State of the art and upcoming trends in claudin-directed therapies in gastrointestinal malignancies.

PURPOSE OF REVIEW: Claudins, components of tight cell junctions in epithelial and endothelial cells, have emerged as a therapeutic target in gastrointestinal (GI) malignancies, particularly claudin 18.2 (CLDN18.2). RECENT FINDINGS: Zolbetuximab, a chimeric anti-CLDN18.2 monoclonal antibody (mAb), is currently under FDA review and may emerge as the first claudin targeted therapy approved. Phase 3 trials show that zolbetuximab in combination with front-line fluoropyrimidine plus oxaliplatin improves survival in advanced CLDN18.2 positive (≥75% of tumor cells) gastric adenocarcinoma (GAC) patients. Many other therapies (mAbs; CART; bispecific; ADCs) are under investigation. SUMMARY: CLDN18.2 will be an important target in GAC. Early understanding of how to target CLDN18.2 based on the level of expression (high, moderate, low) will be the key to success in this area. Studying these as separate entities should be considered. Resistance patterns, loss of CLDN18.2 expression, role in the refractory setting, and if any role in localized disease are questions that remain. Other targets for claudin that target claudin six and four are under investigation. Their role in GI malignancies will soon be further clarified.

SMARCA4 Mutations in Gastroesophageal Adenocarcinoma: An Observational Study via a Next-Generation Sequencing Panel.

BACKGROUND: The clinical impact of SMARCA4 mutations (SMARCA4ms) in gastroesophageal adenocarcinoma (GEA) remains underexplored. This study aimed to examine the association of SMARCA4ms with clinical outcomes and co-occurrence with other gene mutations identified through a next-generation sequencing (NGS) panel in GEA patients. METHODS: A total of 256 patients with metastatic or recurrent GEA who underwent NGS panel profiling at the MD Anderson Cancer Center between 2016 and 2022 were included. Comparative analyses were performed to assess clinical outcomes related to SMARCA4ms. The frequency and types of SMARCA4ms and their co-occurrence with other gene mutations were also examined. RESULTS: SMARCA4ms were identified in 19 patients (7.4%). These SMARCA4ms were significantly associated with non-signet ring cell subtype (p = 0.044) and PD-L1 positive expression (p = 0.046). No difference in survival between the SMARCA4m and SMARCA4-normal group was observed (p = 0.84). There were significant associations between SMARCA4ms and FANCA, IGF1R, KRAS, FANCL, and PTEN alterations. Notably, 15 of the 19 SMARCA4m cases involved SNV missense mutations, with frequent co-occurrences noted with TP53, KRAS, ARID1A, and ERBB2 mutations. CONCLUSIONS: These results serve as the first comprehensive examination of the relationship between SMARCA4ms and clinical outcomes in GEA.

Chemotherapy Plus Atezolizumab Pre- and Post-Resection in Localized Esophageal or Gastroesophageal Junction Adenocarcinomas: A Phase I/II Single-Arm Study.

Efforts to improve the prognosis for patients with locally advanced esophageal or gastroesophageal junction (GEJ) adenocarcinoma have focused on neoadjuvant approaches to increase the pathological complete response (pathCR) rate, improve surgical resection, and prolong event-free and overall survival (OS). Building on the recent evidence that PD-1 inhibition plus chemotherapy improves the OS of patients with metastatic GEJ adenocarcinoma, we evaluated whether the application of this strategy in the neoadjuvant setting would improve the pathological response. This single-center phase I/II trial evaluated the safety, toxicity, and efficacy of neoadjuvant atezolizumab with oxaliplatin and 5-fluorouracil (modified FOLFOX) followed by esophagectomy followed by atezolizumab. The primary objective goal was to achieve 20% pathCR. From the twenty enrolled patients, eighteen underwent resection and two (10%, 95% CI: 1.24-31.7%) achieved pathCR. After a median follow-up duration of 40.7 months, 11 patients had disease recurrence and 10 had died. The median disease-free and OS were 28.8 (95% CI: 14.7, NA) and 38.6 months (95% CI: 30.5, NA), respectively. No treatment-related adverse events led to death. Although modified FOLFOX plus atezolizumab did not achieve the expected pathCR, an acceptable safety profile was observed. Our results support the continued development of a more refined strategy (neoadjuvant chemotherapy plus perioperative immunotherapy/targeted agents) with molecular/immune profiling in parallel.

