2 in relapsed or refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT234.

Abstract 5910: Prospective platform to define microbiome correlates of metastasis and therapy resistance in early onset and average onset gastrointestinal cancers

Abstract Background: The incidence of early onset (EO) gastrointestinal (GI) cancers prior to age 50 is rising, and the etiology is unknown. The gut microbiome may contribute to GI cancer pathogenesis, though how bacteria drive metastasis and treatment resistance is not known. Purpose: To define the microbiome contribution to EO-GI cancers and metastasis by analyzing longitudinal samples from previously untreated patients with GI cancers. Methods: We designed a prospective biospecimen collection platform. We selected patients with newly diagnosed, previously untreated colorectal cancer (CRC) and esophagogastric cancer (EGC). We collected stool, biopsy or surgical tissue, and peripheral blood mononuclear cells (PBMCs) at baseline prior to treatment and at each restaging scan for patients with metastatic disease. For those with locally advanced disease, we collected samples at baseline and after each treatment phase (surgery, radiation, chemotherapy). Stool samples were analyzed using shotgun sequencing. Tissue samples were banked for further analysis. Clinical data was manually curated. Relative abundances of bacteria at the species level were compared between groups. Alpha diversity was calculated using the inverse Simpson index and compared between groups using the Wilcoxon signed-rank test. Beta diversity was analyzed using the Bray-Curtis dissimilarity matrix and compared using PERMANOVA. Multivariate association between species abundance and clinical covariates was performed using MaAsLin2 R package. Results: We analyzed a total of 150 stool samples from 76 patients (colorectal n=53, esophagogastric n=23), including up to 6 samples from a single patient over time. Mean alpha diversity did not differ significantly by primary site or age at diagnosis in patients with CRC but was higher in stage IV compared with stage I disease (P=0.054). Beta diversity was significantly different between samples from patients with right- compared with left-sided CRC (P=0.005) but did not differ significantly by diagnosis age (<50 vs. > 50). Among those with EGC, mean alpha diversity was not significantly different in samples from patients with esophagus or gastroesophageal junction (proximal) tumors compared with gastric (distal) tumors and did not differ significantly by age group. Beta diversity was significantly different between patients with EGC over 50 compared with those under 50 (P=0.002). When CRC baseline samples were examined, several bacterial species were associated with age <50 at diagnosis, including Streptococcus anginosus group (P=0.001), Solobacterium moorei (P=0.013), and Firmicutes bacterium CAG83 (P=0.016). Conclusions/Future Directions: Microbiome composition may cluster by primary tumor site and age at diagnosis in patients with previously untreated GI cancers. Functional analysis and is ongoing and will be presented. Citation Format: Melissa A. Lumish, Asha R. Saxena, Nicholas Waters, Anqi Dai, Saskia Hartner, Teng Fei, Matthew Drescher, Jonathan Bermeo, Dorina Ismailgeci, Maggie Fox, Yelena Y. Janjigian, Luis A. Diaz, Martin R. Weiser, Jonathan Peled, Marcel van den Brink, Karuna Ganesh. Prospective platform to define microbiome correlates of metastasis and therapy resistance in early onset and average onset gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5910.

Supracarinal lymph node positivity in esophageal squamous cell carcinoma (ESCC) and factors predicting metastasis in supracarinal compartment nodes: Should a total mediastinal node dissection be the standard of care?

Adequate lymphadenectomy in middle- and lower-third esophagus cancer is still a matter of debate. This study aims to find out the extent of histopathological supracarinal lymph nodes positivity rate to establish an adequate lymph node dissection in esophageal squamous cell carcinoma cases operated up-front or after neoadjuvant chemotherapy (CT) + radiotherapy (RT) and its short-term oncological outcome. After approval from institutional board review, a retrospective study was conducted from April 2017 to September 2019. A total of 76 patients having mid- or lower-third carcinoma esophagus were operated at our institute for partial/total esophagectomy with extended two-field lymph node dissection were followed. Intraoperative nodal stations were harvested separately and lebeled individually according to the Japanese Esophageal Classification and sent for histopathological examination. The patients had an average age of 52 years. Histologically all were squamous cell carcinoma (SCC). Forty-four patients received preoperative concurrent RT plus drug therapy, whereas 18 cases were operated up-front. Fourteen patients were operated after palliative treatment (CT/RT). The average total lymph node yield was 22 nodes (range 3-69). In 26 patients (34.2%), lymph nodes were positive (N+ disease). Supracarinal nodes were positive in 20 cases (26.31%). The average supracarinal lymph node yield was 10.33 nodes (range 2-32). Five patients (6.5%) had only supracarinal lymph nodes positive on histopathological examination. Seventeen patients had a complete pathological response rate (pCR). In cases of mid-third esophageal carcinoma, extended two fields with supracarinal lymphadenectomy is strongly recommended even after the patient has received neoadjuvant treatment, although the same for lower-third/gastroesophageal (GE) junction tumors should be considered.

