A review of esophageal cancer research: emerging trends, progress and perspectives

Introduction

Esophageal cancer (EC) remains a formidable health challenge globally, being the eighth most common cancer and the sixth leading cause of cancer-related mortality (1). This malignancy predominantly manifests in two histological forms: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) (2). While ESCC historically accounted for the majority of cases worldwide, there has been a notable rise in the incidence of EAC, particularly in Western countries (1). This shift in epidemiology underscores the complex interplay of genetic, environmental, and lifestyle factors contributing to the pathogenesis of EC. Understanding the distinct molecular mechanisms driving these two subtypes is crucial for developing targeted therapies and improving patient outcomes (3). The pathophysiology of EAC is intricately linked to chronic gastroesophageal reflux disease (GERD), which leads to the development of Barrett’s esophagus (BE). BE is characterized by the metaplastic transformation of normal squamous epithelium to columnar epithelium, a process driven by bile and gastric acid exposure (4,5). ESCC remains prevalent in many parts of the world, particularly in Asia and among populations with high rates of tobacco and alcohol consumption. The molecular pathogenesis of ESCC involves multiple genetic and epigenetic alterations induced by carcinogens in tobacco smoke and alcohol (3). These substances cause direct DNA damage, form DNA adducts, and generate reactive oxygen species (ROS), leading to mutations in key regulatory genes such as TP53 and CDKN2A (p16). Additionally, the overexpression of cyclin D1 and epidermal growth factor receptor (EGFR) in ESCC contributes to aberrant cell cycle regulation and enhanced proliferative capacity (6).

Furthermore, the distinct molecular landscapes of EAC and squamous cell carcinoma necessitate tailored therapeutic approaches. The rise in EAC incidence in Western countries, driven by lifestyle factors such as obesity and GERD, contrasts with the more stable incidence of ESCC, linked to tobacco and alcohol use (7). Advances in molecular biology have elucidated key pathways involved in the pathogenesis of both subtypes, providing a foundation for the development of targeted therapies (8).

This study aims to shed light and provide a thorough analysis of of research that continues to uncover the genetic and epigenetic underpinnings of EC, suggesting that there is hope for more effective treatments and improved prognosis for patients afflicted by this challenging disease.

Epidemiology and global risk factors

EC is a significant global health concern, characterized by high incidence and mortality rates (9). In 2020, approximately 604,100 new cases and 544,076 deaths were reported worldwide, making it the seventh most common cancer and the sixth leading cause of cancer-related death (3). The incidence and prevalence of EC exhibit considerable geographical variation. ESCC is predominant in regions like Eastern Asia, Eastern and Southern Africa, and South-Central Asia, where it accounts for the majority of cases. EAC has become more common in Western countries, particularly in North America and Europe. This shift is largely attributed to changing lifestyle factors (8).

The epidemiology of EC is influenced by various risk factors that differ between ESCC and EAC. In regions like China, where ESCC is highly prevalent, additional factors such as the consumption of hot beverages, exposure to nitrosamines from preserved foods, and poor nutritional status contribute to its incidence. Moreover, unhealthy lifestyle habits such as alcohol consumption and smoking are also prevalent risk factors for ESCC. Conversely, the rising incidence of EAC in Western countries is closely related to obesity, GERD, and BE. These conditions lead to chronic inflammation and subsequent malignant transformation in the lower esophagus (6,8).

Pathophysiology and molecular mechanisms

Adenocarcinoma primarily develops from BE, a condition where the normal squamous epithelium is replaced by columnar epithelium due to chronic GERD (4,5). This metaplastic transformation is driven by bile and acid reflux, which upregulates the transcription factor CDX-2 through the EGFR pathway (10). CDX-2 promotes intestinal differentiation of esophageal cells, facilitating the progression to adenocarcinoma. Additionally, chronic inflammation, activation of cyclooxygenase-2 (COX-2), and epigenetic changes, such as hypermethylation of tumor suppressor genes like p16, contribute to carcinogenesis. Molecular alterations commonly observed in adenocarcinoma include mutations in TP53, overexpression of EGFR, and amplification of the Her2/neu gene, all of which promote uncontrolled cell proliferation and survival (11).

Squamous cell carcinoma is more prevalent globally and is strongly associated with environmental risk factors, such as smoking and alcohol consumption. The carcinogenic effects of these factors involve multiple molecular mechanisms. Ethanol is metabolized to acetaldehyde, a compound that forms DNA adducts, leading to mutations. It also generates ROS, causing oxidative DNA damage, and inhibits DNA repair mechanisms, further contributing to mutagenesis. Smoking introduces carcinogens like polycyclic aromatic hydrocarbons (PAHs) and N-nitrosamines, which also form DNA adducts and induce mutations. ESCC frequently exhibits mutations in tumor suppressor genes such as TP53 and CDKN2A(p16), as well as overexpression of cyclin D1, which drives cell cycle progression. Additionally, the EGFR pathway is often upregulated in ESCC, promoting cellular proliferation and survival through downstream signaling cascades like MAPK/ERK and PI3K/AKT (12).

Both histological subtypes of EC share some molecular features, such as the involvement of the EGFR pathway, but differ significantly in their etiology and specific molecular alterations. The integration of molecular diagnostics and targeted treatments holds promise for improving outcomes in EC patients.

Diagnostic modalities

The detection and diagnosis of EC have advanced significantly with the development of various endoscopic techniques, imaging technologies, and biomarker research. Endoscopy remains the cornerstone for the detection of early esophageal neoplasia. High-resolution white-light endoscopy (WLE) is the standard initial approach for visualizing mucosal abnormalities (13). Advanced endoscopic imaging techniques such as chromoendoscopy, which uses stains like acetic acid and Lugol’s iodine, enhance the visualization of dysplastic lesions by highlighting abnormal epithelial cells. Narrow-band imaging (NBI) and magnification endoscopy further improve the detection rates by providing enhanced contrast and detailed views of the mucosal and vascular patterns. Studies have shown that NBI, combined with magnifying endoscopy, significantly increases the accuracy of detecting early EC, allowing for more precise targeting of biopsies (13,14).

In addition to endoscopic techniques, imaging modalities such as endoscopic ultrasound (EUS) play a crucial role in the staging of EC. EUS is highly effective in determining the depth of tumor invasion and detecting regional lymph node involvement, which is critical for treatment planning. The combination of EUS with fine-needle aspiration (FNA) enhances the accuracy of lymph node staging. Novel imaging technologies, including confocal laser endomicroscopy (CLE) and volumetric laser endomicroscopy (VLE), provide real-time, high-resolution images of the esophageal mucosa at the cellular level, aiding in the early detection of dysplasia and carcinoma (15).