Direct Clinical Pharmacist-Patient Telephone Follow-Up: A Focus on GI Medical Oncology Symptom Management.

PURPOSE: GI medical oncology care presents unique medication challenges. Here, we captured our clinical pharmacy specialists' (CPSs) involvement in patients with GI cancers starting cycle 1 of a new treatment. METHODS: Our quality initiative was performed in three stages (preintervention, intervention, and postintervention). Preintervention: retrospective baseline data collection from May to December 2019. Intervention: one-time telephone encounters were conducted by a CPS between March 15 and June 11, 2021. The primary objective of the quality improvement initiative was to increase patient interaction with a CPS to 80%. Postintervention: data collection to review the impact of CPS telephone encounters. RESULTS: Preintervention: we reviewed the electronic health records of 262 patients. Sixty nine percent of patients reported at least one adverse event (AE; range 1-6 AEs) at the first physician follow-up after treatment start. Most reported AEs (78%) were considered modifiable within the scope of CPS practice. Postintervention: during the intervention, 92% of patients (n = 389) received a telehealth encounter with the CPS. At the encounter, 315 patients (81%) reported at least one AE. CPS provided recommendations and/or additional education for 88% of reported AEs. Medication lists required correction 75% of the time. The median time for CPS encounters (including documentation) was 40 minutes. CONCLUSION: During a 3-month period, this quality improvement initiative successfully provided an early CPS-based telehealth intervention to identify and make initial recommendations for management of AEs for patients on cycle 1 of systemic therapy for GI cancer.

Evidence to Date on the Therapeutic Potential of Zolbetuximab in Advanced Gastroesophageal Adenocarcinoma.

Gastric adenocarcinoma (GAC) continues to be a prevalent worldwide malignancy and a leading cause of cancer death, and it is frequently cited as incurable. Targeted therapy in GAC has lagged behind other solid tumors. The human epidermal growth factor receptor-2 (HER-2) represented the single target in GACs for many years, seen in approximately 20% of patients with advanced GAC. Recent advances in management now include the addition of immunotherapy checkpoint inhibition to select front-line advanced GACs. Unfortunately, outcomes remain poor for most patients. We anticipate finding a key to future discoveries in GACs in next-generation sequencing and more targeted approaches. Claudin 18.2 (CLDN18.2) has emerged as a therapeutic target in GACs. CLDN18.2 is reportedly expressed in 14-87% of GACs, and CLDN18.2 is available for monoclonal antibody (mAb) binding as it is expressed on the outer cell membrane. Here, we review the exploration of CLDN18.2 as a target in GACs via the use of zolbetuximab (IMAB362). Zolbetuximab is now under priority FDA review for GACs, and we eagerly await the review outcome.

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target.

Human epidermal growth factor receptor-2 (HER2) is a well-known cancer target. Many HER2-targeted agents are marketed and being investigated. Unfortunately, these therapies lack consistent responses and outcomes amongst different tumors. Questions remain as to why HER2 biology is different in different tumor types. Gastric adenocarcinomas (GACs) demonstrate both intra- and inter-tumor HER2 expression heterogeneity and show discordance amongst primary and metastatic disease sites. This creates barriers in determining HER2 agents' effectiveness and contributes to the failure of some HER2-targeted agents in the treatment of HER2-positive advanced GACs. Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients. There are exciting and newer therapies under investigation. Examining resistance patterns (both adaptive and acquired) along with establishing a better understanding of the intra- and inter-tumor heterogeneity is necessary to ensure successful progress. Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.

Postpartum haemorrhage occurring in UK midwifery units: A national population-based case-control study to investigate incidence, risk factors and outcomes.

