Expanding horizons in esophageal squamous cell carcinoma: The promise of induction chemoimmunotherapy with radiotherapy

Abstract

Esophageal squamous cell carcinoma (ESCC) remains a highly aggressive malignancy with limited effective therapeutic options for patients with locally advanced unresectable disease. The study by Wei et al, featured in this issue, highlights the potential of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy to improve treatment outcomes in this challenging patient population. This retrospective analysis of 132 patients demonstrates promising results, including a median progression-free survival of 14.2 months and overall survival of 19.9 months, alongside an acceptable safety profile. Notably, the study identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors, emphasizing the synergistic potential of integrating immune checkpoint inhibitors with radiotherapy. While these findings are encouraging, they require further validation through prospective trials, along with biomarker-based and immune response studies, to refine patient selection and maximize therapeutic benefits. This editorial explores the implications of this research, its impact on clinical practice, and future directions for advancing the treatment landscape of ESCC.

Key Words: Esophageal squamous cell carcinoma; Chemoimmunotherapy, Radiotherapy; Immune checkpoint inhibitors; Locally advanced cancer; Treatment outcomes

Core Tip: This editorial highlights the study by Wei et al, which examines the impact of induction chemoimmunotherapy followed by radiotherapy or concurrent chemoradiotherapy in patients with locally advanced esophageal squamous cell carcinoma (ESCC). The study demonstrates improved survival outcomes and a manageable safety profile, identifies the effectiveness of induction therapy and maintenance immunotherapy as key prognostic factors. This innovative approach represents a promising advancement in the treatment of ESCC and underscores the need for future prospective trials and mechanistic studies incorporating biomarker investigations to refine therapeutic strategies and enhance patient outcomes.

INTRODUCTION

Cancer remains a major global health challenge, with an estimated 19.3 million new cases and 10 million cancer-related deaths worldwide in 2022[1]. Advances in cancer treatment, ranging from traditional approaches to emerging therapies, have been crucial in improving patient outcomes[2]. Esophageal cancer ranks among the most lethal malignancies, with 510716 new cases and 445129 deaths, making it the 11th most common cancer and the 7^th leading cause of cancer-related mortality globally[1]. Despite advancements in diagnosis and treatment, the overall five-year survival rate for esophageal cancer remains dismal at approximately 20%[3].

Among the histological subtypes, esophageal squamous cell carcinoma (ESCC) poses a significant challenge, particularly in China, where it accounts for the majority of esophageal cancer cases[4]. Patients with locally advanced unresectable ESCC face especially poor prognoses, with five-year survival rates ranging from 10% to 30% or even lower, reflecting both global trends and regional variations influenced by factors such as healthcare access, treatment availability, and early detection rates[5,6]. These alarming statistics underscore the urgent need for improved therapeutic strategies and prognostic biomarkers to guide clinical decision-making and enhance patient outcomes[2,7].

Over the past decades, cancer therapies have evolved significantly, transitioning from surgery and radiotherapy to the advent of chemotherapy, targeted therapies, and immunotherapy[1]. Despite these advancements, the standard treatment for locally advanced ESCC remains chemoradiotherapy[5], which is an effective regimen yet often associated with high toxicity and limited long-term survival benefits[8]. Furthermore, recurrence rates remain high, and not all patients respond favorably to existing regimens[9]. This highlights a critical gap in the treatment landscape, where durable tumor control and improved survival outcomes remain elusive for many patients[10]. Addressing these unmet needs requires innovative treatment combinations that enhance efficacy while maintaining tolerability[11].

The recent focus on combining treatment modalities, such as chemoimmunotherapy with radiotherapy, has emerged as a promising approach to improve tumor control and survival while managing toxicity[12]. Such strategies aim to exploit the synergistic effects of chemotherapy, immunotherapy, and radiotherapy[13]. In ESCC, this multimodal combination represents a novel therapeutic avenue that could potentially overcome the limitations of conventional treatments, offering a pathway to more durable responses and prolonged survival[14].

