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All issues Volume 6 (2025) Vis Cancer Med, 6 (2025) 5 Full HTML
Open Access
Review
Issue
Vis Cancer Med
Volume 6, 2025
Article Number 5
Number of page(s) 11
DOI https://doi.org/10.1051/vcm/2025004
Published online 04 April 2025

© The Authors, published by EDP Sciences, 2025

Licence Creative CommonsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction

About 20–30% of patients with esophageal cancer have distant metastasis at first diagnosis and a 5-year overall survival (OS) rate of less than 10% [1]. A high recurrence rate has been detected even in patients with relatively early-stage lesions who receive standard radical treatment. Besides, salvage treatments following recurrence remain unsatisfactory, contributing to poor prognosis.

Systemic therapy combined with palliative and best supportive treatment is recommended for selective advanced patients, according to the National Comprehensive Cancer Network (NCCN) guidelines for Esophageal and Esophagogastric Junction Cancers. Specifically, only palliative or optimal supportive treatment is recommended for patients with Eastern Cooperative Oncology Group performance status (ECOG PS) > 2; additional systemic treatment is recommended for patients with ECOG PS 0–2, and two-agent chemotherapy is recommended for first-line treatment. Trastuzumab is recommended for patients with human epidermal growth factor receptor 2 (HER2) overexpression-positive adenocarcinoma. Local treatments, such as radiotherapy and surgery, are primarily used for palliative care [2].

Advanced esophageal cancer has an extremely poor prognosis, with cancer-specific survival (CSS) of 2–11 months [3]. Although the recent introduction of immunotherapy has led to a breakthrough in systemic treatment regimens, OS in advanced patients has only been extended from 12 months to 15.3 months [4].

Advanced esophageal cancer, as a highly heterogeneous disease, consists of a variety of disease states ranging from relatively limited non-regional lymph node metastasis to oligometastasis and extensive multi-organ metastasis. However, current guidelines cannot sufficiently guide individualized treatment. Second, the efficacy of systemic treatment alone is not satisfactory, with only 0.5–1 year. The promotion of immunotherapy has gradually improved the effect of systemic therapy. Longer patient survival gives local treatments a better chance of working. Meanwhile, local treatment is suitable for liver, lung, brain, and other metastatic sites of esophageal cancer. Therefore, local treatment combined with systemic treatment may improve patient survival. Clinically, significant benefits have been observed in some patients with advanced esophageal cancer who underwent chemoradiotherapy, as exemplified by the case presented in Video 1 from our center. However, clinical consensus has not been reached regarding the optimal local treatment, systemic treatment plan, modality, timing, or appropriate patient population for combining local and systemic treatments.

This review focuses on the research status of radiotherapy combined with systemic therapy in advanced esophageal cancer under the background of chemotherapy and immunotherapy to provide a reference for clinical practice.

A comprehensive literature review was performed to investigate esophageal cancer. The PubMed, EMBASE, and CENTRAL databases were searched using the following keywords: “esophageal cancer,” “metastasis/recurrence/advanced,” “local treatment/surgery/radiotherapy,” “chemotherapy/immunotherapy/drug,” and related synonyms. The search was restricted to articles published in English. Additionally, ongoing and completed trials related to advanced esophageal cancer were obtained from ClinicalTrials.gov.

Treatment intent and patient selection

Palliative treatment

Systemic treatment should be considered, with or without adjunctive palliative or supportive care, for patients with a Karnofsky Performance Scale (KPS) score ≥ 60 or PS ≤ 2, according to the current NCCN guidelines. However, only palliative or supportive care is recommended for patients with a KPS < 60 or ECOG PS > 2 [2].

Palliative and supportive care primarily aims to alleviate pain and maximize patients’ quality of life. The interventions aimed at symptom relief, nutritional improvement, and addressing psychological issues of esophageal cancer patients may extend survival and improve prognosis. Symptoms of advanced esophageal cancer commonly include dysphagia, obstruction, pain, bleeding, nausea, and vomiting. However, these symptoms often show limited response to systemic treatment, necessitating a multidisciplinary approach involving endoscopy, surgery, and radiation therapy. Common palliative treatments encompass palliative radiation therapy (external beam radiotherapy [EBRT], brachytherapy, irradiation stents, etc.), surgery, and stent placement.

