Carcinoma Of Gastroesophageal Junction Research Articles

Fecal Microbiome Composition Correlates with Pathologic Complete Response in Patients with Operable Esophageal Cancer Treated with Combined Chemoradiotherapy and Immunotherapy

Background: Preclinical and clinical data indicate that chemoradiotherapy (CRT) in combination with checkpoint inhibitors may prime an anti-tumor immunological response in esophageal cancer. However, responses to neoadjuvant therapy can vary widely and the key biomarkers to determine response remain poorly understood. The fecal microbiome is a novel and potentially modifiable biomarker of immunotherapy response, and both fecal and tumor microbes have been found to associate with outcomes in esophageal cancer. Methods: Fecal and tumor samples were collected from patients with stage II–III resectable esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immune checkpoint inhibitors (ICIs) plus CRT prior to surgical resection. Microbiome profiles were analyzed by 16S rRNA amplicon sequencing and taxonomic data were integrated with fecal metabolite analysis to assess microbial function. Results: The fecal microbiome of patients with pathological complete response (PCR) grouped in distinct clusters compared to patients with residual viable tumor (RVT) by Bray–Curtis diversity metric. Integrated taxonomic and metabolomic analysis of fecal samples identified a sphingolipid and primary bile acid as enriched in the PCR, the levels of which correlated with several bacterial species: Roseburis inulinivorans, Ruminococcus callidus, and Fusicantenibacter saccharivorans. Analysis of the tumor microbiome profiles identified several bacterial genera previously associated with esophageal tumors, including Streptococcus and Veillonella. Conclusions: These results further characterize the fecal and tumor microbiome of patients with operable esophageal cancer and identify specific microbes and metabolites that may help elucidate how microbes contribute to tumor response with neoadjuvant CRT combined with ICI.

A Prospective Pilot Study of Pencil Beam Scanning Proton Radiation Therapy as a Component of Trimodality Therapy for Esophageal Cancer

PurposeTo evaluate the safety and efficacy of pencil beam scanning (PBS) proton radiotherapy (RT) in trimodality therapy for esophageal cancer. MethodsThis prospective pilot study was planned to accrue 30 patients with locally advanced esophageal or gastroesophageal junction (GEJ) carcinoma, medically suitable for chemoRT (CRT) followed by esophagectomy. PBS proton RT consisted of 25 fractions, 50 Gy to tumor + 1 cm and 45 Gy to a 3.5 cm mucosal expansion and regional lymph nodes. Chemotherapy was weekly carboplatin (AUC = 2) and paclitaxel (50 mg/m2). At 4-8 weeks after CRT, patients underwent restaging and potential esophagectomy. The primary endpoint was acute grade 3+ adverse events (AEs) attributed to CRT. Overall (OS) and progression-free survival (PFS) were assessed by Kaplan-Meier methodology; local-regional recurrence (LRR) and distant metastases (DM) rates were assessed by cumulative incidence methodology. The Functional Assessment of Cancer Therapy-Esophagus (FACT-E) assessed quality of life. ResultsThirty eligible patients enrolled June 2015-April 2017. Median age was 68 years. Histology was adenocarcinoma in 87% and location was distal esophagus/GEJ in 90%. Stage was T3-4 in 87% and N1-3 in 80%. All patients completed the planned RT dose. Acute grade 3+ AEs occurred in 30%, most commonly leukopenia and neutropenia. Acute grade 3+ non-hematologic AEs occurred in 3%. Esophagectomy was performed in 90% of patients (R0 in 93%). Pathologic complete response rate was 40%. Major post-operative complications (Clavien-Dindo score ≥ III) occurred in 34%. Postoperative mortality at 30 days was 3.7%. Median follow-up was 5.2 years. 5-year outcome estimates were OS 46%, PFS 39%, LRR 17%, and DM 40%. FACT-E scores (medians) were baseline (145), end of CRT (136, p=0.0002 vs. baseline), before esophagectomy (144), 12 months (146), and 24 months (157). ConclusionsPBS proton RT is feasible and safe as a component of trimodality therapy for esophageal cancer.

The role of determining HER2neu status in patients with gastric cancer.