Treating ESCC with multimodal approaches is challenging due to several factors. Anatomically, the proximity of the esophagus to vital structures such as trachea, heart, and major blood vessels limits surgical options and the safe delivery of radiotherapy. Clinically, ESCC is often diagnosed at advanced stages because early symptoms are nonspecific, reducing the effectiveness of localized treatments[15]. Biologically, the tumor’s heterogeneity and its tendency to spread through lymphatic channels complicate disease control[16]. Although chemoradiotherapy is the standard treatment, it often causes significant side effects, such as esophagitis and nutritional issues, which can limit patient tolerance to therapy[17]. Additionally, the tumor microenvironment (TME) may further suppress immune responses, reducing the effectiveness of immunotherapies[18,19]. Patient-related factors, including malnutrition, comorbidities, and poor overall health, may also preclude aggressive treatment options. These challenges underscore the urgent need for personalized approaches that balance treatment efficacy with patient safety.

In this issue of the World Journal of Clinical Oncology, the study by Wei et al[20] critically examines the use of induction chemoimmunotherapy followed by definitive radiotherapy or concurrent chemoradiotherapy as a promising strategy to address this critical unmet clinical need. By incorporating immune checkpoint inhibitors (ICIs) with standard chemotherapy and radiotherapy protocols, this approach seeks to improve treatment response rates, prolong progression-free survival (PFS), and enhance overall survival (OS) while mitigating the adverse effects commonly associated with conventional therapies[20,21]. The findings of this study have the potential to reshape current treatment paradigms and offer new hope for patients with advanced ESCC, who have historically faced limited therapeutic options and poor prognoses.

KEY INSIGHTS AND INNOVATIONS

This retrospective study offers a comprehensive evaluation of combining chemotherapy with ICIs and radiotherapy in patients with locally advanced ESCC[22,23]. The findings are particularly noteworthy when compared to conventional chemoradiotherapy (CRT) approaches.

In terms of safety profile, treatment-related adverse events (AEs) aligned with expectations, with no treatment-related deaths[24]. Grade 3 and 4 toxicities were common, with esophagitis occurring in 63.6% of patients and neutropenia in 25%. Postoperative Grade 3-4 morbidities were less frequent, including surgical wound infection (2.3%), acute renal failure (2.3%), and anastomotic stricture (2.3%). These rates are comparable to those reported in previous studies evaluating chemoradiotherapy alone, where grade 3 or higher toxicities have ranged from 60% to 70% for esophagitis and approximately 20% to 30% for neutropenia[25]. Importantly, the addition of ICIs did not significantly increase the incidence of severe AEs compared to historical data, underscoring the manageable safety profile of this regimen despite incorporating immunotherapy.

For survival outcomes, the study reported a median PFS of 14.2 months and OS of 19.9 months, which represent significant improvements over historical benchmarks with standard CRT, where median PFS typically ranges from 8 to 10 months, and median OS from 12 to 16 months[26]. A similar study reported a median PFS of 9.7 months and an OS of 18.5 months in patients undergoing definitive chemoradiotherapy, further supporting these survival benchmarks[27]. This improvement highlights the potential survival benefit of integrating induction chemoimmunotherapy with radiotherapy compared to traditional approaches. Additionally, the study identified the effectiveness of induction therapy and maintenance immunotherapy as independent prognostic factors for OS, highlighting their critical role in improving patient outcomes[28].

These findings are particularly significant given the challenges associated with combining systemic therapies and radiotherapy in patients who have historically faced poor prognoses, high toxicity risks, and limited treatment options. By demonstrating improved survival without a corresponding increase in severe AEs, this approach offers a clinically meaningful advancement over conventional CRT regimens.