Biomarker research also contributes significantly to the early detection and diagnosis of EC. Circulating biomarkers such as autoantibodies (e.g., p53 antibody), circulating tumor cells (CTCs), and microRNAs (miRNAs) have shown promise in detecting esophageal neoplasia non-invasively. Methylated DNA markers and specific gene mutations detected in esophageal biopsy samples are under investigation for their potential to identify early-stage cancer and high-grade dysplasia. Breath and saliva tests analyzing volatile organic compounds (VOCs) and the oral microbiome are emerging as non-invasive screening tools (13). These biomarkers, combined with endoscopic techniques, provide a comprehensive approach to early detection, enabling timely and targeted interventions.

Advancements in radiation therapy

Radiotherapy plays a crucial role in managing EC, with recent advances aimed at balancing increased treatment efficacy with reduced toxicities. This review focuses on advances in treatment modalities, radiation techniques, radiation dose, target volume (16,17).

Treatment modalities: focus on radiation and chemoradiotherapy

Neoadjuvant chemoradiotherapy remains the standard treatment for locally advanced EC, as demonstrated by meta-analyses and the CROSS trial (18). This trial showed that neoadjuvant chemoradiotherapy significantly increased R0 resection rates and improved median overall survival. Although perioperative or preoperative chemotherapy has also been applied, it remains to be seen which approach is superior. Some studies have shown that neoadjuvant chemoradiotherapy offers higher pathologic complete response rates and lower lymph node metastases but with the potential for more severe postoperative complications (17,18).

Advancements in radiation techniques: 3D conformal radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and beyond

3DCRT has been the standard technique for EC, but IMRT has emerged as a more advanced option. IMRT employs advanced computer algorithms and imaging to create detailed 3D maps of the tumor and surrounding organs. The process begins with imaging scans, such as computed tomography (CT) or magnetic resonance imaging (MRI), to visualize the tumor’s exact location and shape. Using these images, a treatment plan is developed where the radiation beams are precisely shaped, and their intensity modulated. This allows higher doses to be concentrated on the tumor while minimizing exposure to surrounding healthy tissues (19). The modulation of beam intensity is achieved through dynamic multi-leaf collimators that adjust the beam shape in real-time as the treatment machine rotates around the patient (19,20). This precision is particularly beneficial for treating tumors with complex shapes or those near vital organs. SCINTIX (Scintillation-Guided Intensity-Modulated Radiation Therapy) represents a novel approach in radiation therapy that further refines the precision and efficacy of IMRT. SCINTIX integrates real-time feedback from scintillation detectors, which are devices that detect and measure the radiation dose delivered to the tumor and surrounding tissues. These detectors provide immediate information on the actual dose distribution, enabling on-the-fly adjustments to the radiation beams during treatment.

The incorporation of scintillation technology into IMRT allows for unprecedented accuracy in dose delivery. As the radiation is administered, the scintillation detectors capture the light emitted by the interaction of radiation with the tissue, converting this light into signals that can be analyzed in real time. This real-time feedback ensures that the planned dose is accurately delivered to the intended target, with any deviations promptly corrected by adjusting the beam intensity or position. This dose reduction has been associated with lower rates of acute and late toxicities, such as radiation pneumonitis and cardiac events. IMRT has shown advantages over 3DCRT in reducing these risks. A study conducted by Wang et al. reported that IMRT reduced the total lung volume receiving 20 Gy (V20) and 30 Gy (V30) from 31% and 16% with 3DCRT to 22% and 13%, respectively, and decreased the heart volume receiving 30 Gy (V30) and 40 Gy (V40) from 29% and 21% to 28% and 20%, respectively (21). A study from MD Anderson Cancer Center, involving 676 EC patients, found that IMRT was associated with significantly longer median overall survival (43.2 vs. 25.2 months with 3DCRT, P<0.001) and reduced locoregional recurrence (P=0.0038) (17). Although cancer-specific death rates were similar, cardiac deaths were lower in the IMRT group (P=0.049), suggesting that improved dosimetric parameters with IMRT lead to survival benefits (18,22).

These improvements in radiotherapy have led to better local control of the tumor, fewer side effects, and improved overall survival rates for patients with EC.

Photodynamic therapy (PDT): a targeted approach in EC

PDT involves administering photosensitizing agents that preferentially accumulate in cancer cells. These agents are then activated by specific wavelengths of light, producing ROS that destroy cancer cells. The light is delivered to the tumor site using endoscopic techniques or optical fibers, ensuring precise targeting. PDT is particularly effective for superficial tumors and can be used in combination with other treatments to enhance efficacy as shown in Figure 1 (19,20).

Figure 1 Illustration of PDT alone and of the combination of PDT with radiation therapy. The image showcases the before and after stages of PDT using NP dye, a type of photosensitizer, to treat cancer. In the “before” stage, depicted in the top panel, NP dye molecules selectively target and accumulate in cancer cells. Upon activation by specific light exposure, shown in the bottom panel as the “after” stage, the NP dye produces reactive molecules that destroy the cancer cells. This process highlights the precision of PDT in eradicating cancerous cells with minimal impact on surrounding healthy tissue, leveraging the unique properties of NP dyes for effective cancer treatment. PDT, photodynamic therapy; NP, nanoparticle.

Real-time tumor targeting with SCINTIX™ technology

SCINTIX™ tracks the movement of tumors and adjusts radiation delivery multiple times per second, based on signals emitted by cancer-targeting PET tracers. These tracers are administered intravenously, with one part binding to cancer cells and the other emitting detectable signals. This allows for continuous detection and precise targeting of active cancer areas during treatment, as shown in Figure 1. The real-time feedback mechanism sets SCINTIX™ apart from conventional radiation therapy, which relies on static 3D images taken days to weeks before treatment (19). The new method aims to make radiation treatment faster, more precise, and less invasive, potentially improving patient comfort and minimizing side effects. The SCINTIX™ machine, named X1, was developed by RefleXion Medical in collaboration with Stanford Medicine’s clinicians and medical physicists (23). The platform received Food and Drug Administration (FDA) approval in February for treating certain lung and bone tumors, based on a clinical trial at Stanford that simulated patient treatment delivery. SCINTIX™ could significantly improve treatment. By providing real-time feedback and adjusting radiation delivery accordingly, the technology eliminates the need for invasive procedures like implanting metal markers, which were previously necessary for patients with irregular breathing patterns (24). Additionally, SCINTIX offers the ability to precisely target multiple tumors simultaneously and allows for endless possibilities for patients with advanced metastatic cancer. Biology-guided radiation therapy, through the integration of PET technology and radiotherapy, represents a major advancement in cancer treatment (25). Its real-time feedback and precision targeting promise to enhance treatment efficacy, reduce side effects, and improve patient outcomes. Ongoing clinical trials will further elucidate its potential and establish its place in the future of cancer care. These have been conducted both domestically (US) and internationally through various research institutes. Circulating DNA as a predictor for II-IVA operable ESCC (NCT05759325) is currently being investigated and studies. On the treatment end, ideal combinations of paclitaxel with cisplatin (DDP), fluorouracil (5-FU), or carboplatin alongside radiotherapy was recently completed (NCT02459457). Efficacy of nivolumab and ipilimumab on patients with esophageal and gastroesophageal adenocarcinoma in combination with standard treatments like chemotherapy and radiotherapy is also ongoing (NCT03604991).