Guidelines for Radiotherapy of Esophageal Carcinoma (2020 Edition) recommend palliative radiation therapy for several patient groups, including patients with advanced disease who exhibit reduced or stable metastatic foci after chemotherapy; those with extensive multistation lymph node metastasis unsuitable for curative radiation therapy; individuals experiencing clinical symptoms caused by distant metastasis; advanced patients requiring relief from esophageal obstruction and nutritional enhancement; and those with residual uncontrolled recurrent disease after radical treatment [5].

Radioactive stent implantation, brachytherapy, and EBRT can provide survival benefits, alleviate dysphagia, and maintain manageable toxicity levels. Stent implantation can rapidly ameliorate dysphagia symptoms, while radioactive stents incorporating I131 particles can improve therapeutic effect in advanced-stage cases through radiation therapy, potentially extending OS by 1–3 months [6–8].

Notably, brachytherapy can escalate the local dose of the esophageal cancer lesion while minimizing the impact on vital organs. Brachytherapy demonstrates superior long-term relief of dysphagia to stent implantation, making it suitable for patients with an expected survival of more than 3 months [9]. Common doses include a single dose of 12 Gy and 6–8 Gy administered 2–3 times. The palliative dose of external radiation therapy is below 50 Gy (30–45 Gy) with a daily fraction of 2–3 Gy [10]. A retrospective study indicated that palliative external beam radiation therapy was associated with a lower risk of adverse reactions than stent implantation while demonstrating similar pain and dysphagia relief effects [11]. Another study suggested that external radiation therapy significantly relieved symptoms compared with internal radiation therapy [12]. Although the three common palliative radiotherapy modalities can relieve symptoms and may improve survival, combined treatment does not demonstrate significant advantages and may increase toxicity. Therefore, combined treatment is not recommended as routine practice [10]. A phase 3 randomized controlled trial revealed that adding palliative radiotherapy to standard treatment did not improve survival but significantly delayed the occurrence of bleeding events [13].

Curative-intent treatment

Some patients may derive additional benefit from local treatment, particularly those with limited disease, such as oligometastases or regional recurrences. Post-treatment recurrence can manifest as either locoregional recurrence, distant metastatic recurrence, or both. Such patients often present with an earlier initial staging and may have a more favorable prognosis than those with more extensive disease, especially those with locoregional recurrence. These patients should be prioritized for active curative treatment.

Some patients exhibit relatively limited metastatic lesions where distant metastases are identified at the initial diagnosis and may benefit from curative treatment, particularly in the context of oligometastases. Oligometastases are considered an intermediate state between localized disease and widespread distant metastasis [14]. The European Society for Radiotherapy and Oncology (ESTRO) /European Organization for Research and Treatment of Cancer (EORTC) developed a binary decision tree through Delphi consensus based on tumor progression and metastatic characteristics to categorize oligometastases into nine distinct states using five key questions [15]. Two multicenter phase II studies initiated by Canada (SABR-COMET [16] and SABR-5 [17]), including various tumors with 1–5 metastatic lesions, demonstrated that stereotactic ablative radiotherapy (SABR) combined with palliative supportive care significantly extended progression-free survival (PFS) and OS while maintaining safety and manageability. Subsequent secondary analysis of SABR-5 revealed that synchronous oligometastasis (metastasis diagnosed within 6 months of primary tumor diagnosis) was associated with a favorable prognosis, whereas oligoprogression (presence of new metastases during active systemic therapy) was associated with poorer outcomes [18].

However, there is no consensus regarding the specific definition of oligometastasis, with definitions ranging from ≤3 to ≤6 metastatic foci. Some scholars argue that all lesions classified as oligometastases can be effectively treated using radical local therapies. A systematic review and meta-analysis [19] focusing on the definitions and local treatments for esophageal and gastric cancer-related oligometastases summarized 28 studies or protocols, of which most defined oligometastasis as having ≤3 metastatic foci in one organ. Notably, some studies defined oligometastasis as having ≤4 metastatic foci in one organ. However, recent clinical investigations have adopted more lenient criteria. For instance, the ESO-Shanghai 13 study limited inclusion criteria for patients with oligometastasis to those with 1–3 metastatic foci across 1–4 organs, of which eligible candidates could benefit from radical radiotherapy [20].