e16067 Background: Over the past two decades, gastric cancer has continued to maintain a leading position in both incidence and mortality rates among all malignant neoplasms in the Republic of Kazakhstan. Recent data indicate that amplification or overexpression of the HER2 gene is detected in 7-34% of gastric cancer cases, significantly impacting treatment outcomes. Studying a specific group of patients with HER2 overexpression in gastric cancer is of great interest in clinical oncology. Research aim: To examine the long-term treatment outcomes in patients with gastric cancer depending on the status and level of HER-2 expression in real clinical practice. Methods: Analysis was conducted on 172 formalin-fixed paraffin-embedded samples of gastric adenocarcinoma and gastroesophageal junction carcinoma, subjected to immunohistochemical examination to determine HER2 protein expression. Patients' ages ranged from 18 to 85 years, with a mean age of 61.7 years; among them, 106 (61.6%) were male and 66 (38.4%) were female. Of the 172 patients, 64 (37.2%) had primary tumors located at the gastroesophageal junction, while 108 (62.8%) had tumors located in the body of the stomach. Based on differentiation grade, the majority were G3-100 (50%), G2-91 (45%), G1-9 (5%). HER2 testing was performed on the Ventana BenchMark Ultra platform using the HER2 (4B5) antibody. Results: HER2 overexpression was detected in 26 (15.1%) of the 172 patients. Patients with HER2 2+ non-amplified were 6 (3.5%), HER2 2+ amplified were 8 (4.6%), HER2 1+ was detected in 19 (11%) cases, and HER2 0 was found in 121 (80.9%) cases. Long-term results revealed statistically significant differences, notably the highest overall survival rate in patients with HER-2 overexpression compared to HER-2 low and absence of HER-2. The HER2 3 (+FISH/SISH) variant was significantly more prevalent in 84.6% compared to HER2 0 in 52%, and HER2 1 in 48%, p < 0.05. Comparison of Her2 status using the chi-square method in groups revealed probable differences concerning tumor localization, with a criterion value of 0.034; morphological form (criterion value = 5.83); and differentiation grade (criterion value = 10.05). Conclusions: These results underscore the importance of further HER2 research in gastric cancer and gastroesophageal junction carcinoma for the development of personalized therapeutic strategies.

Distinct tumor microbiome and metabolomic profiles to inform responses of patients with esophageal cancer to neoadjuvant chemoradiotherapy and immunotherapy.

4084 Background: Preclinical and clinical data indicate that neoadjuvant chemoradiotherapy (CRT) may prime an anti-tumor immunological response in esophageal cancer driven by intratumoral CD8+ T cells. However, responses to neoadjuvant therapy can vary widely across patients. The microbiome, a novel and potentially modifiable biomarker of immunotherapy response, may inform neoadjuvant response. Methods: Fecal and tumor samples were collected from patients with stage II-III resectable distal esophageal or gastroesophageal junction carcinoma treated with neoadjuvant immunotherapy followed by chemoradiotherapy (CRT) and immunotherapy (IO). Patients on arm A (n=15) received 2 cycles of induction with nivolumab plus 3 additional cycles with CRT. Patients on arm B (n=10) received nivolumab and relatlimab on a similar induction schedule, but concurrent IO and CRT resulted in immune related adverse events and a protocol amendment to CRT (NCT03044613). We examined fecal (n=19) and tumor (n=12) patient samples across both arms using 16S rRNA amplicon sequencing and high-resolution taxonomic assignment. Additionally, fecal samples were analyzed using an untargeted panel (General Metabolics) and pathway analysis was performed using Metaboanalyst (v6.0). Results: The fecal microbiome of patients with pathological complete response (pCR) grouped in distinct clusters compared to patients without pathological complete response (non-pCR) using Bray-Curtis (p < 0.001). Patients with >10% and <10% residual tumor grouped similarly but were significantly different from patients with 0% residual tumor (p < 0.001). On a linear discriminant axis, the top 10 abundant bacteria were significantly increased in pCR compared to non-pCR (p < 0.001). After FDR correction, six bacteria had significantly differing abundances. Bacteroides finegoldii, Paraprevotella clara, Ruminococcus callidus, and Roseburis inulinivorans were significantly enriched in pCR patients. Clostridiales and Bacteroides were significantly enriched in non-pCR patients. Fecal metabolomic analysis demonstrated six significant metabolites: in non-pCR, ropinirole, valine, phenylalanine, and isoleucine were enriched; in pCR, C16cer and D-urobilinogen were enriched (p < 0.05). Patients with improved neoadjuvant response had significantly higher abundances of Bacteroides and corresponding C16cer levels. Pathway analysis revealed significant involvement in aminoacyl-tRNA biosynthesis and sphingolipid metabolism. Conclusions: Patients with complete responses to combined CRT and IO for operable esophageal cancer had distinct fecal microbiome profiles as well as metabolomic pathways. These results may be useful to further characterize and predict patients who have improved responses to neoadjuvant therapy and serve as a basis for therapeutic intervention.

Perioperative Chemotherapy for Gastro-Esophageal or Gastric Cancer: Anthracyclin Triplets versus FLOT.

Background: The FLOT4-AIO trial (2019) showed improved survival with perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) compared to anthracyclin triplets in gastric cancer treatment. It is unclear whether these results extend to real-world scenarios in the Netherlands. This study aimed to compare outcomes of perioperative FLOT to anthracyclin triplets in a real-world Dutch gastric cancer population. Methods: Patients diagnosed with resectable (cT2-4a/cTxN0-3/NxM0) gastric or gastro-esophageal junction carcinoma between 2015-2021 who received neoadjuvant FLOT or anthracyclin triplets were selected from the Netherlands Cancer Registry. The primary outcome was overall survival (OS), analyzed through multivariable Cox regression. Secondary outcomes included pathological complete response (pCR), neoadjuvant chemotherapy cycle completion, surgical resection rates, and adjuvant therapy. Results: Adjusted OS showed no significant survival benefit (HR = 0.88, 95% CI 0.77-1.01, p = 0.07), even though the median OS was numerically improved by 8 months with FLOT compared to anthracyclin triplets (48.1 vs. 39.9 months, p = 0.16). FLOT patients were more likely to undergo diagnostic staging laparoscopies (74.2% vs. 44.1%, p < 0.001), had higher rates of completing neoadjuvant chemotherapy (OR = 1.35, 95% CI 1.09-1.68, p = 0.007), receiving adjuvant therapy (OR = 1.34, 95% CI 1.08-1.66, p = 0.08), and achieving pCR (OR = 1.52, 95% CI 1.05-2.20, p = 0.03). No significant differences were observed in (radical) resection rates. Conclusion(s): Real-world data showed no significant OS improvement for FLOT-treated patients compared to anthracyclin triplets, despite more staging laparoscopies. However, FLOT patients demonstrated higher rates of neoadjuvant therapy completion, proceeding to adjuvant therapy, and increased pCR rates. Therefore, we recommend the continued use of neoadjuvant FLOT therapy in the current clinical setting.