Chemotherapy

The mechanism behind chemotherapy

Chemotherapy is the standard first-line therapy for metastatic EC. Through uncontrolled proliferation, cancer cells rapidly divide and cause the formations of lumps and tumors. As shown in Figure 2, chemotherapy drugs work to target and kill these rapidly dividing cells by disrupting the cell division cycle through damaging the DNA and genes inside of the nucleus of the cell, preventing it from being replicated (26). Unlike cancer cells, resting non-cancerous cells are usually not affected by chemotherapy. By targeting rapidly dividing ROS cells, chemotherapy shrinks tumors and prevents the spread of cancer, ultimately improving survival rates.

Figure 2 Chemotherapy drugs target rapidly dividing cells. Cancer cells lacking repair mechanisms die, while healthy cells recover.

Recovery of normal cells: the key to chemotherapy’s effectiveness

Since chemotherapy targets rapidly dividing cells, this means it also affects normal cells that are also rapidly growing and dividing (27). Therefore, chemotherapy treatment affects rapidly growing and dividing hair cells (28), bone marrow that is constantly producing blood cells, as well as the skin and lining of the digestive system (29) because they are in a constant state of renewal. The result of targeting these otherwise healthy rapidly dividing cells leads to a few side effects of chemotherapy which include hair loss, lowered blood cell counts, immunosuppression, and nausea.

Although chemotherapy does not only precisely target cancer cells, it remains a fundamental approach in cancer treatment because normal cells that have been targeted by chemotherapy have intact repair mechanisms that can restore their function after being damaged (30). On the other hand, chemotherapy is ultimately successful in killing off cancer cells because they not only have mutations that allow them to grow repeatedly but also impair their ability to repair themselves after being damaged by chemotherapy (Figure 3). While normal cells can be harmed, their recovery is what allows chemotherapy to be a viable treatment option.

Figure 3 Cancer cells lack repair mechanisms and die when treated with chemotherapy, while healthy cells recover.

Approaches to chemotherapy

• Neoadjuvant chemotherapy: given before surgery to shrink the tumor, making it easier to remove with less invasive methods (31).
• Adjuvant chemotherapy: administered after surgery to eliminate any remaining cancer cells, preventing recurrence (32).
• Chemotherapy for advanced cancer: used to treat cancer that has spread to other organs, aiming to shrink tumors and relieve symptoms (Figure 4).
  

  Figure 4 Neoadjuvant, surgical, and adjuvant approaches in tumor management, targeting cancer cells at different stages of treatment.

Chemotherapy drugs: mechanisms and functions

Doxorubicin (Dox)

Dox is a chemotherapeutic drug that works through 3 mechanisms displayed in Figure 5 to damage DNA, forcing rapidly growing cells into cell cycle arrest and preventing the cells from further division and proliferation. The first mechanism Dox works by is intercalating into the DNA (33). Dox inserts itself in between base pairs thereby distorting the DNA structure. The cell with a now-damaged DNA structure goes into cell cycle arrest and undergoes apoptosis (27). A second method by which Dox works is through the generation of ROS. Dox accumulates in the mitochondria where it is transformed into a free radical that reacts with oxygen, generating ROS. ROS build up in the cell and damage DNA, leading to cell stress and apoptosis (34). Last, Dox inhibits topoisomerase II, an enzyme that aids in winding and unwinding DNA (35). The inhibition of topoisomerase II results in DNA strands breaking, which prevents replication and sends the cell into apoptosis. Dox interacts with rapidly dividing cells and induces DNA damage in order to induce apoptosis and prevent further proliferation of rapidly dividing cells.

Figure 5 Doxorubicin’s mechanisms for inducing apoptosis in rapidly dividing cells.

5-FU

5-FU is used as a first-line treatment in ESCC but not as a single drug therapeutic due to its toxicity, drug resistance, and presence of side effects as the dosage increases (36). Used in combination with other chemotherapeutic drugs, the recommended dose of 5-FU varies between individuals. 5-FU prevents cell proliferation by inhibiting the formation of the enzyme thymidylate synthase, which is essential in DNA synthesis (37). By blocking the synthesis of one of the four nucleotides required for DNA replication, 5-FU stalls the replication, causes DNA damage, and leads to apoptosis. Leucovorin is a folate derivative that may be used in conjunction with 5-FU to enhance its effects. It works to stabilize the complex formed between 5-FU and thymidylate synthase (38) so that 5-FU becomes more efficient in inhibiting DNA synthesis.

DDP

DDP works by damaging DNA structure in order for a rapidly dividing cell to halt proliferation and undergo apoptosis (39). DDP promotes methods of intrastrand and interstrand cross-linking, causing either linking between adjacent guanines and adenines on the same DNA strand or linking between two DNA strands, respectively (Figure 6).

Figure 6 Intrastrand and interstrand cross-linking promoted by cisplatin in rapidly dividing cells.

The damage and distortion to the DNA structure inhibit replication and transcription. The DNA damage from cross-linking renders the DNA unreadable and therefore RNA will not be produced during transcription. The distorted, unreadable, and untranscribable DNA leads the cell into cell cycle arrest. The cell cycle ends up undergoing apoptosis due to the irreparable damage done to the DNA, ending the proliferation of the potential cancer cell. Chemotherapy drugs carboplatin and oxaliplatin work in the same way to induce apoptosis in rapidly dividing cells (40).

Paclitaxel

Paclitaxel is a chemotherapeutic that works to stabilize microtubules and protects them from disassembling, as shown in Figure 7 (41). In doing so, paclitaxel inhibits the M phase of cell division by not allowing the microtubules to pull the chromosome apart after duplication, for example. The cells are prevented from going through the mitotic phase of cell division, and the irreparable damage causes the cell to undergo apoptosis.

Figure 7 Paclitaxel stabilizes microtubules, preventing disassembly and disrupting cell division.

Enhancing chemotherapy efficacy

Increasing DDP sensitivity through protein inhibition

The optimization of chemotherapeutic drugs is a current field of focus in the treatment of EC. Aside from using combination therapy with multiple chemotherapeutic drugs to increase the efficacy of treatment, another approach is to increase the efficacy of current drugs by manipulating the pathways by which they work. DDP’s sensitivity has been found to increase through the inhibition of proteins BMI1 and MEL18. These proteins are involved in chromatin DNA repair and work to keep c-MYC (42), an oncogene that promotes cell proliferation and growth, under control. When c-MYC goes unchecked, it can lead to uncontrollable cell growth- a hallmark of cancer (43,44). When BMI1 and MEL18 are inhibited, they fail to repress c-MYC. This results in uncontrollable proliferation of the cells, which ironically makes the cells more sensitive to DDP (45), for they are more focused on dividing rather than repair. When DDP distorts the DNA through cross-linking, the cell will be too focused on proliferation to initiate repair, driving the cell towards apoptosis. In summary, repair mechanisms are already inhibited in cancer cells. Therefore, this environment allows for further inhibition, increasing the efficacy of DDP in initiating apoptosis.