Recent Advances in the Systemic Treatment of Localized Gastroesophageal Cancer.

The overall survival expectancy of localized gastroesophageal cancer patients still remains under 5 years despite advances in neoadjuvant and adjuvant treatment strategies in recent years. For almost a decade, immunotherapy has been successfully implemented as a first-line treatment for various oncological diseases in advanced stages. In the case of advanced gastroesophageal cancer, 2021 witnessed several approvals of immune checkpoint inhibitor therapies by different authorities. Although it is still a debate whether this treatment should be restricted to a certain subgroup of patients based on biomarker selection, immunotherapy agents are making remarkable steps in resectable settings as well. The Checkmate-577 study demonstrated significant benefits of nivolumab as an adjuvant treatment for resectable esophageal and gastroesophageal junction tumors and thereby obtained approvals both from U.S. American and European authorities. First results of further potential practice-changing clinical trials are expected in 2023, which might change the treatment armamentarium for resectable gastroesophageal cancers significantly. This review aims to demonstrate the advances of immunotherapy and targeted therapies in treatment of localized gastric, gastroesophageal junction and esophageal tumors and gives a short summary on promising ongoing clinical trials.

The effect of gastric fundus radiation dose on postoperative anastomotic leakage in esophageal cancer.

Standard-of-care treatment for locally advanced esophageal carcinoma (LAEC) includes neoadjuvant chemoradiotherapy followed by esophagectomy. A potentially catastrophic surgical complication is the development of a postoperative anastomotic leak. To date, the association with radiation dose exposure had been inconclusive. We examined the correlation between radiation exposure to the gastric fundus and risk of postoperative leakage using contemporary radiation doses and fractionation. A total of 69 consecutive patients with LAEC who underwent neoadjuvant chemoradiotherapy followed by esophagectomy in our tertiary center were prospectively followed (median, 27 months). Neoadjuvant regimen included 50.4 Gy in 28 fractions with 5-fluorouracil and cisplatin and 41.4 Gy in 23 fractions with carboplatin and paclitaxel. The gastric fundus was contoured and dosimetric and radiation technique parameters were retrospectively evaluated. Of the total number of patients, 71% and 29% had esophageal and gastroesophageal junction (GEJ) tumors, respectively. Fourteen patients (20.3%) experienced anastomotic leaks within a median of 2 days postoperatively, 78.6% of whom had lower third esophagus or GEJ primaries. Mean and minimum fundus dose did not significantly differ between those with and those without leakage (p = 0.42, p = 0.51). Mean fundus V25, V30, and V35 doses were numerically but not statistically higher in those with anastomotic leak (p = 0.58, p = 0.39, and p = 0.30, respectively). No correlation with incidence of leakage was seen between 3D and IMRT treatment modalities. In our comparatively large prospectively collected series of patients treated for LAEC, radiation dose to the gastric fundus during neoadjuvant combination therapy prior to surgery did not correlate with the risk of postoperative anastomotic leak.

Relation between mismatch repair status, chemoresponse, survival and anatomic location in gastroesophageal adenocarcinoma.

It has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location. We investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis. In all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94). Our study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.

Tumor Regression Grade and Overall Survival following Gastrectomy with Preoperative Therapy for Gastric Cancer.

Pre-/perioperative chemotherapy is well-established for management of locoregional gastric cancer (LRGC). The American Joint Committee on Cancer advocates histopathologic assessment of tumor regression grade (TRG) but does not endorse a specific schema. We sought to examine the prognostic value of the recently revised National Comprehensive Cancer Network (NCCN) definition of TRG specifying TRG0 as no disease in primary tumor or lymph nodes. Patients with clinical-stage T2+/N+/M0 LRGC receiving preoperative chemotherapy and curative-intent gastrectomy were identified (2000-2020). TRG using the current NCCN definition was retrospectively assigned. Factors associated with TRG were examined using ordinal logistic regression and overall survival (OS) was assessed using the Kaplan-Meier method and Cox regression. Among 117 patients, the most common chemotherapy regimen was epirubicin, cisplatin, plus fluorouracil or capecitabine (ECF/ECX) (n = 48, 41%), followed by folinic acid, fluorouracil, and oxaliplatin (FOLFOX) (n = 30, 26%), and fluorouracil, leucovorin, oxaliplatin, plus docetaxel (FLOT) (n = 13, 11%). TRG3 was the most common histopathologic response (n = 68, 58%), followed by TRG2 (n = 25, 21%), TRG1 (n = 18, 15%), and, lastly, TRG0 (n = 6, 5.1%). The only preoperative factor independently associated with lower TRG was gastroesophageal junction tumor location (OR 0.24, p = 0.012). Higher TRG was independently associated with worse OS in a stepwise fashion (HR 1.49, p = 0.026). Posttreatment pathologic lymph node status was the strongest prognostic factor (HR 1.93, p = 0.026). Independent prognostic value of TRG and ypT stage could not be shown due to substantial overlap. TRG using the contemporary NCCN definition is associated with OS in LRGC. TRG0 is uncommon but with excellent prognosis. ypN status is the strongest prognostic factor and the revised NCCN definition acknowledging this is appropriate.