CLINICAL AND RESEARCH IMPLICATIONS

The study by Wei et al[20] highlights the therapeutic potential of integrating ICIs, including pembrolizumab and camrelizumab, with conventional therapies, underscoring the synergy between immunotherapy and radiotherapy. This combination appears to enhance tumor control while maintaining an acceptable safety profile[22,29]. However, the translation of these findings into clinical practice presents several practical challenges, warranting careful consideration. While the combination of immunotherapy and radiotherapy shows promising efficacy, understanding the full spectrum of treatment-related AEs, including long-term toxicities, remains essential[30]. Potential long-term toxicities of this combination therapy include radiation-induced esophageal strictures, pulmonary fibrosis, cardiotoxicity, and chronic dysphagia[31], all of which may significantly impact patients' quality of life. Additionally, ICIs have been associated with prolonged immune-related AEs (irAEs), such as endocrine dysfunction (e.g., hypothyroidism, adrenal insufficiency), persistent pneumonitis, and chronic colitis[32,33]. Given these risks, long-term follow-up and proactive management strategies are crucial to optimizing patient outcomes while minimizing late-onset complications[22]. Future studies should prioritize comprehensive safety assessments and strategies to manage potential side effects in diverse patient populations.

The TME, including immune evasion pathways such as CD47-SIRPα signaling, plays a pivotal role in determining treatment response[34], particularly in ESCC[35]. The TME comprises immune cells, stromal cells, blood vessels, and extracellular matrix components, all orchestrated by cytokines and soluble mediators that modulate tumor cell behavior, disease progression and therapy outcomes[18,36]. An immunosuppressive TME, often driven by CD39-mediated adenosine signaling, characterized by high levels of regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor-associated macrophages[37,38], can hinder the efficacy of both radiotherapy and ICIs[39].

Radiotherapy has been shown to modulate the TME through multiple mechanisms[40]. On one hand, it can enhance antitumor immunity by promoting antigen release, increasing major histocompatibility complex expression, and facilitating T-cell infiltration into tumors[41]. On the other hand, radiotherapy may also induce immunosuppressive effects that limit sustained immune responses[42]. These effects include the upregulation of programmed death-ligand 1 (PD-L1) on tumor and immune cells, increasing recruitment of Tregs and MDSCs[43], and the release of immunosuppressive cytokines such as TGF-β and IL-10[44]. Additionally, high-dose radiation can damage vascular integrity within the tumor, reducing immune cell infiltration[40], while low-dose radiation may reprogram certain immune cells into more suppressive phenotypes[45]. The dual nature of radiotherapy underscores the complexity of its interaction with the immune system.

Despite these promising mechanistic insights, several practical challenges arise when translating combination therapies into routine clinical practice. Managing treatment-related AEs, such as esophagitis, hematologic toxicities, and irAEs, is critical to preventing treatment interruptions and ensuring patient adherence[33,46]. Management strategies, including prophylactic supportive care and dose modifications, play a key role in mitigating these toxicities and improving patient outcomes[47]. Early initiation of supportive measures (e.g., nutritional support, growth factor administration, and corticosteroids for irAEs) is essential[48]. Patient-specific factors, including comorbidities, age, and performance status, may limit tolerance to aggressive regimens, underscoring the importance of individualized treatment planning[49]. Real-world considerations, such as resource availability, cost, and patient compliance with frequent treatment visits, can also impact therapy implementation. Multidisciplinary care teams and clear patient education are vital in addressing these challenges. Future research should explore adaptive treatment strategies, such as precision dosing using model-informed reinforcement learning, to improve tolerability without compromising efficacy[50]. By addressing these practical concerns, clinicians can optimize patient outcomes while minimizing treatment-related risks.

MECHANISMS OF ICI AND RADIOTHERAPY SYNERGY

Combining ICIs with radiotherapy aims to overcome these barriers by enhancing antitumor immunity while counteracting TME-mediated resistance[40,51]. Radiotherapy-induced tumor cell death promotes the release of tumor-associated antigens, facilitating antigen presentation by dendritic cells and triggering the activation of cytotoxic CD8⁺ T cells[40,52]. However, sustained antigen exposure can lead to T-cell exhaustion, characterized by the upregulation of inhibitory receptors such as programmed cell death protein 1 (PD-1), lymphocyte activation gene 3 (LAG-3), and TIM-3, which impairs T-cell functionality[53,54]. Strategies aimed at reversing T-cell exhaustion, such as mitochondrial modulation as well as combination therapies targeting multiple immune checkpoints and cytokine signaling have shown promise in restoring anti-tumor immunity[55]. For example, dual blockade of PD-1 and LAG-3 has been demonstrated to enhance T-cell reinvigoration, while cytokine-based interventions, including IL-2 and IL-12, have been explored to promote effector T-cell function and improve response durability in ESCC[56]. ICIs, particularly those targeting the PD-1/PD-L1 axis, help to reverse T-cell exhaustion, restore effector T-cell activity, thereby enhancing antitumor responses[57].