Combination therapy for improved outcomes

A phase II study comparing the efficacy of DDP and 5-FU versus DDP alone in individuals with metastatic ESCC showcased an increased efficacy for the combination therapy (46). Patients were randomly assigned and received either 100 mg/m² of DDP with a continuous infusion of 5-FU 1,000 mg/m² every day for 1–5 days, while others received only 100 mg/m² of DDP. These dosages would be readministered every 3 weeks. Although not statistically significant, the patients in the DDP/5-FU arm experienced both a higher response rate (35%) as well as a higher median survival (33 weeks) when compared to the DDP group, with a response rate of 19% and a median survival of 28 weeks.

Immunotherapy

The mechanism behind immunotherapy

Unlike chemotherapy and radiation therapy, immunotherapy is a newer approach that enlists the body’s defenses to fight against cancer and works by harnessing the body’s immune system to recognize and attack cancer cells (47). Immunotherapy drugs are designed to target checkpoints on immune cells and/or cancer cells in order for the immune system to recognize cancer cells (48). In doing so, immunotherapeutics prepare and utilize the body’s immune system to recognize and fight cancer cells.

Types of immunotherapies for EC

Checkpoint inhibitors

The body contains checkpoints in order to keep the immune system from overreacting and harming healthy cells. For example, T-cells fight off infections and cancer cells. Immune checkpoint proteins regulate T-cell activity by binding to specific surface receptors on these cells (49).

Checkpoint proteins allow or restrict signals from reaching the immune system’s T-cells, thereby either causing the T-cells to turn “on” and kill cancer cells or turn “off” and spare healthy cells. Checkpoint inhibitors block this interaction between checkpoint proteins and T-cells, releasing the brakes off the immune system. Therefore, T-cells are not signaled to “stop” by these now-inhibited checkpoint proteins. This allows for a stronger anti-cancer response (50).

Checkpoint inhibitors are beneficial in allowing for a stronger anti-cancer defense because they prompt the immune cells to go into overdrive to kill cancer cells, for they are no longer signaled to “stop”. This overactivation of the immune system can cause T-cells to also attack healthy cells, causing immune-related adverse events, such as dermatitis or skin rashes due to the immune system’s attack on the skin (51).

Pembrolizumab, marketed as Keytruda, is an FDA-approved immunotherapeutic for unresectable and metastatic cancer (52). The Keynote-181 clinical trial was pivotal in demonstrating the efficacy and safety of pembrolizumab for advanced EC, leading to its FDA approval as a second-line treatment for patients with PD-L1 combined positive score (CPS) ≥10 and squamous cell carcinoma (53). The objective of this study is to compare the overall survival of patients with advanced or metastatic ESCC on pembrolizumab versus standard chemotherapy. The eligibility of patient participation requires patients to have advanced or metastatic EC and have shown cancer progression even after first-line chemotherapy. This phase III study has 628 participants with advanced/metastatic ESCC that progressed after one prior chemotherapy (53). The treatment arms were separated into the pembrolizumab group and chemotherapy group. Patients in the pembrolizumab group were injected with 200 mg of pembrolizumab every 3 weeks for 2 years. The chemotherapy group was either treated with paclitaxel, docetaxel, or irinotecan, depending on the investigator’s choice of chemotherapy. The primary endpoints were overall survival in patients with PD-L1 with a CPS ≥10 in patients with ESCC. Results yield that overall survival (OS) was improved with pembrolizumab in comparison to standard chemotherapy for patients with CPS ≥10. Over 12 months, OS with pembrolizumab was 43% compared to chemotherapy’s 20%. Median OS was 8.2 months with pembrolizumab vs. 7.1 months with chemotherapy. In terms of adverse events grade 3–5, pembrolizumab was the lowest with 18.2% of patients vs. 40.9% of chemotherapy patients. This trial was significant in demonstrating the effectiveness and safety of pembrolizumab in comparison to standard chemotherapy for advanced EC. FDA has approved pembrolizumab as a second line treatment for patients with PD-L1 CPS ≥10 and ESCC.

Another trial done with the goal of offering immunotherapeutic pembrolizumab as a first line of treatment in combination with chemo rather than chemo alone being the standard first line therapeutic was Keynote-590 (54). Keynote-590 led to the FDA’s approval (March 22, 2021) of pembrolizumab plus chemotherapy as a first line treatment for patients with metastatic EC regardless of PD-L1 expression (55). Figure 8 illustrates the binding of PD-L1 and PD-1, which leads to the inactivation of the T-cell and therefore its inability to kill the cancer cell as well as a demonstration of how Keytruda works to block the binding of PD-L1 and PD-1 to keep the T-cell active and effective in killing the cancer cell.

Figure 8 PD-1/PD-L1 interaction and T-cell activation with and without Keytruda. PD-1, programmed death-1; PD-L1, programmed death ligand 1.

Monoclonal antibody

An antibody is a Y-shaped protein (Figure 9) that is produced by the immune system in response to foreign pathogens, viruses, etc. (56). They recognize and bind to antigens on the surface of foreign invaders. The binding of the antibody to the antigen on the surface of a pathogen, for example, triggers the immune response to eliminate the threat. A monoclonal antibody is a lab-produced molecule that is designed to mimic the function of the body’s natural antibodies (57).

Figure 9 Structure of a cancer cell and T-cell engaged to a monoclonal antibody.

For example, B-cells, which work to produce antibodies, are cloned and made to produce specific, artificial antibodies. Therefore, these lab-made antibodies are specific and engineered to recognize and bind to a specific target. In the case of cancer application, monoclonal antibodies are created to target certain checkpoint molecules, such as PD-1. These antibodies are highly specific and made to be able to target and bind to PD-1 receptors to stop them from binding to PD-L1, which downregulates the immune response of T-cells (58). This ends up taking the breaks off the immune system.

Adoptive cell therapy (ACT)

ACT involves infusing patients with active anti-tumor immune cells to eliminate tumor cells either directly or by way of stimulating the body’s immune response. ACT works by utilizing immune cells from either the patient or a donor to engineer and improve the body’s immune response (59). There are currently three approaches in ACT that are being used or developed to treat cancer. These approaches are tumor-infiltrating lymphocyte therapy (TIL), engineered T-cell receptor (TCR) therapy, and chimeric antigen receptor T-cell therapy (CART).