Treatment strategies

Radiation therapy in the context of chemotherapy

The recommended dose for curative-intent concurrent chemoradiotherapy is 50–50.4 Gy via conventional fractionation, according to Guidelines for Radiotherapy of Esophageal Carcinoma. Some patients may benefit from an increased dose of up to 60 Gy. However, the adverse effects (AEs) associated with high doses may outweigh the benefits. The recommended dose for patients receiving radiotherapy alone is 60–70 Gy via conventional fractionation [5]. The standard curative radiotherapy for advanced esophageal cancer involves applying the same dose and fractionation regimen as that for locally advanced disease. The primary tumor is treated via conventional fractionation, delivering single doses of 1.8–2.0 Gy and a total dose of 50 Gy, while metastatic lesions are treated with larger fractions.

Furthermore, retrospective studies have demonstrated that the median progression-free survival (mPFS) for patients with advanced esophageal cancer receiving only systemic therapy is about 4–8 months, which can be extended to 8–10 months with the addition of local therapy. Similarly, combined treatment modalities can improve the median overall survival (mOS) from 12–15 months to 16–18 months. The designs and results of relevant studies are summarized in Table 1 [21–31].

Table 1

Studies investigating the combination of radiotherapy and chemotherapy.

Most previous investigations combining radiotherapy and chemotherapy are retrospective. A meta-analysis that combined six non-randomized controlled trials assessing metastatic gastric or esophageal cancer with few metastases found that local plus systemic treatment was associated with improved OS in patients with few metastases (Hazard ratio [HR] = 0.47, 95% CI: 0.30–0.74), particularly those involving liver metastasis. Notably, HR was reported to be as low as 0.39 (95% CI: 0.22–0.59). However, bias may exist within these findings due to the inclusion of all retrospective studies [19]. Another recent meta-analysis demonstrated that local combined systemic therapy extended both PFS and OS among advanced esophageal cancer patients compared with single systemic therapy (HR = 0.55 [95% CI: 0.37–0.72] and HR = 0.69 [95% CI: 0.58–0.81], respectively). Patients exhibiting fewer metastases and lower recurrence rates had significantly better OS [32].

ESO-Shanghai 10 represents a pioneer prospective single-arm investigation in this domain, including 34 patients with PS of 0–1, involvement at 1–2 sites, 1–2 metastatic lesions, and maximum tumor diameter < 5 cm of esophageal squamous cell carcinoma, necessitating primary tumor resection or radiotherapy with no progression for over 3 months [33]. The metastatic lesions underwent stereotactic body radiation therapy (SBRT) concomitant with chemotherapy at a recommended dose of 48 Gy/8f, achieving a biologically effective dose (BED) > 80, except for bone metastasis. The mPFS and mOS reached 13.3 months and 24.6 months, respectively. The one-year and two-year local control rates were 92.1%. Besides, tolerability was favorable without significant adverse reactions related to SBRT observed, except for a singular instance of grade three toxicity. Compared with locally advanced esophageal cancer within the same center, the authors concluded that SBRT with or without chemotherapy could yield near-curative outcomes in meticulously selected patients with low-burden metastatic esophageal squamous cell carcinoma. However, most patients had only one metastatic lesion (82%), and a relatively higher proportion exhibited lymph node involvement in the abdominal cavity (38%), potentially contributing to the favorable prognosis relative to other studies.

In summary, local treatment combined with systemic therapy can significantly extend the survival of patients with advanced esophageal cancer under general conditions while maintaining safety and tolerability. However, it should be noted that the current research evidence primarily stems from chemotherapy-based retrospective studies on well-conditioned subjects.

Radiation therapy in the context of immunochemotherapy

Current research suggests that radiation therapy has a dual effect on the immune system, with its positive effects outweighing the negative ones, ultimately promoting the development of anti-tumor immune responses. Apoptotic substances are internalized by immune cells, such as macrophages and dendritic cells, after radiation therapy, leading to the induction of immune tolerance. Additionally, radiation-induced cell necrosis and necroptosis can enhance tumor lymphocyte infiltration. Furthermore, a systemic anti-tumor effect can be induced beyond the irradiated area, a phenomenon known as the distant effect [34, 35]. Therefore, radiation therapy combined with immunotherapy/enhances local tumor control and elicits a synergistic anti-tumor response throughout the body.