In addition to modulating T-cell responses, the cytokine milieu plays a crucial role in shaping treatment outcomes. Radiotherapy can induce the release of pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and IL-2, which promote immune activation and T-cell recruitment[58]. However, these effects are often counterbalanced by the simultaneous release of immunosuppressive cytokines like TGF-β and IL-10, which inhibit effective antitumor immunity[40]. Targeting these cytokine pathways in combination with ICIs and radiotherapy may further enhance immune activation and improve treatment efficacy[59].

Additionally, immune activation pathways involving STING signaling and cGAS-STING pathways are activated following radiotherapy-induced DNA damage, leading to the production of type I interferons (IFNs) that promote dendritic cell maturation and T-cell priming[60]. The integration of ICIs into this context amplifies the T-cell-mediated cytotoxic response, creating a robust immune attack against the tumor[61]. Emerging strategies, such as combining radiotherapy with STING agonists or targeting MDSCs that contribute to immune evasion, are being explored to further optimize the efficacy of this multimodal approach[62].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

Understanding and targeting the TME, cytokine release patterns, T-cell exhaustion pathways, and immune activation cascades are crucial for optimizing therapeutic strategies and improving patient outcomes in ESCC[63]. However, several questions remain that warrant further investigation.

First, the interplay between radiotherapy and the immune microenvironment, including potential immunosuppressive effects, requires deeper exploration[64]. Second, identifying biomarkers predictive of treatment responses is critical for enhancing the clinical utility of this regimen[65]. Ongoing efforts focus on evaluating PD-L1 expression, which has been widely studied as a potential predictor of response to ICIs[66]; however, its predictive value in ESCC remains inconsistent due to variability in detection methods and cutoff thresholds[67]. Another biomarker is circulating tumor DNA (ctDNA) has emerged as a promising non-invasive biomarker, enabling the monitoring of tumor burden, detection of minimal residual disease, and prediction of treatment response, thereby supporting personalized oncology approaches[68]. Furthermore, dynamic changes in ctDNA levels during therapy have been associated with survival outcomes and could serve as an early indicator of treatment efficacy[69]. Despite these advancements, challenges remain, including standardizing testing protocols, establishing universally accepted thresholds, and integrating biomarker data into clinical decision-making[70]. Further research is needed to validate these biomarkers in larger, prospective cohorts.

Finally, the retrospective design of this study and its limited sample size necessitate validation through well-designed prospective trials[71,72]. Such prospective studies are essential for minimizing bias, enhancing generalizability, and providing more robust evidence of the treatment’s efficacy and safety in diverse patient populations.

LIMITATIONS AND FUTURE RESEARCH NEEDS

While the results of this study are promising, several limitations should be acknowledged. First, the retrospective study design is inherently prone to selection bias, information bias, and confounding factors that may affect the generalizability of the findings[73]. Second, the limited sample size restricts the statistical power of the study and may not adequately capture the variability in patient responses or rare AEs[74]. This limitation highlights the necessity of conducting power analyses in future studies to determine an adequate sample size capable of detecting clinically meaningful differences with statistical significance[75].

To address these limitations, there is an urgent need for well-designed, prospective multicenter clinical trials to validate the efficacy, safety, and long-term outcomes of the combination therapy across diverse patient populations[76]. Such trials would not only enhance the robustness of the findings but also improve their generalizability to different clinical settings. As emphasized by Subbiah[77], global collaboration in multicenter studies is essential to account for regional variations in treatment response, healthcare access, and genetic diversity, ultimately ensuring broader applicability of results.