TIL

Killer T-cells can identify and attack cancer cells. Before they can attack, these T-cells must be activated. Moreover, aside from the need to be activated before they could recognize and attack cancer cells, there might not be enough T-cells to initiate a successful anti-tumor response. As demonstrated in Figure 10, through the use of TIL, providers specifically harvest the body’s immune system’s naturally occurring T-cells that have already recognized and infiltrated the tumor and can therefore be specific in recognizing cancer cells. During this therapeutic approach, the T-cells are multiplied in number and activated before they are reinfused back into the patient, creating a larger, more specific targeted approach to attack cancer cells (60).

Figure 10 An illustration of the TCR method, TIL method, and of the combination of a CAR to a T-cell in the creation of a CAR T-cell. CAR, chimeric antigen receptor; TCR, T-cell receptor; TIL, tumor-infiltrating lymphocyte.

TCR

TCR is utilized in the case of patients who do not have T-cells that have already recognized the target cancerous tumors. As demonstrated in Figure 10, the method behind TCR is that T-cells are extracted from the patient, activated, and then expanded (61). Moreover, this approach also equips these T-cells with new receptors so that they could target specific cancer antigen markers. Therefore, this treatment allows for personalization to each individual patient.

CART

A limitation of TIL and TCR is that both therapies only equip the T-cells to eliminate cancer cells that present their antigens on their surface bound to the MHC. CART aids to overcome this limitation, for scientists equip a patient’s T-cells with a synthetic receptor, known as a CAR as shown in Figure 10 (62). CARs can bind to the cancer cells even if they are not presenting their antigens on the surface via MHC. CART therefore allows the T-cells to recognize antigens that are naturally present on cancer cell surfaces, eliciting a specified attack.

Cancer vaccines

The final immunotherapeutic approach is the potential for a therapeutic cancer vaccine. The vaccine is intended to treat existing cancers by stimulating and enhancing the body’s immune response against cancer cells. The potential for the vaccine banks on cancer-testis antigens (CTAs) (63), which are expressed only in the testis as well as in various cancer types, including EC (New York ESCC 1/NY-ESO-1). Because of their limited expression in normal tissue and expression in tumors, CTAs are great targets for cancer vaccines.

The four different kinds of immunotherapeutic approaches, TIL, TCR, CART and vaccines, offer a means of equipping the body with defenses against cancer cells. The strengthening of the immune system using these approaches makes way for a promising approach of immunotherapy that does not kill healthy cells like chemotherapy or produce a high chance of recurrence, like radiation therapy (64).

Induced pluripotent stem cells (iPSCs)

IPSCs have revolutionized the landscape of regenerative medicine and cancer research by offering a powerful platform to study disease mechanisms and develop innovative therapeutic strategies. These cells are generated by reprogramming adult somatic cells, such as fibroblasts, into a pluripotent state that closely resembles embryonic stem cells, without the associated ethical concerns of using embryos. These cells are created by reprogramming adult somatic cells to a pluripotent state. iPSCs can be generated from a patient’s own cells, which not only mitigates the risk of immune rejection but also allows for the development of personalized cancer models and therapies. The ability of iPSCs to differentiate into various cell types, including those found in esophageal tissue, provides a unique platform to study the molecular mechanisms of EC, model its progression, and screen for effective drugs (65,66).

Traditional cancer models, such as cell lines and animal models, often fail to capture the full complexity of human tumors, leading to significant challenges in translating preclinical findings into successful clinical therapies. iPSCs address this limitation by allowing the generation of EC-specific cell lines that retain the genetic and phenotypic characteristics of the original tumors, enabling researchers to recreate the tumor microenvironment in vitro. This approach facilitates the study of tumorigenesis in a controlled setting, allowing for a deeper understanding of the genetic and epigenetic changes driving cancer progression. Moreover, iPSCs have been utilized to develop three-dimensional organoid models of the esophagus, which closely mimic the structure and function of the human organ. These models are invaluable for investigating the effects of genetic mutations on cancer development and for testing the efficacy of targeted therapies thereby, increasing the likelihood of identifying drugs that will be effective in patients (66,67).

Beyond drug screening, iPSCs hold immense potential for developing cell-based therapies aimed at treating EC. One promising approach involves using iPSC-derived immune cells, such as T cells or natural killer (NK) cells, which can be engineered to specifically target and eliminate cancer cells. For instance, iPSCs can be reprogrammed to generate CAR T cells that are tailored to recognize antigens expressed on EC cells. This approach offers a highly personalized form of immunotherapy that could significantly enhance the effectiveness of treatment for EC patients, particularly those with advanced or resistant disease (67). Additionally, iPSCs could be used to model and overcome the mechanisms of therapy resistance which has been a major hurdle in the treatment of EC (67).

However, while the potential of iPSCs in EC treatment is immense, several challenges remain that must be addressed before these therapies can be widely adopted in clinical practice. One of the primary concerns is the risk of tumorigenicity associated with iPSC-derived therapies, as the reprogramming process can lead to genetic and epigenetic changes that may predispose the cells to form tumors (67). Therefore, it is crucial to develop rigorous methods for ensuring the safety and stability of iPSC-derived cells before they are used in patients. Additionally, the efficiency of differentiating iPSCs into the desired cell types, such as fully functional immune cells or esophageal epithelial cells, must be improved to make these therapies viable on a large scale. As research in this field continues to advance, iPSCs are poised to play a transformative role in the treatment of EC, offering new hope for patients through the development of personalized, targeted therapies that can overcome the limitations of current treatment options.

Human stem cells

Human umbilical cord stem cells

Human umbilical cord stem cells are considered adult stem cells as they are not a part of the fetus, but merely attached to the placenta. They are extracted from the umbilical cord either before or after the delivery of the placenta. Due to the easy extraction technique and the ability of these cells to be cryopreserved, this makes them a popular option out of the adult stem cell category. Another reason for their popularity is that they have less ethical concerns than embryonic cells, as those are extracted from embryos themselves and create ethical issues surrounding the morality of the use of stem cells. This type of adult stem cells will be focused on.

Human umbilical cord mesenchymal stem cells

Zhao et al. [2019] delved into the effects that human umbilical cord mesenchymal stem cells have on the proliferation and apoptosis of EC1 cells (68). These mesenchymal cells were both isolated and cultured in vitro, with the cell phenotype being flow cytometry, and their conditioned medium was co-cultured with EC1 cells. Zhao et al. discovered that the presence of mesenchymal stem cells inhibited the proliferation of EC1 cells; when the ratio of mesenchymal stem cells to EC1 cells was 0:1, 1:1, 2:1, 5:1, the apoptotic rate of the EC1 cells was respectively (4.07%±0.34%), (8.90%±0.36%), (10.80%±0.50%), and (15.23%±1.06%), as shown in Figure 11. Along with induced apoptosis, benign transdifferentiation appeared to occur instead of cell transformation into cancerous cells (69). Combining the umbilical cord mesenchymal stem cells with the EC1 cells also showed a reduction of tumorigenicity and metastasis (70). MiR-375 was gathered from human umbilical cords and its effect on ESCC was examined in He et al. [2020], and it was found that the expression of miR-375 and its target enabled homolog showed tumor inhibition in vivo (8). The increase in miR-375 expression suppressed ESCC proliferation in vitro, thus decreasing the progression of ESCC. While the use of adult stem cells to treat EC is not yet as advanced as other treatments, as it continues to develop there are promising results showing many possible emerging uses that adult stem cells have to offer to treat this type of cancer.