OBJECTIVES: To estimate the incidence of, and investigate risk factors for, postpartum haemorrhage (PPH) requiring transfer to obstetric care following birth in midwifery units (MU) in the UK; to describe outcomes for women who experience PPH requiring transfer to obstetric care. METHODS: We conducted a national population-based case-control study in all MUs in the UK using the UK Midwifery Study System (UKMidSS). Between September 2019 and February 2020, 1501 women with PPH requiring transfer to obstetric care following birth in an MU, and 1475 control women were identified. We used multivariable logistic regression, generating adjusted odds ratios (aORs) and 95% confidence intervals (CIs) to investigate risk factors for PPH requiring transfer to obstetric care. RESULTS: The incidence of PPH requiring transfer to obstetric care following birth in an MU was 3.7% (95% CI 3.6%-3.9%). Factors independently associated with PPH requiring transfer to obstetric care were smoking during pregnancy (aOR = 0.73; 95% CI 0.56-0.94), nulliparity (aOR = 1.96; 95% CI 1.66-2.30), previous PPH (aOR = 2.67; 95% CI 1.67-4.25), complications in a previous pregnancy other than PPH (aOR = 2.40; 95% CI 1.25-4.60), gestational age ≥41 weeks (aOR = 1.36; 95% CI 1.10-1.69), instrumental birth (aOR = 2.69; 95% CI 1.53-4.72), third stage of labour ≥60 minutes (aOR = 5.56; 95% CI 3.93-7.88), perineal trauma (aOR = 4.67; 95% CI 3.16-6.90), and birthweight 3500-3999g (aOR = 1.71; 95% CI 1.42-2.07) or ≥4000g (aOR = 2.31; 95% CI 1.78-3.00). One in ten (10.6%) cases received a blood transfusion and one in five (21.0%) were admitted to higher level care. CONCLUSIONS: The risk factors identified in this study align with those identified in previous research and with current guidelines for women planning birth in an MU in the UK. Maternal outcomes after PPH were broadly reassuring and indicative of appropriate management. NHS organisations should ensure that robust guidelines are in place to support management of PPH in MUs.

Can You Establish the Cause of This Patient's Shortness of Breath?

Mr. B is a 56-year-old man diagnosed with metastatic HER2-positive gastroesophageal adenocarcinoma. He received front-line leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) and trastuzumab for 10 months before restaging imaging revealed progressive disease. He then received second-line trastuzumab deruxtecan. His treatment was complicated by several admissions felt to be unrelated to his cancer therapy. He was discharged after an episode of pneumonia on a steroid taper with prophylactic trimethoprim/sulfamethoxazole. Once he recovered, he was given a fourth dose of chemotherapy. About a week later, wheezes were noticed on physical exam, and he was given a 5-day course of levofloxacin. Around the same time, he also finished his steroid taper. Twelve days after his dose of chemotherapy, he presented to the emergency room with 3 to 4 days of progressive shortness of breath and dry cough following the completion of levofloxacin without symptom improvement. A CT scan showed increasing airspace opacities and multifocal areas of consolidation. Blood, nasal, and sputum cultures were negative. A bronchoscopy was performed that did not reveal findings concerning for capillaritis. He was ultimately diagnosed with drug-induced pneumonitis/interstitial lung disease (ILD). Mr. B continued to experience worsening hypoxic respiratory failure despite continuous IV steroids. He was discharged to an inpatient hospice facility where he passed away 2 weeks later. Drug-induced pneumonitis/ILD should be considered in all patients receiving trastuzumab deruxtecan who develop progressive shortness of breath or other respiratory complaints.

Hepatic Metastasectomy in Squamous Cell Carcinoma of the Anal Canal: A Case Series of a Curative Approach.

BACKGROUND: Squamous cell carcinoma of the anal canal (SCCA) is rare. Most cases are diagnosed in a localized setting. Metastatic SCCA is rare, and investigation has been limited in the past for these patients. We believe that hepatic-only metastatic disease could have a unique treatment landscape compared to diseases with diffuse metastatic involvement. Here, we describe cases at our institution. METHODS: We reviewed eight SCCA cases with hepatic-only metastatic disease (diagnosed February 2018-January 2022). The objectives were to determine the overall survival and disease-free survival with this approach. RESULTS: The median age was 62 years old (yo). Patients had an ECOG of 0-1. All patients received definitive chemoradiation to their primary anal tumor. A median of three months of neoadjuvant systemic therapy was provided. All patients had a response on their first scan after systemic therapy. Sixty-two percent received carboplatin + paclitaxel. A complete pathologic response was seen in 62% of patients. At their last follow-up, all patients were alive. Three patients had recurrent disease. The estimated 1-year disease-free survival probability was 56.2%. CONCLUSION: Our report shows the feasibility of a curative-intent approach for patients with hepatic-only metastatic SCCA following the neoadjuvant application of carboplatin + paclitaxel. This approach appears promising in these select patients and warrants further investigation.