Wu et al. retrospectively reported that radiotherapy combined with immunotherapy or chemotherapy for patients with recurrent or metastatic esophageal squamous cell carcinoma significantly improved dysphagia relief (from 30% to 64%). However, this combined treatment did not improve the PFS and OS in the general population, showing significant prolongation only in the local region recurrence population [36]. Furthermore, 44% of the patients received palliative radiotherapy (30–48 Gy/10–24 fractions). Notably, only the lymph node recurrence population had a lower acceptance rate of radiotherapy compared with the previous studies. This difference may explain the slight differences in treatment effects between groups. There are a few prospective studies focusing on local treatments for advanced esophageal cancer. The recently published randomized controlled phase II study ESO-Shanghai 13 and its preliminary single-arm study ESO-Shanghai 10 [20, 33] concluded that SBRT combined with chemotherapy achieved nearly curative effects with lower toxicity in carefully selected low-burden metastatic esophageal squamous cell carcinoma patients with metastatic lesions. Furthermore, ESO-Shanghai 13 expanded the criteria for oligometastatic disease to include 1–4 metastatic lesions in 1–3 sites. The patients were then randomized into a local combined systemic treatment group and a pure systemic treatment group. The recommended sequence of local treatments is as follows: SBRT > thermal ablation > conventional radiotherapy > surgery. Finally, over 80% of patients received radiotherapy. The systemic treatment regimen included chemotherapy, immunotherapy, and chemo-immunotherapy at almost the same ratios.

Furthermore, the addition of local treatment extended mPFS from 6.4 months to 15.3 months (HR = 0.26, p < 0.0001) at a median follow-up time of 30.5 months, while mOS was extended from 18.6 months to not reached (HR = 0.42, p = 0.0020). However, the addition of local treatment in the group receiving immunotherapy significantly improved PFS but did not improve survival (mPFS 18.0 vs. 9.6 months, p = 0.044; mOS 30.0 vs. 20.6 months, p = 0.19). About 45% of patients in both groups had non-regional lymph node metastasis as a favorable prognostic factor, and about 80% of patients had only 1–2 metastatic lesions in a single organ, explaining the better treatment effect. However, further research should analyze PD-L1 expression status to fill this gap. Fatigue, neutropenia, and leukopenia were the most common adverse reactions reported in the above study. The incidence of grade 3 or higher adverse reactions was similar in both groups (combined treatment vs. systemic treatment: 47% vs. 45%). The incidence of treatment-related esophagitis was significantly higher in the combined treatment group (21% vs. 2%, p = 0.036) than in the systemic treatment. The incidence of treatment-related death was similar in both groups. Specifically, two (4%) patients in the combined treatment group died of esophageal fistula, and one (2%) patient in the systemic treatment group died of immune-related pneumonia. Another prospective single-arm study included patients with metastatic squamous cell carcinoma who had failed first-line treatment and found that low-dose radiotherapy (esophageal lesion: 40 Gy/20 fractions; metastatic lesions: 30 Gy/10 fractions) combined with chemo-immunotherapy improved survival. The mPFS and mOS were 6.9 months and 12.8 months. However, the treatment-related grade 3 or higher adverse reactions were relatively high (63.3%) [37]. The findings in the aforementioned studies are detailed in Table 2.

Table 2

Studies investigating the combination of radiotherapy and immune checkpoint inhibitors in esophageal squamous cell carcinoma.

In summary, immunotherapy has further enhanced the prognosis of advanced esophageal cancer. Although the incorporation of local therapy enhances survival, the associated toxic reactions should be taken into consideration. Besides the molecular biological mechanisms discussed above, the evolution of systemic therapy should also be considered. Local treatments are more likely to be effective as patient survival in advanced stages improves. Moreover, common metastases of esophageal cancer, particularly those in the liver, lung, and bone, are often amenable to radiotherapy. Therefore, insights from the management of oligometastatic lung cancer and prostate cancer may inform esophageal cancer treatment strategies. However, the effectiveness of adding local therapy to the new first-line systemic therapy remains uncertain due to the lack of high-quality evidence. Therefore, extensive phase III studies are needed to validate the efficacy and safety of combining radiotherapy with systemic therapy. There are several ongoing prospective studies on combining radiotherapy with immunotherapy for advanced esophageal cancer (Table 3).

Table 3

Ongoing studies investigating the combination of radiotherapy and immune checkpoint inhibitors.