BIOMARKERS AND PERSONALIZED TREATMENT STRATEGIES IN CLINICAL PRACTICE

Biomarkers play a pivotal role in predicting treatment responses, monitoring therapeutic efficacy, and guiding personalized treatment strategies in ESCC[78]. Despite the promising results of combining ICIs with radiotherapy, heterogeneous patient responses underscore the need for reliable predictive biomarkers to improve patient selection and outcomes[33,79].

Among the most widely studied biomarkers is PD-L1 expression, which is often used to predict ICI responsiveness[67,80]. Higher PD-L1 levels correlate with improved outcomes in some studies; however, its predictive value remains inconsistent due to variations in detection methods, cutoff thresholds, and tumor heterogeneity[69]. Ongoing trials are working to establish standardized PD-L1 scoring systems to enhance predictive accuracy[69,81].

Another promising biomarker is ctDNA, which provides a non-invasive approach for tracking tumor burden, detecting minimal residual disease, and predicting early treatment response[82]. Fluctuations in ctDNA levels during therapy have been linked to PFS and OS[69]. Active clinical trials aim to validate ctDNA-guided treatment adjustments in ESCC[82,83].

Additional biomarkers, such as tumor mutational burden (TMB) and microsatellite instability (MSI), have shown potential in predicting ICI efficacy, with higher TMB and MSI-high tumors generally associated with better responses[84]. While these markers are well established in other cancers, their clinical relevance in ESCC requires further investigation[85]. Advances in next-generation sequencing (NGS) and multi-analyte platforms, including liquid biopsy technologies are enabling the development of multi-biomarker signatures such as PD-L1, TMB, MSI, and immune gene profiles for improved patient stratification and early detection[86].

Beyond molecular biomarkers, personalized treatment strategies should also consider TME characteristics and patient-specific factors[36]. Tumors with immune-inflamed phenotypes, characterized by high CD8⁺ T-cell infiltration and elevated IFN-γ signatures, are more likely to benefit from ICI-based therapies[87,88]. Conversely, immune-excluded or immune-desert phenotypes may require strategies to modulate the TME, such as combining radiotherapy to enhance immune cell infiltration[89].

NGS-based genetic profiling can identify actionable mutations, enabling tailored therapy combinations[90]. For instance, patients with high TMB or specific immune gene expression profiles may benefit from intensified combination regimens, while those with low biomarker expression may be considered for alternative approaches[91]. Emerging evidence suggests that dynamic biomarker monitoring (e.g., serial ctDNA measurements) can help adjust treatment plans in real-time, further personalizing therapy[92].

In clinical practice, integrating biomarker data into treatment algorithms ensures that patients most likely to benefit from combination therapies receive them while minimizing unnecessary toxicity in non-responders[93]. Prospective, biomarker-driven trials are essential to establish the clinical utility of these markers and to develop personalized decision-making frameworks for ESCC[94]. Such trials should also include diverse patient populations, accounting for variations in age, gender, comorbidities, and tumor staging to enhance the generalizability of findings[95].

FUTURE DIRECTIONS

The findings presented in this study pave the way for significant advancements in management of ESCC[96]. Incorporating maintenance immunotherapy into treatment regimens holds the potential to achieve sustained tumor control[97,98]. Additionally, exploring dose escalation strategies and implementing novel radiation techniques, such as proton therapy and intensity-modulated proton therapy, could further enhance treatment outcomes by delivering higher radiation doses to tumors while sparing surrounding healthy tissues, thereby reducing toxicity and improving patient tolerance[99]. Both adaptive radiotherapy, which allows for real-time adjustments based on patient-specific anatomical and tumor changes, and proton-based therapies, known for their favorable dose distribution, represent promising approaches to maximize therapeutic efficacy while minimizing collateral damage to normal tissues[100,101]. Future clinical studies should consider integrating these technologies to further refine treatment protocols and optimize patient outcomes.

Beyond clinical application, investigating multimodal treatment strategies that extend beyond the combination of ICIs and radiotherapy is crucial for enhancing therapeutic efficacy[102]. Future research should explore the potential synergistic effects of combining ICIs with targeted therapies, chemotherapy, and other modalities to overcome resistance and improve patient outcomes[103]. Such approaches may offer distinct advantages in different molecular subtypes and stages of esophageal cancer, underscoring the need for personalized treatment strategies[104]. Key areas of interest include identifying optimal sequencing and dosing regimens, as well as understanding how these combinations affect tumor biology, immune modulation, and treatment resistance[105].