Therapeutic Advances in the Treatment of Gastroesophageal Cancers.

Gastroesophageal cancers are a group of aggressive malignancies that are inherently heterogeneous with poor prognosis. Esophageal squamous cell carcinoma, esophageal adenocarcinoma, gastroesophageal junction adenocarcinoma, and gastric adenocarcinoma all have distinct underlying molecular biology, which can impact available targets and treatment response. Multimodality therapy is needed in the localized setting and treatment decisions require multidisciplinary discussions. Systemic therapies for treatment of advanced/metastatic disease should be biomarker-driven, when appropriate. Current FDA approved treatments include HER2-targeted therapy, immunotherapy, and chemotherapy. However, novel therapeutic targets are under development and future treatments will be personalized based on molecular profiling. Herein, we review the current treatment approaches and discuss promising advances in targeted therapies for gastroesophageal cancers.

Nivolumab combination therapy as first-line treatments for unresectable, advanced or metastatic esophageal squamous cell carcinoma.

INTRODUCTION: Esophageal cancers continue to confer a dismal prognosis. Targeted and immune therapies have skyrocketed in the world of cancer management. Unlike other solid tumors, esophageal squamous cell carcinoma (ESCC) has lacked effective targeted therapy. Promising outcomes with immune checkpoint inhibitors (ICIs) have recently changed ESCC management. AREAS COVERED: Nivolumab has been granted several approvals to treat ESCC patients. Nivolumab is recommended as adjuvant therapy for localized ESCC patients following trimodality therapy who have residual cancer in the surgical specimen (lymph node(s) and or the primary). CheckMate-648 led to dual ICI therapy approval with nivolumab plus ipilimumab or nivolumab plus platinum with fluoropyrimidine as first-line treatment for unresectable ESCC patients. ATTRACTION-3 resulted in nivolumab approval for second-line therapy of unresectable ESCC patients who have not been exposed to ICI. Here we provide a review of nivolumab and how this relates to ESCC management. EXPERT OPINION: Some ESCC patients will not experience a response to ICIs. Determining intrinsic and acquired resistance patterns are needed to further capitalize on ICI therapy for ESCC patients. PD-L1 expression has been explored as a potential biomarker. Data show, however, PD-L1 positive tumor patients benefit but this assessment is not always needed.

Feasibility and safety of shortened hypofractionated high-dose palliative lung radiotherapy - A retrospective planning study.

OBJECTIVE: Assess the safety and feasibility of shortened hypofractionated high-dose palliative lung radiotherapy in a retrospective planning study. METHODS: Fifteen late stage (III or IV) NSCLC lung radiotherapy patients previously treated with the standard palliative 36 Gy in 12 fractions (12F) schedule were non-randomly selected to achieve a representative distribution of tumour sizes, volumes, and location. Plans were produced using 30 Gy in 5 fractions (5F) and 6 fractions (6F) using a 6MV FFF co-planar VMAT technique. Plans were optimised to meet dose-constraints for planning target volumes (PTVs) and organs at risk (OARs) with established OAR constraints expressed as biological equivalent doses (BEDs). The potential safety was assessed using these BEDs and also with reductions of 10% (BED-10%) and 20% (BED-20%) to account for a reduction in tolerance doses from the effects of chemotherapy or surgery. RESULTS: Mandatory BED constraints were met for all fifteen 5F and 6F plans; BED-10% constraints were met by all 6F plans and six 5F plans. BED-20% constraints were met by six 6F and three 5F respectively. CONCLUSION: It is potentially safe and feasible to deliver high-dose palliative radiotherapy for late stage NSCLC using the 5F or 6F regimes described, when planned to comparable OAR BEDs as standard radical techniques. It appears toxicity from these regimes should be within acceptable limits provided the dose-constraints described are met. A Phase II study is required to fully assess safety and feasibility, the outcomes of which could reduce the number of patient hospital visits for radiotherapy, thereby benefiting patients and optimising resource utilisation.