A phase 1a dose-escalation, multicenter trial of anti-claudin 18.2 antibody drug conjugate CMG901 in patients with resistant/refractory solid tumors.

352 Background: CMG901, an anti-claudin 18.2 (CLDN18.2) antibody-drug conjugate, has demonstrated potent preclinical anti-cancer activity through monomethyl auristatin E (MMAE)-mediated cytotoxicity with bystander killing, antibody-dependent cellular cytotoxicity, and complement-dependent cytotoxicity. Methods: This Phase 1a trial uses a modified 3+3 dose-escalation design to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary anti-tumor activity in subjects (ages 18-75 years) with advanced gastric, gastroesophageal junction (GEJ), pancreatic cancers, and other solid tumors. Eligible subjects are refractory and/or intolerant to standard therapies. CLDN18.2 expression was not required for study entry, but was retrospectively tested by the central lab. CMG901 was administered intravenously on Day 1 in 3-week (Q3W) cycle at doses of 0.3, 0.6, 1.2, 1.8, 2.2, 2.6, 3.0, and 3.4 mg/kg. Primary endpoints include safety and tolerability. Major efficacy endpoints include objective response rate (ORR) and disease control rate (DCR) based on RECIST v1.1. Pharmacokinetics (PK) and immunogenicity are also assessed. Results: As of August 4, 2022, 27 subjects (13 gastric/GEJ cancer and 14 pancreatic cancer patients) received CMG901 at dose levels up to 3.4 mg/kg. The median prior lines of systemic therapy were 2 (range: 1 to 5). Drug-related grade ≥3 adverse events (AEs) occurred in 3/27 (11.1%) patients. No drug-related grade 4 or 5 AEs were reported. MTD was not reached. In CLDN18.2-positive gastric/GEJ cancer patients, ORR and DCR were 75.0% and 100%, respectively, with ORR of 100% in the 2.6, 3.0, and 3.4 mg/kg Q3W dose cohorts. Median progression-free survival (mPFS) and median overall survival (mOS) were not reached yet. PK data showed that patients had low systemic exposure to unconjugated MMAE. Subsequent results will be presented. Conclusions: CMG901 was well-tolerated with preliminary promising clinical efficacy in patients with CLDN18.2-positive gastric/GEJ cancer. The Phase 1b dose-expansion trial in gastric/GEJ adenocarcinoma, pancreatic cancer, and other solid tumors is rapidly enrolling, with multiple pivotal (Phases 2 and 3) trials planned. Clinical trial information: NCT04805307 . [Table: see text]

Regorafenib (REG) combined with irinotecan (IRI) versus IRI alone as second-line treatment in patients with metastatic gastro-oesophageal adenocarcinomas (mGA): A randomized phase II trial (PRODIGE 58 – UCGI 35 – REGIRI).

