Evolving Therapeutic Strategies in Esophageal Squamous Cell Carcinoma: Advances and Perspectives

Abstract

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent forms of esophageal cancer globally, with a particularly high incidence in developing countries. Notably, Asia accounts for approximately 80% of global esophageal cancer cases, with China alone contributing to 54% of this burden. The primary treatment modality for ESCC remains esophagectomy, primarily employed for locally advanced disease, often in combination with chemotherapy and radiotherapy for advanced-stage cases. Despite significant advancements in surgical techniques and the advent of precision medicine, which has facilitated the development of targeted and immune-based therapies, critical challenges persist, including suboptimal therapeutic efficacy and the emergence of drug resistance. A comprehensive understanding of the current treatment landscape for ESCC is essential to overcoming these barriers and improving patient outcomes.

INTRODUCTION

Esophageal cancer is generally classified into two main histological subtypes: esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) [1]. ESCC is the predominant type globally, particularly in developing countries, whereas EAC is more prevalent in developed nations, with a significant incidence in Western populations [2]. The rising incidence of EAC has been strongly associated with gastroesophageal reflux disease, Barrett’s esophagus, obesity, and chronic acid exposure [3]. ESCC is among the most prevalent forms of esophageal cancer worldwide, particularly in developing countries [4]. Notably, Asia accounts for 80% of global cases, with China contributing 54%, underscoring the substantial patient burden in this region [5]. Clinical manifestations, including dysphagia, chest pain, retrosternal burning, weight loss, fatigue, and bleeding, pose significant challenges to treatment and complicate post-surgical recovery.

Despite advancements in surgical techniques and the development of diverse therapeutic strategies, esophageal cancer remains one of the most difficult malignancies to treat effectively [6,7]. Adjuvant chemotherapy and radiotherapy are commonly employed in advanced cases [8,9]. Furthermore, lifestyle-related factors such as smoking, alcohol consumption, malnutrition, anemia, and chronic inflammation have been identified as major risk factors for ESCC, contributing to its rising incidence in recent years [10-13]. This review provides a discussion of the roles and efficacy of surgical, chemotherapeutic, and radiotherapeutic approaches in the management of ESCC, with reference to the most recent studies.

ESOPHAGECTOMY

Esophagectomy remains the most reliable curative option for early-stage, locally advanced, and non-metastatic ESCC. Common surgical approaches include traditional open surgery and minimally invasive techniques. Traditional open surgery: techniques such as the Ivor-Lewis procedure and three-incision esophagectomy, involving cervical, thoracic, and abdominal incisions, are particularly suited for early and locally advanced cases [14,15]. Minimally invasive esophagectomy (MIE): this emerging approach utilizes thoracoscopic or laparoscopic techniques and is recommended for patients in good physical condition without extensive tumor invasion [16-18]. Endoscopic therapy: endoscopic mucosal resection and endoscopic submucosal dissection are preferred for early-stage lesions [19,20]. Lymphadenectomy is an integral component of esophagectomy, with notable geographical variations in practice. Western surgeons generally perform two-field lymphadenectomy, whereas three-field dissection is advocated by many Asian surgeons, particularly in Japan, for SCC [21,22]. Although debates persist regarding its associated risks and benefits, esophagectomy remains the gold standard for surgical management of ESCC [23].

An overview of the historical evolution of surgical approaches for esophageal cancer, along with their respective advantages and limitations, is presented in Figure 1 and Table 1. These findings provide a valuable framework for evaluating the progression of treatment strategies and guiding future clinical decision-making [24-28].

Figure 1. Timeline of esophageal cancer surgical techniques.

This figure illustrates the chronological development of surgical techniques for esophageal cancer treatment. Key milestones include the first successful esophagectomy performed by Franz Torek in 1909, which laid the foundation for modern esophageal surgery. In the 1960s, systematic two-field (thoracic and abdominal) and three-field (cervical, thoracic, abdominal) lymphadenectomy were introduced to enhance surgical outcomes. The advent of endoscopic mucosal resection in 1978 marked a significant step toward less invasive treatment for early-stage esophageal cancer. By 1992, minimally invasive esophagectomy emerged, combining laparoscopy and thoracoscopy to reduce surgical traumas and improve patient recovery.

Table 1.