Figure 11 The number of mesenchymal cells increases in the ratios as mentioned previously, as the EC1 cells remain at a constant 1 for each ratio.

Surgical techniques

EC remains a significant challenge in oncology, with surgery playing a crucial role in its management. Over the years, advancements in surgical techniques have aimed to improve patient outcomes, reduce complications, and enhance recovery. This review focuses on the latest developments in surgical methods for EC, including minimally invasive esophagectomy (MIE), robot-assisted minimally invasive esophagectomy (RAMIE) (71), and innovative perioperative strategies. MIE represents a significant advancement over traditional open esophagectomy. This technique involves smaller incisions and the use of laparoscopic tools, which reduces surgical trauma and promotes quicker recovery (72). The MIE procedure typically involves thoracoscopic and laparoscopic phases. Surgeons use small incisions to insert a camera and surgical instruments, allowing them to view and operate on the esophagus with precision. The thoracoscopic phase focuses on mobilizing the esophagus and nearby lymph nodes, while the laparoscopic phase involves creating a conduit from the stomach or colon to reconstruct the esophagus (73).

RAMIE is an advanced surgical technique that combines the precision of robotic technology with minimally invasive approaches to treat EC. Utilizing the da Vinci Surgical System, surgeons operate from a console, manipulating robotic arms equipped with high-definition 3D cameras and specialized instruments (73,74). The procedure involves two phases: the abdominal phase and the thoracic phase. In the abdominal phase, small incisions are made to mobilize the stomach and create a gastric conduit, often monitored by indocyanine green (ICG) to ensure adequate blood supply. The thoracic phase involves thoracoscopic access, where the esophagus is mobilized and a high intrathoracic esophagogastric anastomosis is performed using a circular stapler. The robotic system enhances dexterity and control, allowing precise dissection and suturing in confined spaces, thus reducing surgical trauma and improving recovery outcomes (73).

A study conducted at a European high-volume center involving 611 patients compared postoperative outcomes of RAMIE and hybrid esophagectomy (HE). The results indicated that RAMIE significantly reduced ICU stays (P=0.0218) and had fewer postoperative complications (Clavien Dindo 0: 47.1% vs. 27.1%, P=0.0225). While lymph node yield and R0 resection rates were similar in both groups, the RAMIE group showed a trend towards lower anastomotic leakage rates (4.3% vs. 14.3%, P=0.07) (74,75). For patients, these findings are highly significant. The shorter ICU stays, and reduced complication rates translate to quicker recovery times and less postoperative discomfort, which can enhance overall patient well-being and reduce the emotional and physical strain associated with prolonged hospitalizations. Lower rates of anastomotic leakage—a severe complication in esophageal surgery—further indicate that RAMIE may provide a safer postoperative course, potentially reducing the need for additional interventions and associated morbidities. The comparable lymph node yields and R0 resection rates between RAMIE and HE suggest that RAMIE does not compromise the oncologic efficacy of the surgery. This means that patients can benefit from the minimally invasive nature of RAMIE without sacrificing the thoroughness of cancer removal, which is crucial for long-term survival outcomes (73-75).

Overall, these results underscore the feasibility and enhanced safety profile of RAMIE, making it a promising alternative to traditional surgical methods. For patients, this translates to improved surgical experiences, better recovery trajectories, and possibly enhanced long-term health outcomes. Further studies, particularly randomized controlled trials, will be essential to validate these findings and solidify RAMIE’s place in the standard treatment protocol for EC.

Anastomotic leak is a major surgical complication that occurs when the connection (anastomosis) made between two parts of the gastrointestinal (GI) tract fails to heal properly and leaks the contents into the surrounding area. This complication is particularly concerning in GI surgeries, such as those for esophageal and gastric cancers, where such leaks can lead to severe infections, prolonged hospital stays, and even mortality. Despite advancements in surgical techniques, including the adoption of minimally invasive methods like laparoscopic and robotic surgery, anastomotic leaks remain a persistent challenge. The rates of leakage vary depending on the surgical approach and specific anastomotic techniques employed, such as end-to-side circular stapling, double stapling, or side-to-side linear stapling. Factors influencing the success of an anastomosis and the risk of leakage include the choice of stapling technique, the physical condition of the patient, tissue perfusion at the anastomosis site, and the surgeon’s experience.

Furthermore, GI surgery has significantly advanced in recent years, particularly with the adoption of laparoscopic and robotic techniques as standard procedures. These minimally invasive methods have resulted in lower morbidity, higher lymph node yields, and faster recovery times. However, there remain several unresolved issues in esophageal and gastric cancer surgeries, especially concerning anastomotic techniques. Despite technical advancements, anastomotic healing remains a critical challenge in MIE, with leakage rates ranging from 8% to 24% depending on the technique used (73). A two-round Delphi process identified three main techniques for intrathoracic anastomosis: end-to-side circular stapling, end-to-side double stapling, and side-to-side linear stapling. While meta-analyses suggest comparable leak rates between linear and circular stapled anastomoses, other studies highlight lower leak rates with end-to-side purse string anastomosis. Additional factors, such as omental wraps, stapler diameter, intraoperative perfusion monitoring, and preemptive endoluminal vacuum sponge usage, add to the complexity of anastomotic procedures (73). Current research also suggests varying impacts of circular anastomosis sizes on leak rates, highlighting the need for further evaluation through randomized controlled trials.

Training and quality assessment in minimally invasive upper GI surgery are crucial due to the technical challenges of these procedures. A recent study found that the learning curve for laparoscopic gastrectomy was completed after 44 cases, with no impact on anastomotic leak rates, mortality, or overall survival. This suggests that surgical and oncological quality can be maintained while training new surgeons, aligning with the increasing emphasis on both educational outcomes and surgical standards. Complication management, particularly “failure to rescue”, has become a focal point in recent years. Endoscopic vacuum therapy (EVT) has emerged as a superior alternative to endoscopic stents for treating anastomotic leaks, offering better success rates, shorter treatment durations, and fewer complications. Although some studies report comparable outcomes between EVT and stent use, EVT’s popularity is growing, especially for high-risk anastomoses or ischemic conditions. Its use has been shown to lower morbidity and anastomotic leak rates (76-79). EVT is applicable for all wall defects in the upper GI tract, provided there is sufficient blood perfusion around the defect and a closed compartment that can collapse around the negative pressure device. The size of the defect and cavity can influence the initial approach and therapy duration, but EVT has been effective in large defects up to 15 cm, as long as the conditions for collapse around the device are met.