Evaluating Treatment Response in GEJ Adenocarcinoma: The Role of Pretherapeutic and Posttherapeutic Iodine Mapping.

Neoadjuvant therapy regimens have significantly improved the prognosis of GEJ (gastroesophageal junction) cancer; however, there are a significant percentage of patients who benefit from earlier resection or adapted therapy regimens, and the true response rate can only be determined histopathologically. Methods that allow preoperative assessment of response are lacking. The purpose of this retrospective study is to assess the potential of pretherapeutic and posttherapeutic spectral CT iodine density (IoD) in predicting histopathological response to neoadjuvant chemotherapy in patients diagnosed with adenocarcinoma of the GEJ. In this retrospective cohort study, a total of 62 patients with GEJ carcinoma were studied. Patients received a multiphasic CT scan at diagnosis and preoperatively. Iodine-density maps were generated based on spectral CT data. All tumors were histopathologically analyzed, and the tumor regression grade (TRG) according to Becker et al ( Cancer . 2003;98:1521-1530) was determined. Two experienced radiologists blindly placed 5 defined ROIs in the tumor region of highest density, and the maximum value was used for further analysis. Iodine density was normalized to the aortic iodine uptake. In addition, tumor response was assessed according to standard RECIST measurement. After assessing interrater reliability, the correlation of IoD values with treatment response and with histopathologic TRG was evaluated. The normalized ΔIoD (IoD at diagnosis - IoD after neoadjuvant treatment) and the normalized IoD after neoadjuvant treatment correlated significantly with the TRG. For the detection of responders and nonresponders, the receiver operating characteristic (ROC) curve for normalized ΔIoD yielded the highest area under the curve of 0.95 and achieved a sensitivity and specificity of 92.3% and 92.1%, respectively. Iodine density after neoadjuvant treatment achieved an area under the curve of 0.88 and a sensitivity and specificity of 86.8% and 84.6%, respectively (cutoff, 0.266). Iodine density at diagnosis and RECIST did not provide information to distinguish responders from nonresponders. Using the cutoff value for IoD after neoadjuvant treatment, a reliable classification of responders and nonresponders was achieved for both readers in a test set of 11 patients. Intraclass correlation coefficient revealed excellent interrater reliability (intraclass correlation coefficient, >0.9). Lastly, using the cutoff value for normalized ΔIoD as a definition for treatment response, a significantly longer survival of responders was shown. Changes in IoD after neoadjuvant treatment of GEJ cancer may be a potential surrogate for therapy response.

Real-world (RW) effectiveness of nivolumab plus chemotherapy (NIVO+chemo) in patients (pts) with advanced or metastatic gastric carcinoma, gastroesophageal junction carcinoma, or esophageal adenocarcinoma (GC/GEJC/EAC).

295 Background: In the CheckMate 649 trial, NIVO+chemo demonstrated superior efficacy vs chemo alone in pts with previously untreated, advanced, non-human epidermal growth factor receptor 2 positive GC/GEJC/EAC. Our study was the first to evaluate the RW adoption patterns and effectiveness of NIVO+chemo as a first-line (1L) treatment of advanced GC/GEJC/EAC in the immediate period after NIVO approval in this setting. We report the 18-mo follow-up results. Methods: Pts in the United States ≥ 18 years of age with previously untreated advanced or metastatic GC/GEJC/EAC receiving NIVO+chemo or chemo alone (FOLFOX or CAPEOX) between 04/01/2021 and 12/31/2022 were identified in the Flatiron Health database. Pts were followed from the start of 1L therapy to death, loss of data availability, or the end of data abstraction, whichever occurred first. Results: 528 pts were eligible for the analysis (231 [44%] NIVO+chemo, 297 [56%] chemo). The prevalence of PD-L1 combined positive score (CPS) ≥ 5 before the 1L therapy was 55% for NIVO+chemo and 27% for chemo. Baseline demographic and clinical characteristics were comparable between treatment groups in the overall cohort and the CPS subgroups. Median follow-up (interquartile range) was 6.0 (2.4−9.8) mo for NIVO+chemo and 6.1 (2.5−9.7) mo for chemo. There were 87 (37.7%) deaths in the NIVO+chemo cohort and 138 (46.5%) in the chemo cohort. NIVO+chemo demonstrated superior overall survival (OS) in the overall cohort, with a 12-mo OS rate of 53.3% vs 38.1% for chemo and a 2.6-mo improvement in median OS (12.6 [95% confidence interval (CI), 10.2−17.9] mo vs 10.0 [8.9−11.5] mo, P = 0.047). Univariate Cox regression analysis of OS yielded a hazard ratio (HR) of 0.76 (95% CI, 0.58−1.00; P = 0.048) and multivariate Cox regression yielded an HR of 0.74 (95% CI, 0.56−0.98; P = 0.033) for NIVO+chemo vs chemo. There was also a consistent trend toward OS benefit with NIVO+chemo vs chemo in all CPS subgroups (Table). Multivariate analysis in the CPS ≥ 1 subgroup yielded a HR of 0.51 (95% CI, 0.30−0.89) for NIVO+chemo vs chemo but was not feasible in other subgroups due to sample size. Conclusions: NIVO+chemo showed superior OS vs chemo alone in previously untreated pts with advanced GC/GEJC/EAC in the RW setting. A trend toward OS benefit was also observed in all CPS subgroups, which will be further examined in future analyses with larger samples and longer follow-up. Clinical trial information: NCT02872116 . [Table: see text]