Preclinical research into the mechanisms underlying the synergy between ICIs and radiotherapy will be essential for refining and expanding these therapeutic approaches[51]. Future studies should focus on elucidating the biological pathways that contribute to overcoming immunotherapy resistance and enhancing radiotherapy response[41]. Key areas of interest include understanding how radiotherapy modulates the TME, enhances antigen presentation, and promotes immune cell infiltration[106]. Investigating the role of the cGAS-STING pathway activation, changes in MDSCs, and the influence of Tregs following combined therapy could provide critical insights into mechanisms of action and resistance[107].

To facilitate these mechanistic studies, patient-derived xenograft (PDX) and syngeneic mouse models are valuable preclinical tools. PDX models, which involve implanting human tumor tissues into immunodeficient mice, can recapitulate the complexity and heterogeneity of human tumors, allowing for the assessment of therapeutic efficacy and resistance mechanisms in a patient-relevant context[108]. Syngeneic models, which use immunocompetent mice bearing murine tumors, are particularly useful for studying immune-tumor interactions and the immune-mediated effects of combination therapies such as ICIs and radiotherapy[109]. Incorporating these models into future studies could elucidate the contribution of different immune cell populations to treatment outcomes and help identify predictive biomarkers, ultimately guiding the development of more effective ESCC treatment strategies[110].

Identifying mechanisms of drug resistance remains a significant barrier to long-term treatment efficacy. Techniques such as CRISPR-Cas9 screening offer powerful tools for discovering key genetic drivers of resistance to chemoimmunotherapy and radiotherapy[111]. For instance, recent studies have demonstrated how genome-wide loss-of-function screens can uncover critical resistance pathways, providing potential targets for combination therapies[112]. Integrating such approaches into ESCC research could facilitate the development of strategies to overcome resistance, personalize treatment regimens, and ultimately improve patient outcomes[113]. Moreover, incorporating molecular profiling into clinical trials could enhance patient stratification, enabling biomarker-driven treatment decisions and better identification of patients most likely to benefit from multimodal therapies[114].

Addressing patient diversity in future studies is equally crucial for enhancing the applicability and generalizability of research findings[115]. The current study, while informative, is limited by its sample size and may not fully capture the variability in clinical characteristics such as age, gender, comorbidities, and tumor staging[116]. Future prospective multicenter trials should prioritize the inclusion of diverse patient populations to better reflect real-world clinical settings and ensure broader applicability[117]. Incorporating patients from different demographic backgrounds and with varied clinical profiles will provide more comprehensive insights into treatment efficacy, safety, and patient-specific outcomes, ultimately improving clinical decision-making and patient care[118].

Lastly, evaluating the long-term effects of combining immunotherapy with radiotherapy is vital. Long-term follow-up studies are essential to assess the durability of treatment benefits, monitor potential late-onset toxicities, and understand the impact on OS and quality of life[119]. Such data will be critical in optimizing treatment regimens for sustained patient benefit while minimizing adverse effects.

CONCLUSION

The study by Wei et al[20] represents a significant advancement in addressing the poor prognosis associated with advanced ESCC[120]. By integrating induction chemoimmunotherapy with radiotherapy in a clinically well-characterized ESCC cohort, this research provides valuable insights into treatment efficacy and safety. The findings highlight the potential of combining established therapies with innovative approaches to expand therapeutic options and improve patient outcomes[121].

To fully validate these findings and optimize treatment strategies, there is an urgent need for well-designed, multicenter, prospective trials to assess the efficacy, safety, and long-term outcomes of combination therapies across diverse patient populations[122]. Furthermore, collaborative efforts at a global scale will be essential for translating these promising results into standardized clinical practice[123,124]. As the field progresses, such insights will play a crucial role in reshaping the prognosis and outcomes for patients with this challenging malignancy.