Utility of Established Prognostic Scoring Systems for Patients with Advanced Pancreatic Adenocarcinoma Enrolled in Immunotherapy-Based Early-Phase Clinical Trials.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy for which multiagent chemotherapy is the mainstay of treatment resulting in limited survival and symptomatic benefit. Treatment with immune checkpoint inhibitors (ICI) has proven effective in a growing number of solid tumors but has yet to show clinical benefit in patients with PDAC. Given the growing number of ICI-based clinical trials in development for patients with PDAC and lack of clinical benefit thus far with ICI-based therapies in these patients, we sought to (1) determine the outcomes of patients with PDAC treated with ICI-based therapies as part of an early phase clinical trial, (2) validate the utility of established prognostic scoring systems, and (3) identify novel prognostic factors in an attempt to better identify patients that would benefit from enrollment onto an ICI-based early phase clinical trial. METHODS: We conducted a single-center retrospective analysis of patients with advanced PDAC who were treated with ICI-based therapy as part of an early-phase clinical trial. RESULTS: Patients were only able to stay on study for a limited time due to disease progression and/or a change in performance status and had a poor overall survival. Established prognostic scoring systems were not effective in predicting outcomes in this patient population, but factors such as pre-treatment albumin neutrophil to lymphocyte ratio (NLC) may be helpful in patient selection. CONCLUSIONS: This study underscores the need for larger studies to help identify patient and tumor intrinsic factors that predict response to ICI-based therapies in patients with PDAC.

Recent advances in the management of gastric adenocarcinoma patients.

Gastric adenocarcinomas are a significant cause of cancer and cancer death, globally. The curative approach for those with diagnosed localized disease is with surgical resection and an adjunctive approach of perioperative chemotherapy, postoperative adjuvant therapy, or postoperative chemoradiation. Unfortunately, a universal standard approach is lacking for adjunctive therapy which in part has limited the progress achieved in this area. Metastatic disease is common in the Western world at diagnosis. Metastatic disease is treated palliatively with systemic therapy. Targeted therapy has stalled in approvals in gastric adenocarcinomas. Recently, we have seen the exploration of promising targets along with the addition of immune checkpoint inhibitors in select patients. Here, we review recent advances seen in gastric adenocarcinomas.

Outcomes for women admitted for labour care to alongside midwifery units in the UK following a postpartum haemorrhage in a previous pregnancy: A national population-based cohort and nested case-control study using the UK Midwifery Study System (UKMidSS).

BACKGROUND: Women who have experienced a postpartum haemorrhage (PPH) 'requiring treatment or transfusion' are typically advised to plan birth in obstetric-led settings in subsequent pregnancies. Many UK alongside midwifery units (AMU) admit women for labour care following a previous PPH. We aimed to describe outcomes in women admitted for labour care to AMUs following a previous PPH, compare outcomes with other multiparous women admitted to the same AMUs, and explore risk factors for recurrence. METHODS: A national cohort and nested case-control study using the UK Midwifery Study System (UKMidSS), between August 2018 and April 2019. Multivariable Poisson regression and logistic regression were performed to compare outcomes and investigate risk factors for recurrence. FINDINGS: Women who experienced a previous PPH were significantly more likely than comparison women to: have a PPH requiring transfer to obstetric care (4·2% vs. 2·4%, aRR=1·65, 95% CI 1·14-2·38), be transferred to obstetric care for any reason (17·8% vs 11·9%; aRR=1·41; 95% CI 1·09-1·83), and have any PPH≥ 500 ml (22·7% vs 11·1%, aRR=1·86, 95% CI 1·49-2·32). Among women with a previous PPH, previous blood loss > 1500 ml; uterotonics for previous PPH; Caesarean associated with previous PPH; gestation at admission and higher birthweight were independent risk factors for PPH. CONCLUSION: Women considering birth in an AMU after a previous PPH should be advised that they are at increased risk of experiencing a subsequent PPH requiring transfer to obstetric care, compared with other multiparous women who have not had a PPH. The absolute risk of a subsequent PPH in this group is low and comparable to the overall risk of having a PPH among women having a spontaneous vaginal birth in England.

Localized Gastroesophageal Adenocarcinoma in the Elderly: Is Age a Factor Associated with Suboptimal Treatment?