Gastroesophageal junction cancer - current topic and treatment dilemmas

Treatment of gastroesophageal junction carcinomas have been debated for many years. This type of carcinomas has been classified as either gastric or esophageal carcinomas until Siewert's classification was established and they were defined as a distinct entity. Risk factors for development of these cancers are gastroesophageal reflux and Barrett's esophagus, obesity, Helycobacter pylori infection, smoking, and alcohol. Symptoms of this disease include retrosternal pain, dysphagia to aphagia and weight loss. Esophagogastroduodenoscopy with biopsy and pathohistological verification as well as CT of the chest and abdomen are crucial in establishing the diagnosis. Adenocarcinoma is predominant histological type of these tumors. The stage of the disease is defined by the TNM classification. Treatment of gastroesophageal junction cancer is complex, multidisciplinary and multi-modal, and involves the use of surgery, chemotherapy and radiotherapy, alone or in different combinations. Surgery is the major treatment modality for these tumors, especially in local stages. Radiotherapy is used in the treatment of these tumors in all stages of the disease, and especially in the multimodal treatment of locally advanced gastroesophageal junction cancer, both preoperatively and postoperatively, usually in combination with chemotherapy. Chemotherapy is used in the treatment of these cancers as preoperative, postoperative and systemic. Immunotherapy and target therapy, as new promising therapy is usually applied in a systemic and postoperative approach. Future directions in the treatment of these cancers are directed towards new surgical procedures, new types of immunotherapy, as well as new radiotherapy techniques.

Multimodal Therapy Versus Primary Surgery for Gastric and Gastroesophageal Junction Diffuse Type Carcinoma, with a Focus on Signet Ring Cell Carcinoma: A Nationwide Study.

Diffuse type adenocarcinoma and, more specifically, signet ring cell carcinoma (SRCC) of the stomach and gastroesophageal junction (GEJ) have a poor prognosis and the value of neoadjuvant chemo(radio)therapy (nCRT) is unclear. All patients who underwent surgery for diffuse type gastric and GEJ carcinoma between 2004 and 2015 were retrospectively included from the Netherlands Cancer Registry. The primary outcome was overall survival after surgery. Kaplan-Meier curves were plotted. Furthermore, multivariable Poisson and Cox regressions were performed, correcting for confounders. To comply with the Cox regression proportional hazard assumption, gastric cancer survival was split into two groups, i.e. <90 days and >90 days, postoperatively by adding an interaction variable. Analyses included 2046 patients with diffuse type cancer: 1728 gastric cancers (50% SRCC) and 318 GEJ cancers (39% SRCC). In the gastric cancer group, 49% received neoadjuvant chemotherapy (nCT) and 51% received primary surgery (PS). All-cause mortality within 90 days postoperatively was lower after nCT (hazard ratio [HR] 0.29, 95% confidence interval [CI] 0.20-0.44; p<0.001). Also after 90 days, mortality was lower in the nCT group (HR for the interaction variable 2.84, 95% CI 1.87-4.30, p<0.001; total HR 0.29*2.84=0.84). In the GEJ group, 38% received nCT, 22% received nCRT, and 39% received PS. All-cause mortality was lower after nCT (HR 0.63, 95% CI 0.43-0.93; p=0.020) compared with PS. The nCRT group was removed from the Cox regression analysis since the Kaplan-Meier curves of nCRT and PS intersected. The results for gastric and GEJ carcinomas were similar between the SRCC and non-SRCC subgroups. For gastric and GEJ diffuse type cancer, including SRCC, nCT was associated with increased survival.