Stents

A stent is a small, hollow tube that can be made of plastic, metal mesh, or silicone that is inserted into the esophagus where the tumor(s) are constricting the pathway for food and liquids. This keeps the blocked area in the esophagus open to allow the passage of solids and liquids. There are several types of stents, including self-expanding metallic stents (SEMs), self-expanding plastic stents (SEPs), biodegradable stents (BD), etc. The most used type of stent is the metal mesh are research suggests this type of stent results in fewer complications compared to the plastic stents, however dysphagia appears to improve at a similar rate to both stents, thus different factors come into consideration when choosing which type of stent is suitable for a patient (80).

Abdelshafy et al. [2017] conducted a review of 350 patients who suffered from malignant dysphagia as a side effect of advanced EC (81). The average age of the participants was 62.3±12.44, with 264 (75.4%) males and 86 (24.6%) females; 203 (58%) had squamous cell carcinoma, 141 (40.3%) had adenocarcinoma, and 6 (1.7%) had another type. To be accepted into this review, it was necessary for patients to have malignant dysphagia secondary to inoperable primary EC, or they needed to be unfit for surgery. The stent of choice was a polyethylene-uncovered stent that was placed into all patients, who were positioned left laterally. An endoscope was inserted into the esophagus and used to deliver the guidewire through the esophageal stricture. The endoscope was used to approximate the size of the tumor and margins under fluoroscopic guidance, then the stent, at least 4 cm longer than the stricture, was placed. After the placement of the stent, an endoscopy and chest X-ray were utilized to confirm the position of the stent. Post-op, the patients were followed at 1–2 weeks and then every month. Seventeen patients were lost to follow-up. The pre-stent dysphagia score was an average of 3, while the post-op average was a score of 1, showing a statistically significant improvement (P<0.001). Grade 3 dysphagia was classified as being able to swallow only liquids, no solids and grade 1 dysphagia is the ability to swallow some solid foods. The average post-op patient survival rate was 96.6% at 1 month, 67.0% at 3 months, and 55.0% at 6 months, as shown in Figure 12.

Figure 12 The average survival rate of patients for all cohorts and treatments at the 1-, 3-, and 6-month post-op time mark.

Stents provide relatively quick relief to patients suffering with dysphagia due to opening the blockages in their esophagus, making this a highly considered palliative treatment plan.

Anastomotic leaks

Anastomotic leaks are one of the primary indications for EVT. These leaks, which occur in 5–30% of patients following esophageal or gastric surgery, are associated with high morbidity and mortality rates of 20–50%. Traditionally, surgical revision for esophageal leaks carried high mortality rates (up to 64%) and often resulted in esophageal discontinuity, which posed significant challenges for patient recovery and quality of life (79). EVT offers a minimally invasive alternative that combines defect coverage with adequate drainage of any associated cavities, achieving success rates between 78–100%. However, EVT is not suitable for very early leaks with massive or complete anastomotic rupture and excessive tissue necrosis, which require surgical intervention (76,82). EVT has also been effectively employed for managing complications post-bariatric surgery, such as leaks after sleeve gastrectomy or Roux-en-Y gastric bypass. Staple line leaks occur in 1–2% of patients after sleeve gastrectomy and 2–5% after Roux-en-Y gastric bypass. These leaks are typically caused by intragastric pressure exceeding staple line resistance and are characterized by a late onset and often asymptomatic presentation. EVT has demonstrated high success rates in managing such leaks, especially for patients unsuitable for surgery due to poor tissue healing or other comorbidities (72,75).

In a study, analyzed patients treated with EVT at a tertiary center between 2012 and 2021 were analyzed. The patients were divided into two cohorts (period 1 and period 2) to assess the impact of several quality improvement strategies implemented over time (76). The primary endpoint was the MTL30 composite score, which includes mortality, transfer, and length-of-stay (LOS) greater than 30 days. Secondary endpoints included EVT efficacy, complications, in-hospital mortality, LOS, and nutritional status at discharge. A total of 156 patients were included in the study. Significant improvements were observed in the latter period (period 2) compared to the earlier period (period 1) (76). The MTL30 composite score decreased from 60.8% to 39.0% (P=0.006), and EVT efficacy increased from 80% to 91% (P=0.049). Additionally, the need for additional procedures for leakage management decreased from 49.9% to 29.9% (P=0.013), and reoperations became less frequent (38.0% vs. 15.6%; P=0.001). The duration of leakage therapy was shortened from 25 to 14 days (P=0.003), and the LOS was reduced from 38 to 25 days (P=0.006). Comprehensive Complication Index decreased from 54.6 to 46.5 (P=0.034), and a higher percentage of patients were discharged on oral nutrition (70.9% vs. 84.4%, P=0.043). This study confirms the efficacy of EVT in managing upper GI leaks and highlights the positive impact of quality improvements in EVT management. The findings demonstrate that advancements in EVT techniques and earlier intervention lead to accelerated recovery, reduced complications, and improved functional outcomes for patients with upper GI leaks (76,82,83).

Palliative care

Palliative care is an approach aimed at optimizing a patient’s quality of life and mitigating the effects an illness has on an individual. Broad examples include different surgical options, pain management, physical therapy, dietary changes, and emotional support. In the case of EC, the most common methods in alleviating a patient’s cancer related symptoms are palliative radiotherapy and stents. The most common side effect of EC is dysphagia, the difficulty of swallowing liquids or solids which can range from slight difficulty to absolute blockage. Dysphagia can then lead to malnutrition and unintentional weight loss in the patient.

Palliative radiotherapy

Palliative radiotherapy is performed on a patient with the intention of relieving their symptoms, not to cure the EC itself. The aim could be to either shrink or slow the growth of the malignancies to manage symptoms related to the tumor(s). The two most common types of radiotherapy utilized for EC are external beam radiation therapy (EBRT) and brachytherapy, also known as internal radiation therapy.

Jeene et al. [2020] compared data between the original cohorts and then after 1:1 propensity score matching was done, to see the effectiveness that these two types of palliative radiotherapies have on EC patients (84). All participants needed a dysphagia grade that was equal or more than 2 according to the Ogilvie scale; original cohort had 38 with a score of 2, 36 with a score of 3, and 19 with a score of 4, while the matched cohorts had 56 with a score of 2, 42 with a score of 3, and 16 with a score of 4. The average age for the original cohorts who received brachytherapy was 69±12 and for EBRT it was 72±9; for the matched cohorts, the average was 70±13 for brachytherapy and 70±9 for EBRT. The original cohorts had 69 male participants for brachytherapy and 24 females, 91 male participants for EBRT and 24 females; the matched cohorts had 50 male participants for brachytherapy 19 females, 52 male participants for EBRT and 17 females. In total, the study had 208 participants. Within the original cohorts, 154 participants had adenocarcinoma and 49 had squamous cell carcinoma. Within the matched cohorts, 98 participants had adenocarcinoma and 38 had squamous cell carcinoma. Onto the radiotherapies themselves, the EBRT had a dosage of 20 Gy given in 5 fractions of 4 Gy which was then delivered using a linear accelerator that had a photon energy of 6 to 18 MV. The brachytherapy was instead given as a single dose therapy of 12 Gy at 1 cm from the source axis of the applicator.