Advantages and disadvantages of surgical techniques for esophageal cancer

Surgical technique	Advantage	Disadvantage
Traditional open surgery	- High efficacy for complete tumor removal in locally advanced cases - Established technique with predictable outcomes	- High invasiveness with significant postoperative complications, such as respiratory infections and wound issues - Prolonged recovery time
Lymphadenectomy	- Improves staging accuracy and reduces local recurrence - Three-field dissection offers superior long-term survival for specific cases	- Increased surgical complexity and operative time - Higher rates of complications, such as lymphedema and nerve injury
Endoscopic therapy (endoscopic mucosal resection/endoscopic submucosal dissection)	- Minimally invasive, with reduced risk and faster recovery - Preserves organ function, suitable for early-stage disease	- Limited to early-stage, superficial lesions - Risk of incomplete resection in larger or invasive tumors
Minimally invasive esophagectomy	- Reduced surgical trauma and blood loss - Shorter hospital stay and faster recovery	- Requires advanced surgical expertise and equipment - Limited availability in some regions due to technical demands

CHEMOTHERAPY AND RADIATION THERAPY

Chemotherapy and radiotherapy are well-established standard treatment modalities for the majority of cancers [29-31]. Specifically, for advanced ESCC, these therapies serve as essential components of treatment, often employed as adjuvant therapies following esophagectomy to mitigate the risks of recurrence and metastasis. Furthermore, for patients deemed ineligible for surgical intervention, chemotherapy and radiotherapy remain the primary therapeutic options [32]. Chemotherapeutic regimens for advanced or metastatic ESCC commonly include combinations such as cisplatin with 5-FU, paclitaxel, or docetaxel, which have been shown to prolong survival and enhance the efficacy of radiotherapy [33]. Despite these benefits, chemotherapy is limited by considerable systemic toxicities, including nausea, vomiting, alopecia, and the development of drug resistance (Table 2) [34-36]. Radiotherapy, utilizing advanced techniques such as three-dimensional conformal radiotherapy [37,38], intensity-modulated radiotherapy (IMRT) [39-41], and proton therapy, offers targeted treatment with varying levels of precision [42,43]. It is particularly effective in cases where surgery is not feasible or for addressing post-surgical residual disease. However, radiotherapy is associated with significant adverse effects, including radiation-induced esophagitis and pneumonitis (Table 3) [44-46].

Table 2.

Chemotherapy for esophageal cancer: indications and pros and cons

Treatment method	Indication	Advantage	Disadvantage
Preventive agents	- Aspirin, NSAIDs and statins:high-risk populations (e.g., chronic esophagitis, Barrett’s esophagus), patients with dyslipidemia or metabolic syndromes	- Reduces inflammation and carcinogenesis risk (e.g., COX-2 inhibition with aspirin) - May lower cancer incidence (e.g., statins suppress proliferation)	- Potential gastrointestinal bleeding (e.g., with NSAIDs) - Limited evidence in large-scale clinical trials
First-line chemotherapy	- Cisplatin + 5-FU: used for advanced or metastatic ESCC patients, significantly extending survival - Cisplatin + paclitaxel/docetaxel: for metastatic or recurrent ESCC, enhancing efficacy - Other combinations (e.g., irinotecan, nedaplatin): used as second-line treatment for chemotherapy-resistant patients	- Extends survival for advanced or metastatic patients - Preoperative chemotherapy reduces tumor size, improving surgical outcomes - Effective in combination with radiation therapy for better local control	- Significant side effects: nausea, vomiting, hair loss, immunosuppression, etc. - Potential drug resistance with long-term use, reducing effectiveness - Limited efficacy for some late-stage patients, especially those with chemotherapy-resistant tumors
Neoadjuvant chemotherapy	- Locally advanced esophageal cancer patients, preoperative chemotherapy shrinks tumors, enhancing resection success	- Shrinks tumors, improving chances for successful surgery	- Toxicity risks similar to first-line chemotherapy
Adjuvant chemotherapy	- Postoperative patients, used to clear micrometastases and reduce recurrence risk	- Reduces recurrence by clearing residual cancer cells	- Side effects: nausea, fatigue, and long-term toxicity
Chemoradiotherapy combined	- For inoperable advanced esophageal cancer patients, combining chemotherapy and radiotherapy to enhance local control	- Improves local control, especially for non-surgical patients	- Increased side effects due to combination therapy

NSAID, nonsteroidal antiinflammatory drugs; ESCC, esophageal squamous cell carcinoma.