Early Outcomes from Proton Craniospinal Irradiation (pCSI) for Leptomeningeal Disease from Solid Tumors

Prospective data suggest that proton craniospinal irradiation (pCSI) improves overall survival (OS) in patients with leptomeningeal disease (LMD) from solid tumors, compared to the historical standard of involved field radiation. To evaluate outcomes of this novel approach in a real-world setting, our institutional experience with treating adults with pCSI for LMD from solid malignancies was evaluated. On an IRB-approved protocol, medical records of adults with LMD from solid tumors treated with pCSI were retrospectively reviewed for patient, disease and treatment characteristics and outcomes. CNS-PFS and OS were calculated from the last day of pCSI, and survival was modeled using Kaplan-Meier analysis. From December 2021 to November 2022, 17 patients with median age 51y (range 22-71y) were treated with pCSI for LMD from solid tumors. Thirteen patients (76%) were female. Ten had ECOG PS of 0-1, and seven had PS 2-3. Nine patients (53%) had breast cancer, 3 (18%) had non-small cell lung cancer (NSCLC), 2 (12%) had melanoma, 1 (6%) had colorectal adenocarcinoma, 1 (6%) had endocervical adenocarcinoma, and 1 (6%) had two synchronous primaries (adenocarcinoma of the gastro-esophageal junction and neuroendocrine carcinoma of the lung). All patients had prior radiation; ten had prior radiation to the brain, one had prior radiation to the spine, and six had other sites previously radiated. Fourteen patients (82%) were treated to 30 Gy in 10 fractions and 3 (18%) were treated to 25 Gy in 10 fractions due to overlap with prior radiation fields. Median follow-up was 4 months (range, 1-13 months). Among 15 evaluable patients, median CNS-PFS and median OS were 3.6 months and 4.7 months, respectively. For patients with breast cancer or NSCLC, 62% were alive at 6 months; median OS has not been reached. Treatment was well tolerated with no grade 3-4 non-hematologic adverse events. pCSI is a novel method for treatment of LMD from solid tumors that has been rapidly adopted. Based on our preliminary review, it is safe and well-tolerated; patient selection is critical. As these patients are often heavily pretreated, prior radiation fields must be considered in pCSI planning.

Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in locally advanced gastroesophageal junction and gastric carcinoma.

Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post-therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC). Besides, we aimed at making clear the association of different neoadjuvant regimens with different TRG and ypN status. 376 patients with GEJ or GC accepting NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1-3N0, TRG0-1N+, and TRG2-3N+. We applied Kaplan-Meier method and log-rank test to testify the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to examine the relationships between TRG combined with ypN status and prognosis. We observed significant survival differences among the four groups (p < 0.001, respectively). Median DFS and OS of patients with TRG0N0, TRG1-3N0, and TRG0-1N+ were not reached, whereas these of patients with TRG2-3N+ were 17.37 months (95% CI, 14.14-20.60 months) and 39.97 months (95% CI, 27.05-52.89 months). TRG combined with ypN status was still an independent predictor for both DFS (p < 0.001) and OS (p < 0.001) in multivariate analysis. Chi-squared test showed TRG combined with ypN status was significantly associated with different preoperative treatments (p < 0.001). Patients receiving immunotherapy achieved the highest TRG0N0 rate (31.9%). Our results demonstrate that TRG combined with ypN status is a novel independent predictor of both DFS and OS in resectable, locally advanced GEJ and GC. Neoadjuvant immunotherapy achieved the highest TRG0N0 rate.

Emerging insights into mechanisms of trastuzumab resistance in HER2-positive cancers.

HER2 is an established therapeutic target in breast, gastric, and gastroesophageal junction carcinomas with HER2 overexpression or genomic alterations. The humanized monoclonal antibody trastuzumab targeting HER2 has substantially improved the clinical outcomes of HER2-positive patients, yet the inevitable intrinsic or acquired resistance to trastuzumab limits its clinical benefit, necessitating the elucidation of resistance mechanisms to develop alternate therapeutic strategies. This review presents an overview of trastuzumab resistance mechanisms involving signaling pathways, cellular metabolism, cell plasticity, and tumor microenvironment, particularly discussing the prospects of developing rational combinations to improve patient outcomes.

270. PERIOPERATIVE CHEMOTHERAPY FOR OPERABLE GASTRO-ESOPHAGEAL JUNCTION OR GASTRIC CANCER: FLOT VERSUS ANTHRACYCLINE TRIPLETS