After completion of the radiotherapies, each patient was instructed to record the changes, if any, with their dysphagia and this information was collected at their first follow-up visit at the 3-month mark. Fifty-five patients in the original cohorts were available for analysis in the brachytherapy group and 67 from the EBRT group. Thirty-nine patients within the matched cohorts were available for analysis from the brachytherapy group and 42 from the EBRT group. Improvement in dysphagia was determined to be greater than or equal to one point decrease in the dysphagia score. In the original cohort, 35 (64%) patients had improvement with their dysphagia after completing their brachytherapy and 53 (79%) patients had improvement with their dysphagia after completing EBRT (P=0.058). Within the matched cohorts, there was statistically significant improvement in patients’ dysphagia after being treated with EBRT than brachytherapy, 83% improvement with EBRT, while a 64% improvement with brachytherapy (P=0.048), as shown in Figure 13. Along with dysphagia improvement, the length of time until improvement was noticed was faster with EBRT than with brachytherapy; after EBRT, dysphagia improvement was noticed after 2 weeks in 67% of patients, while only in 36% of those treated with brachytherapy and after 4 weeks, 87% treated with EBRT had improvement and 60% treated with brachytherapy had improvement (P=0.01).

Figure 13 The percentage of patient improvement comparing the completion of either EBRT or brachytherapy treatment, showcasing the differences between the original and matched cohorts. EBRT, external beam radiation therapy.

EBRT appears to have greater improvement when it comes to treating dysphagia than brachytherapy; however, the latter still provides improvement for patients. EBRT works on both adenocarcinoma and squamous cell carcinoma showing improvement for both.

Strengths and limitations

The review provides a comprehensive overview of the up-to-date research done on EC. The review goes over the social and epidemiological aspects of EC as well as summarizes the diagnostic advancements, conventional and emerging therapeutics in the field. A strength of this review paper is the broad scope of coverage from providing risk factors, to explaining the molecular underpinnings of current therapeutics, discussing surgical techniques and covering multiple subjects, such as oncology, palliative care, and surgical innovations. Moreover, the paper discusses both ESCC as well as adenocarcinoma, thereby covering the highlights and unique challenges of addressing each subtype. Furthermore, the paper discusses novel treatment modalities, such as immunotherapy and stem cell-based approaches. The paper is comprehensive in explaining multiple approaches to the assessment and treatment of EC. Another strength of the paper is its comparative analysis of treatment modalities, such as the proposal of chemoradiotherapy rather than chemotherapy alone as well as the proposal of minimally invasive surgical techniques, such as RAMIE. The review also presents recent clinical trials in order to discuss the efficacy of current therapeutics. The paper also includes sections on palliative care and relief strategies, such as stent insertion, to ensure that patient-centered care is important in the treatment of EC.

However, there are also limitations to the study. Despite the effort to cover risk factors and demographic disparities, all risk factors and demographics may not be fully represented or mentioned in the paper. Also, while the paper reviews promising new therapies, many remain in the experimental stages or require more studies to evaluate their true efficacy. Moreover, the paper does not expand on or give a detailed mechanistic understanding of the development and pathogenesis of EC, so further discussion of tumor heterogeneity as well as resistance could be further explained. Due to the rapid advancements and developments of therapeutics in the field, ongoing updates are necessary in order to maintain the relevance of the review. Despite these limitations, the review remains a valuable source and mechanism of insight for EC, as it discusses current challenges and future directions that accompany therapeutics and improved patient outcomes.

Conclusions

In this review, we aimed to bring together the latest research on EC, offering a holistic view of its epidemiology, pathogenesis, and emerging treatment options. By exploring both traditional and cutting-edge therapies, our goal was to bridge the gaps in current knowledge and shed light on ways to improve survival rates and quality of life for patients.

The review by Liu et al. (85) provides an in-depth exploration of the etiology, cancer stem cells, and potential diagnostic biomarkers for EC, focusing on the molecular mechanisms underlying the disease and identifying potential targets for early detection and treatment. DiSiena et al. (86) offer an updated overview of EC, discussing the distinct subtypes of adenocarcinoma and squamous cell carcinoma, their specific risk factors, and the challenges in early detection and treatment. Harada et al. (87) review recent advances in treating EC, highlighting the development of novel therapeutic strategies, including chemotherapy, immunotherapy, and molecular targeted therapies, and discussing the challenges in achieving effective treatment outcomes. Rogers et al. (88) discuss emerging therapeutics for EC, focusing on the latest developments in treatment options and the need for personalized medicine approaches to improve patient outcomes. In contrast, the current review aims to synthesize the latest research on epidemiology, pathogenesis, and both standard and novel therapeutic strategies for ESCC and EAC. It emphasizes potential improvements in survival rates and quality of life, examines current clinical management approaches, ongoing controversies, and future directions in EC treatment, and aims to foster a deeper understanding of available therapies and promote the development of innovative treatment options to enhance patient outcomes. We address the knowledge gaps identified in the previous reviews by integrating the latest findings across various aspects of EC, including molecular mechanisms, risk factors, treatment advancements, and patient outcomes, thereby providing a more holistic perspective on the disease.

Recent advancements in EC treatment have revolutionized patient care, particularly through the adoption of minimally invasive techniques such as MIE and RAMIE. These methods offer patients shorter recovery times and fewer postoperative complications. Chemotherapy and radiotherapy remain cornerstone treatments, especially for advanced cases of EC. Innovations like IMRT provide more precise tumor targeting while minimizing harm to surrounding healthy tissues.

Immunotherapy, particularly the use of checkpoint inhibitors such as pembrolizumab, has shown promising results; however, treatment efficacy is still influenced by specific genetic mutations and tumor markers, leading to variability in patient responses. Palliative care continues to play a vital role, especially in alleviating symptoms such as dysphagia in advanced-stage patients. The use of esophageal stents and palliative radiotherapy has proven effective in improving quality of life by offering symptom relief and enabling better nutritional intake. While substantial progress has been made in understanding and treating EC, significant challenges persist. Early detection, overcoming therapy resistance, and further development of personalized treatment options remain critical areas for future research. A multidisciplinary approach that integrates surgery, advanced molecular therapies, and robust palliative care will be essential for improving both survival rates and the overall quality of life for patients battling EC.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-37/prf

Funding: This work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) under grant number (R56DK109376).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://aoe.amegroups.com/article/view/10.21037/aoe-24-37/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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