Table 3.

Radiation therapy for esophageal cancer: indications and pros and cons

Treatment method	Indication	Advantage	Disadvantage
Three-dimensional conformal radiotherapy	- Locally advanced or inoperable patients, can precisely target tumor areas	- Non-invasive; effective for patients who cannot undergo surgery	- Potential side effects include radiation-induced esophagitis and pneumonia
IMRT	- Tumors in complex locations or near critical structures, IMRT optimizes dose distribution and reduces damage to normal tissues	- Precise targeting reduces radiation exposure to surrounding tissues	- Requires advanced technology and may still lead to side effects, especially if not optimally targeted
Proton therapy	- For tumors in complex locations or recurrence after radiation therapy, proton therapy provides higher precision	- Higher precision in targeting tumors, reducing damage to surrounding tissues	- Expensive and limited availability in some regions
Chemoradiotherapy combined	- For locally advanced or inoperable patients, chemoradiotherapy improves treatment outcomes and survival rates	- Enhanced local control and survival rates when chemotherapy is combined with radiotherapy	- Increased side effects due to the combination of chemotherapy and radiation therapy

IMRT, intensity-modulated radiotherapy.

Emerging evidence indicates that neoadjuvant chemoradiotherapy is highly effective for managing locally advanced ESCC [47,48]. Nonetheless, salvage esophagectomy, performed to treat residual or recurrent disease following chemoradiotherapy, carries a high risk of morbidity and mortality [32,43,49]. This underscores the importance of meticulous patient selection to optimize outcomes.

DISCUSSION

ESCC continues to present significant challenges in clinical management, particularly in regions with high incidence rates, such as Asia [50]. Despite advances in surgical techniques, chemotherapy, and radiotherapy, ESCC remains a highly aggressive cancer, with late-stage diagnoses contributing to high mortality rates [51]. One promising development in surgery is MIE, which has been shown to reduce postoperative complications and promote faster recovery compared to traditional open surgery [52,53]. However, the widespread adoption of MIE has been slow due to technical challenges and the steep learning curve associated with thoracoscopic and laparoscopic techniques. Long-term survival benefits of MIE, especially for locally advanced cases, are still under investigation, but it has already established itself as the preferred surgical option for early-stage tumors in well-selected patients [54].

Chemotherapy and radiotherapy are crucial components of ESCC treatment, especially for advanced cases [55,56]. Common chemotherapy regimens, such as cisplatin combined with 5-FU, paclitaxel, or docetaxel, have been shown to improve survival rates, particularly when combined with radiotherapy. However, these regimens are often accompanied by considerable systemic toxicities, including nausea, vomiting, alopecia, and drug resistance [57,58]. Innovations in radiotherapy, such as IMRT and proton therapy, have improved treatment precision, reducing damage to healthy tissues and minimizing side effects like radiation-induced esophagitis and pneumonitis [59].

Neoadjuvant chemoradiotherapy has emerged as an effective treatment for locally advanced ESCC, with evidence suggesting it can reduce tumor size and improve surgical outcomes [60,61]. However, salvage esophagectomy after neoadjuvant therapy remains a high-risk procedure, necessitating careful patient selection and monitoring. Looking ahead, the development of personalized therapies based on molecular profiling and the use of targeted therapies and immunotherapies, such as immune checkpoint inhibitors, offer potential breakthroughs in improving treatment outcomes, particularly for metastatic ESCC. These advancements could revolutionize ESCC treatment, providing new hope for patients with limited options.

CONCLUSION

In conclusion, treatment strategies for ESCC, as with other cancers, are tailored to the stage of the disease and the tumor’s characteristics. MIE has emerged as the preferred approach for early-stage ESCC, offering effective tumor resection with reduced invasiveness and minimized injury to surrounding tissues. In cases of advanced ESCC, chemotherapy and radiotherapy serve as critical components, either as adjuvant therapies or as standalone treatment modalities. Additionally, neoadjuvant and salvage therapies expand the range of options available, though their risks and benefits require careful consideration. Continued advancements in research and the development of precision medicine are expected to further enhance and individualize the management of ESCC.

Funding Statement

FUNDING None.