Abstract Background Since the FLOT4-AIO study (2019) showed improved survival in patients treated with neoadjuvant fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) compared to those treated with neoadjuvant anthracycline triplets, FLOT became standard of care in the Netherlands and most Western countries. The aim of this study was to compare the overall survival (OS), pathological response and surgical outcomes of FLOT chemotherapy to anthracycline triplets in the Netherlands, using real-world population level data. Methods Patients diagnosed with resectable (cT2-4a/cTxN0–3/NxM0) gastro-esophageal junction and gastric carcinoma between 2015–2020 were selected from the Netherlands’ Cancer Registry. Patients were included if they received neoadjuvant FLOT or anthracycline triplets whether this was followed by resection or not. OS was calculated from start of neoadjuvant therapy, analyzed using cox regression analysis and adjusted for sex, age, comorbidities, performance status, cT-stage/cN-stage and tumor grade. Secondary outcomes included the pathological complete response (pCR), proportion of patients that fully completed neoadjuvant chemotherapy (100% of scheduled cycles permitting dose reductions), proportion of patients that underwent (radical) surgical resection and proportion receiving adjuvant therapy. Results 778 included patients were treated with FLOT and 913 with anthracycline triplets. Patients treated with FLOT underwent more staging diagnostic laparoscopies (DLS) (73.5% vs. 44.1%, p &amp;lt; 0.0001). Adjusted OS was better after neoadjuvant FLOT (HR = 0.84, 95% CI 0.72–0.98, p = 0.03). 3-year and 5-year OS were 56.4% and 46.6% after FLOT and 52.7% and 45.5% after anthracycline triplets, respectively. A higher proportion of patients treated with FLOT fully completed neoadjuvant chemotherapy (78.5% vs. 73.1%, p = 0.009) and had R0 resections (86.2% vs. 85.2%, p = 0.007). No statistically significant differences were seen in the proportions of patients that underwent resection, received adjuvant therapy, or had pCR. Conclusion Real-world population level data showed better OS of patients treated with FLOT chemotherapy compared to anthracycline triplets. No statistically significant difference was observed in pCR or resection rates. Thus, not every outcome as described in the FLOT4-AIO trial could be reproduced in a real-world population, despite improved staging with DLS in the FLOT group. Divergent baseline characteristics and less intensive neoadjuvant treatments in real-world patients compared to patients in clinical trials may contribute to this discrepancy.

Relevance of Subcarinal Lymph Node Dissection for Gastroesophageal Junction Adenocarcinoma

IntroductionReported rates of subcarinal lymph node (LN) metastases for esophageal carcinoma vary from 20% to 25% and the relevance of subcarinal lymph node dissection (LND) for gastroesophageal junction (GEJ) adenocarcinoma is poorly defined. This study aimed to evaluate rates of subcarinal LN metastasis in GEJ carcinoma and determine their prognostic significance. MethodsPatients with GEJ adenocarcinoma undergoing robotic minimally invasive esophagectomy from 2019 to 2021 were retrospectively assessed within a prospectively maintained database. Baseline characteristics and outcomes were examined with attention to subcarinal LND and LN metastases. ResultsAmong 53 consecutive patients, the median age was 62, 83.0% were male, and all had Siewert type I/II tumors (49.1% and 50.9%, respectively). Most patients (79.2%) received neoadjuvant therapy. Three patients had subcarinal LN metastases (5.7%) and all had Siewert type I tumors. Two had clinical evidence of LN metastases preoperatively and all three additionally had non-subcarinal nodal disease. A greater proportion of patients with subcarinal LN disease had more advanced (T3) tumors compared to patients without subcarinal metastases (100.0% versus 26.0%; P = 0.025). No patient with subcarinal nodal metastases remained disease free at 3 y after surgery. ConclusionsIn this consecutive series of patients with GEJ adenocarcinoma undergoing minimally invasive esophagectomy, subcarinal LN metastases were found only in patients with type I tumors and were noted in just 5.7% of patients, which is lower than historical controls. Subcarinal nodal disease was associated with more advanced primary tumors. Further study is warranted to determine the relevance of routine subcarinal LND, especially for type 2 tumors.

Abstract 6748: Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in resectable, locally advanced gastroesophageal junction and gastric carcinoma

Abstract Background: Tumor regression grade (TRG) is a measure of histopathological response to neoadjuvant therapy (NAT). Post-therapy lymph node (ypN) metastasis was reported as a prognostic factor. However, the evaluation of the treatment effectiveness of NAT has not been well studied. Here, we explored whether TRG combined with ypN status could be a prognostic factor for gastroesophageal junction (GEJ) and gastric cancer (GC). Methods: 376 patients with GEJ or GC receiving NAT in Peking University Cancer Hospital were retrospectively collected from January 1, 2003 to June 30, 2021. According to TRG and ypN status, patients were innovatively categorized into four groups: TRG0N0, TRG1-3N0, TRG0-1N+, and TRG2-3N+. We applied Kaplan-Meier method and log-rank test to examine the differences in disease free survival (DFS) and overall survival (OS) among four groups. Univariate and multivariate analyses were performed to elucidate the relationships between TRG combined with ypN status and prognosis. Results: We observed significant survival differences among the four groups (P &amp;lt; 0.001, respectively). Median DFS and OS of patients with TRG0N0, TRG1-3N0 and TRG0-1N+ were not reached, whereas median DFS and OS of patients with TRG2-3N+ were 17.37 months (95%CI, 14.14 to 20.60 months) and 39.97 months (95%CI, 27.05 to 52.89 months). TRG combined with ypN status was an independent predictor for both DFS (P &amp;lt; 0.001) and OS (P &amp;lt; 0.001) in multivariate analysis. Additionally, TRG combined with ypN status was significantly associated with different NAT (P &amp;lt; 0.001). The TRG0N0 rate in patients accepting immunotherapy was 31.9%, which was the highest in all regimens. Conclusion: Our results demonstrate that TRG combined with ypN status is a novel independent predictor of both DFS and OS in resectable, locally advanced GEJ and GC. Neoadjuvant immunotherapy achieved the highest TRG0N0 rate. Citation Format: Hongyan Yin, Qian Yao, Keren Jia, Dongfeng Niu, Xiaoyi Chong, Yanyan Li, Xujiao Feng, Yilin Li, Lin Shen, Yang Chen. Tumor regression grade combined with post-therapy lymph node status: A novel independent prognostic factor for patients treated with neoadjuvant therapy followed by surgery in resectable, locally advanced gastroesophageal junction and gastric carcinoma [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 6748.