387 Background: Several options have been evaluated as 2nd line treatment in mGA after failure of 1st line platinum based chemotherapy including taxanes and IRI as monotherapies or paclitaxel combined with ramucirumab but with a limited efficacy. REG monotherapy showed promising efficacy as 2nd or 3rd line treatment in mGA (Pavlakis N et al, J Clin Oncol. 2016). Methods: This comparative phase 2 multicenter randomized study was designed to evaluate the safety and efficacy of REG + IRI (REGIRI) vs IRI alone as 2nd line treatment in MGA patients (pts). Key eligibility criteria were histologically proven mGA (gastric or gastroesophageal junction (GEJ) tumor Siewert II and III), fluoropyrimidine and platinum-based first-line chemotherapy and ECOG PS ≤1. Pts received IRI 180 mg/m2 IV on D1 and D15. In REGIRI arm REG 160 mg/day was added on D2-D8 and D16-D22 every 28 days. Primary endpoint was overall survival (OS). A total of 122 events (154 pts) were required based on an assumption of 4-month (mo) gain in median OS (from 6 to 10 mo, HR=0.60), with a preplanned interim analysis of safety after 38 pts and efficacy after 40 OS events. Genotyping of cyclin-D1 was performed to evaluate the impact of treatment efficacy. Results: A total of 89 patients (REGIRI, n=44; IRI, n=45) with median age of 62 (range: 28-82) years and a mGA (67.4% with GEJ, 22.8% HER2+) were included out of the 154 initially planned by 21 sites in France. Study was prematurely stopped after interim analysis for unfavourable efficacy/toxicity ratio. With a median follow-up of 19.4 mo, 79 OS events were observed and median OS was 6.3 mo (95%CI[5.2-7.1]) with REGIRI vs 8.2 mo (95%CI[5.2-9.7]) with IRI (HR=1.11 CI95%[0.70-1.74], p=0.66). Median PFS was 2.2 mo vs 1.9 mo (NS) with REGIRI and IRI, respectively. Objective response rate was 15.9% and 13.3% respectively. Disease control rate was 45.5% and 33.3%. AEs grade ≥ 3 related to treatment were reported in 52.3% of pts in REGIRI arm vs 23.3% in IRI arm with 4 toxic deaths (diarrhea, sepsis and thromboembolic events) vs 1 (primary tumour perforation), respectively. The main severe toxicities were diarrhea: 18.2% vs 7% and febrile neutropenia: 8.2% vs 0%. Genotyping of cyclin D1 was performed on 72 pts: 19 presented A/A genotype, 38 A/G and 15 G/G. There were no differences in terms of OS according to genotyping. Conclusions: PRODIGE58/REGIRI trial was prematurely stopped after the interim analysis due to high toxicities reported in REGIRI arm with negative results on its primary endpoint. Further ancillary analysis are expected to identify toxicity risk factors and pts subgroups benefit with this combination. Clinical trial information: NCT03722108 .

Safety and Efficacy of OGT-Assisted Overlap Oesophagojejunostomy Versus the Traditional Overlap Method in Laparoscopic Total Gastrectomy for Gastric/Gastroesophageal Junction (G/GEJ) Tumours.

Overlap guiding tube (OGT)-assisted overlap oesophagojejunostomy (EJS), which was first designed and reported by our team, has shown feasibility. However, its safety and efficiency have not yet been compared with the conventional overlap approach. We retrospectively analysed the data of 155 gastric/gastroesophageal junction (G/GEJ) cancer patients who underwent laparoscopic total gastrectomy by conventional (conventional group, n = 83) or OGT-assisted (OGT group, n = 72) overlap methods at Nanfang Hospital. The anastomotic efficiency and surgical outcomes were compared between the two groups. The success rate of inserting an anvil fork into the oesophageal lumen at the first attempt in the OGT group was much higher than in the conventional group (86.7% vs. 97.2%, P = 0.019). Consistently, the duration of EJS (P < 0.001) in the OGT group was significantly shorter than that in the conventional group. Operatively, there was one case in which oesophageal pseudocanals developed; another case was converted to thoracoscopic surgery in the conventional group, but there were no such cases in the OGT group. In terms of postoperative recovery, the OGT group was superior to the conventional group. The incidence of postoperative complications (28.9% vs. 20.8%, P = 0.247) and the classification of complication severity (P = 0.450) were milder in the OGT group, although the difference was not statistically significant. Notably, the conventional group had four cases (4.8%) of oesophagojejunal anastomotic leakage (EJAL) and one case (1.2%) of anastomotic stenosis. In the OGT group, two patients (2.8%) developed EJAL, but none developed anastomotic stenosis or anastomotic bleeding. Neither group had any cases of unplanned secondary surgery or perioperative deaths. The OGT-assisted method reduced the surgical difficulty of overlap EJS with good safety. This study provides new perspectives for optimizing EJS.

ASO Visual Abstract: Safety and Efficacy of OGT-Assisted Overlap Oesophagojejunostomy Versus Traditional Overlap Method in Laparoscopic Total Gastrectomy for Gastric/Gastroesophageal Junction (G/GEJ) Tumours.

ASO Visual Abstract: Safety and Efficacy of OGT-Assisted Overlap Oesophagojejunostomy Versus Traditional Overlap Method in Laparoscopic Total Gastrectomy for Gastric/Gastroesophageal Junction (G/GEJ) Tumours.