INTRODUCTION: Gastroesophageal adenocarcinoma is relatively common in elderly patients as the incidence increases with age. However, the optimal treatment approach is not well established in this group of patients. The aim of this study is to review our experience for localized gastroesophageal adenocarcinoma in patients aged ≥80 years and to assess association between patient characteristics, clinical factors, and overall survival (OS) in order to optimize the therapeutic approaches for this population. METHODS: Patients ≥80 years old treated for localized gastroesophageal adenocarcinoma were retrospectively analyzed. Survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression models were applied to assess the association between patient characteristics and OS. Factors that were significant in the multivariate model were included in the final reduced model. RESULTS: 127 patients ≥80 years old, were included in this study with median age of 83 years. The median follow-up time was 3.2 years, and median OS was 2.5 years (95% CI: 2.0-3.1 years). Independent prognostic factors for OS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) (p = 0.003), baseline clinical stage (p = 0.01), and surgery (p = 0.001). ECOG PS, tumor location, baseline stage, tumor grade, and surgery were included in the final reduced model. CONCLUSION: Surgical treatment can improve survival in elderly patients. Therapeutic decisions should be based on the patients' general condition rather that age alone.

Esophageal cancer: Is the CROSS strategy ready for history books?

The CROSS trial group deserves enormous credit for completing a well-powered randomized trial that has established the CROSS strategy as a standard of care for patients with potentially resectable esophageal cancer. However, the 10-year results are rather disappointing with only 38% of all patients treated with the CROSS strategy cured compared with approximately 25% who had surgery alone. Another standard, perioperative chemotherapy has produced similar disappointing results as the CROSS strategy. Although many of us are consumed by the question as to which option is better for our patients, we conclude that both strategies produce only marginal benefits. We should have better treatment options. The timing may be opportune to reflect on how to develop novel and rational strategies rather than propagate the historical empiric approaches.

Evaluating the Effectiveness of Deep Learning Contouring across Multiple Radiotherapy Centres.

Background and purpose: Deep learning contouring (DLC) has the potential to decrease contouring time and variability of organ contours. This work evaluates the effectiveness of DLC for prostate and head and neck across four radiotherapy centres using a commercial system. Materials and methods: Computed tomography scans of 123 prostate and 310 head and neck patients were evaluated. Besides one head and neck model, generic DLC models were used. Contouring time using centres' existing clinical methods and contour editing time after DLC were compared. Timing was evaluated using paired and non-paired studies. Commercial software or in-house scripts assessed dice similarity coefficient (DSC) and distance to agreement (DTA). One centre assessed head and neck inter-observer variability. Results: The mean contouring time saved for prostate structures using DLC compared to the existing clinical method was 5.9 ± 3.5 min. The best agreement was shown for the femoral heads (median DSC 0.92 ± 0.03, median DTA 1.5 ± 0.3 mm) and the worst for the rectum (median DSC 0.68 ± 0.04, median DTA 4.6 ± 0.6 mm). The mean contouring time saved for head and neck structures using DLC was 16.2 ± 8.6 min. For one centre there was no DLC time-saving compared to an atlas-based method. DLC contours reduced inter-observer variability compared to manual contours for the brainstem, left parotid gland and left submandibular gland. Conclusions: Generic prostate and head and neck DLC models can provide time-savings which can be assessed with paired or non-paired studies to integrate with clinical workload. Reducing inter-observer variability potential has been shown.

Perspectives on the pharmacological management of esophageal cancer: where are we now and where do we need to go?

INTRODUCTION: Esophageal cancer (EC) represents a complicated heterogenous group of malignancies. ECs are divided broadly into two types, histologically: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). Historically, EC study designs have used bucket type groupings (all subtypes and/or all gastroesophageal cancers) reducing contribution to developing precision oncology. AREAS COVERED: Surgery remains the curative modality for resectable disease with reasonable patient physiology. Trimodality is recommended for localized ESCC. An exception is cervical EC. For EAC, preoperative chemoradiation or perioperative chemotherapy is utilized. For those who undergo trimodality, nivolumab is recommended as an adjuvant therapy for those with a non-pathological complete response (pCR). Additionally, immunotherapy and other targets have been added to advanced EC treatment. EXPERT OPINION: Organ sparing approaches for localized tumors are starting to be investigated in many solid tumors and have been standard approaches for decades in certain tumors (i.e. certain head and neck tumors and anal SCCs). pCR differs between esophageal histologies with trimodality indicating potential of discriminating localized approaches. To determine if a watch and wait approach is feasible, prospectively correlating clinical complete response to pCR is needed, determining the best active surveillance strategy, and the best use of tools like liquid biopsies.