Perioperative penpulimab plus anlotinib combined with chemotherapy for locally advanced gastric cancer: A single arm, multicenter, phase II clinical trial.

TPS485 Background: Perioperative therapy, especially whether preoperative neoadjuvant therapy (NAT) can improve R0 resection rate and prolong overall survival of patients with locally advanced gastric cancer, has been paid more and more attention. NAT is mainly defined as a preoperative chemotherapy or chemoradiotherapy, aiming at increasing radical resection rate by downstaging tumor and eliminating micrometastases. Anlotinib is an oral multi-targeted tyrosine kinase inhibitor targeting VEGFR1/2/3, FGFR1-4 and PDGFRα/β, which effectively blocks tumor neovascularization and growth. Previous phase I/II clinical trials suggested that penpulimab monotherapy as second-line therapy was well tolerated and showed clinical anti-tumor activity in gastric or gastroesophageal junction carcinoma (GC/GEJ) (NCT03352531, NCT04172506). It was demonstrated an objective response rate (ORR) of 26.3%, a disease control rate (DCR) of 42.1% in GC/GEJ patients (pts) using penpulimab monotherapy. This trial was designed to assess the feasibility and efficacy of penpulimab plus anlotinib combined with chemotherapy in perioperative treatment of pts with locally advanced gastric cancer. Methods: This is a multi-center, prospective, single-arm, phase II study. Resectable GC pts with TNM stage T3~4N+M0 per AJCC8th, ECOG PS 0-1, were enrolled and treated with 3 cycles of preoperative penpulimab (200mg, iv, d1, q3w) + anlotinib (12mg, qd, d1-d14, q3w)+ SOX (oxaliplatin 130mg/m2, iv, d1 and S-1 40-60mg, po, bid, d1-14, q3w), and 12 months of postoperative adjuvant therapy formulated by investigators according to the individual situation of the pts. Primary endpoint was pathological complete response (pCR) rate. Secondary endpoints included major pathologic response (MPR) rate, disease free survival (DFS), objective response rate (ORR), R0 resection rate and safety. Based on a two-sided test for one proportion with 5.0% type I error, 80% power to detect an improvement in the rate of pCR from 13% to 29%, there will be 57 pts enrolled considering 10% of pts dropping out. Clinical trial information: NCT05385900 .

Pre-diagnostic delay among patients with curative esophageal and gastric cancer during the COVID-19 pandemic.

302 Background: The majority of esophageal and gastric cancers are diagnosed at an advanced stage with poor overall survival (OS), leading some to propose screening, even in countries with a low incidence. Whether diagnostic delay from symptom onset has any impact on OS is unclear. We investigated this question in the peri-COVID19 pandemic era. Methods: We retrospectively analyzed a cohort of 308 patients with esophageal, gastroesophageal junction, or gastric carcinoma treated with curative intent at the Princess Margaret Cancer Centre from January 2017 to December 2021. Clinical details pertaining to the initial presentation were determined through a retrospective chart review. OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to assess the association between pre-diagnostic interval with OS adjusting for baseline patient characteristics. Results: The median interval from symptom onset to diagnosis was 98 days (IQR 47-169 days). Using a cox proportional hazard model, prolonged pre-diagnostic interval was not associated with worse OS (HR 1.00, P=0.62). Comparing patients diagnosed before and during the COVID19 pandemic, there was a notable increase in diagnostic delay with median pre-diagnostic interval increasing from 92 to 126 days (P=0.007). Median age at time of diagnosis was 69.6 during the pandemic vs 64.7 before the pandemic. Linear regression showed squamous cell histology was significantly associated with increasing time to initial diagnosis (P=0.04). Looking at other delay metrics, there were no changes in time interval from diagnosis to treatment during versus before the pandemic (median = 1.7 weeks for both), and there was no change in time from diagnosis to resection in those patients who underwent surgery. Conclusions: The COVID19 pandemic caused significant diagnostic delay for patients presenting with curative esophageal and gastric cancer. We found no evidence of pandemic-related health system delays in treatment, once a diagnosis was made. The lack of correlation of pre-diagnostic interval with OS may reflect underlying tumour biology as the driving force that determines prognosis.

Chemoradiotherapy with concurrent durvalumab for the palliative treatment of oligometastatic oesophageal and gastrooesophageal carcinoma with dysphagia: a single arm phase II clinical trial (PALEO, sponsored by the Australasian Gastro-Intestinal Trials Group)

BackgroundOesophageal and gastrooesophageal junction (GOJ) carcinoma frequently present with dysphagia and de novo metastatic disease. There is scope to improve treatment paradigms to both address symptoms and improve survival. One method is integrating immune checkpoint inhibition with novel treatment combinations.MethodsPALEO is a single arm, phase II clinical trial in patients with previously untreated, oligometastatic or locoregionally advanced oesophageal or GOJ carcinoma and dysphagia. PALEO is sponsored by the Australasian Gastro-Intestinal Trials Group (AGITG). Participants receive 2 weeks of therapy with concurrent hypofractionated radiotherapy of 30Gy in 10 fractions to the primary tumour, weekly carboplatin AUC2, weekly paclitaxel 50 mg/m2 and durvalumab 1500 mg q4 weekly, followed by durvalumab monotherapy continuing at 1500 mg q4weekly until disease progression, unacceptable toxicity or 24 months of therapy. A single metastasis is treated with stereotactic radiotherapy of 24Gy in 3 fractions in week 7. The trial primary endpoint is the progression free survival rate at 6 months. Secondary endpoints include duration of dysphagia relief, nutritional status change, quality of life, response rate, toxicity, progression free survival and overall survival. The tertiary endpoint is prediction of outcome based on biomarkers identified from patient serial blood samples collected pre- and post-radiotherapy.DiscussionThis unique investigator-initiated clinical trial is designed to simultaneously address the clinically relevant problems of dysphagia and distant disease control. The overarching aims are to improve patient nutrition, quality of life and survival with low toxicity therapy. AGITG PALEO is a multidisciplinary collaboration and will add to the understanding of the relationship between radiotherapy and the anti-tumour immune response.Trial registrationAustralian and New Zealand Clinical Trials Registry: ACTRN12619001371189, registered 8 October 2019.

Efficacy and safety of neoadjuvant immunotherapy in resectable esophageal or gastroesophageal junction carcinoma: A pooled analysis of prospective clinical trials.

Neoadjuvant chemoradiotherapy (NCRT) plus radical esophagectomy is currently the standard treatment for resectable esophageal or gastroesophageal junction (GEJ) carcinoma. The aim of this study is to evaluate the efficacy and safety of neoadjuvant immunotherapy in resectable esophageal or GEJ carcinoma. Prospective clinical trials investigating efficacy and/or safety of neoadjuvant immunotherapy with immune checkpoint inhibitors (ICIs) followed by radical esophagectomy in patients with newly diagnosed resectable esophageal or GEJ carcinoma were identified through literature search. Quality assessment was performed by using the Newcastle-Ottawa scale. Preliminary treatment outcomes of pathologically complete response (pCR, ypT0N0) and grade 3-4 adverse effects (AEs) were pooled together and then compared with standard NCRT of the historical control CROSS study by Chi-square (χ2) test. A two-sided P value < 0.05 was considered statistically significant. A total of 17 eligible non-randomized trials with 455 participants were included into analysis. The most common primary endpoint was pCR (n = 7, 41%), and the median sample size and follow-up period was 23 patients and 7.9 months, respectively. For patients receiving neoadjuvant immunotherapy, the overall pCR, R0 resection, and grade 3-4AE rates were 33.2%, 95.5%, and 35.1%, respectively. For esophageal squamous cell carcinoma (ESCC) and adenocarcinoma (EAC), neoadjuvant immunochemoradiotherapy showed no significant improvement in pCR rate than NCRT (ESCC, 50% vs 48.7%, P = 0.9; EAC, 32.6% vs 23.1%, P = 0.22). Grade 3-4 AEs were the most common in patients with neoadjuvant immunochemoradiotherapy, significantly higher than immunochemotherapy (46.7% vs 32.8%, P = 0.04) and NCRT (46.7% vs 18.1%, P < 0.0001). In conclusion, for patients with resectable esophageal or GEJ carcinoma, the addition of ICIs to standard NCRT could not improve pCR rate in both ESCC and EAC, but significantly increased the risk of severe AEs. Large-scale phase 3 randomized trials were urgently needed to further confirm the survival benefit and safety profile of neoadjuvant immunotherapy.

Factors associated with pathologic complete response following neoadjuvant chemoradiation and esophagectomy for carcinoma of esophagus and gastroesophageal junction.

The aim of this study was to analyze factors associated with pathologic complete response (pCR) following neoadjuvant chemoradiation (NCRT) and esophagectomy for carcinoma of the esophagus (EC) and gastroesophageal junction (GEJ). Patients with EC and GEJ tumors who received NCRT and underwent esophagectomy between January 2010 to March 2021 were included. Univariate and multivariate analyses were performed to evaluate the factors associated with pCR by comparing the patients who achieved pCR (pCR group) with those who did not achieve pCR (non-pCR group). A total of 321 patients were included in the study, with squamous cell carcinoma (SCC) accounting for the majority of cases (76%). One hundred and sixty (49.8%) patients had pCR. SCC histology and pretreatment radiographic node-negative status (cN0) were associated with pCR. Patients in the pCR group had significantly better overall and disease-free survival compared with patients in the non-pCR group. SCC histology and pretreatment radiographic node-negative status were associated with pCR. For patients with tumors of EC and GEJ who received NCRT and underwent esophagectomy, pCR was associated with improved prognosis compared with those not achieving pCR.