Adverse effects

The balance between therapeutic efficacy and AEs is critical in the treatment of advanced esophageal cancer. Three prospective studies and four retrospective studies have assessed AEs, with two studies including immunotherapy (Tables 2 and 3) [20, 21, 28, 29, 33, 36, 37]. The incidence of grade 3 or higher AEs in these studies was about 41–63.3%. Common AEs included leukopenia, radiation pneumonitis, and radiation esophagitis. The incidence of any-grade leukopenia ranged from 36% to 47% following systemic therapy alone and increased to 47–80% after combined treatments. The occurrence of grade 3 or higher leukopenia showed either no significant change or a slight increase after combination therapy (from 8% to 41.8%) compared with systemic treatment alone (5–36%). The incidence rates of grade 3 or higher radiation esophagitis and radiation pneumonia were 0–14.5% and 3–10%, respectively. Grade 5 adverse events in a prospective study included fatal complications in 4% of patients receiving combined therapy (esophageal fistula and gastric ulcer perforation) and 2% in systemic therapy-only patients (immune pneumonitis) [20].

Overall, the combination of local and systemic treatments is tolerable. However, retrospective studies may have biases, and prospective studies often involve healthier populations. Besides, rare severe AEs in immunotherapy may be underestimated due to small sample sizes, indicating that risks and benefits must be carefully assessed.

Limitations and future directions

This review has several limitations that may affect its outcomes and interpretations. First, regarding radiotherapy technology and dosage for advanced esophageal cancer management, evidence-based medicine principles predominantly rely on Intensity-Modulated Radiation Therapy (IMRT) technology. However, there is a lack of uniform specifications for dosage administration specifically targeting locally advanced diseases. Therefore, subsequent investigations should focus on precision-based radiation therapies, such as Volumetric Modulated Arc Therapy (VMAT) and Tomotherapy, to compare different dosages and fractionation patterns, to achieve an optimized treatment protocol. Second, the optimal timing for integrating radiation therapy with systemic treatments is unknown. Some clinical trials have implemented concurrent chemo-immunotherapy along with radiation, while others have pursued induction chemo-immunotherapy followed by radiation to address residual lesions. Prospective and retrospective analyses indicate that combined localized intervention with systemic therapies is secure and viable, particularly among patients with limited metastasis or recurrence within advanced esophageal squamous cell carcinoma. This may result in significant survival extension compared to exclusive reliance upon systemic treatments. Other limitations in current relevant studies include small-scale prospective cohorts, bias within retrospective appraisals, and inadequate representation during the immunology era.

Future research should include expansive prospective inquiries, integration of systemic therapies amidst an immunotherapeutic backdrop, advanced radiation delivery techniques, standardized radiation protocols, exploration of molecular mechanisms, and machine learning-assisted precision stratification for patient subgroups.

Conclusions

Radiotherapy, combined with systemic therapies, plays an increasingly important role in the management of advanced esophageal cancer, particularly in patients with limited metastatic disease. Nonetheless, future research should prioritize large-scale prospective clinical trials, integrate radiotherapy with immunotherapy, and apply advanced technologies to identify patients most likely to benefit from various treatment strategies.

Funding

The research was funded by National Key R&D Program of China (2022YFC2705000, 2022YFC2705001).

Conflicts of interest

The authors declare no conflicts of interest.

Data availability statement

Data available within the article or its supplementary material.

Author contribution statement

Jianrui JI and Yunsong LIU: Conceptualization, Writing, Original draft preparation.

Yongxing BAO and Yu MEN: Methodology, Validation.

Jun WANG and Zhouguang HUI: Supervision, Reviewing and Editing.

All authors have revised the paper, approved the submitted version and agreed to be accountable for all aspects of the work.

Ethics approval

Ethics approval was not required.

Supplementary material

Video 1: A case of tumor control in a patient with advanced esophageal cancer treated with chemoradiotherapy. Access here

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Cite this article as: Ji J, Liu Y, Bao Y, Men Y, Wang J & Hui Z. Review of radiotherapy combined with systemic therapy for advanced esophageal cancer: from chemotherapy to immunotherapy era. Visualized Cancer Medicine 2025; 6, 5. https://doi.org/10.1051/vcm/2025004.

All Tables

Table 1

Studies investigating the combination of radiotherapy and chemotherapy.

In the text
Table 2

Studies investigating the combination of radiotherapy and immune checkpoint inhibitors in esophageal squamous cell carcinoma.

In the text
Table 3

Ongoing studies investigating the combination of radiotherapy and immune checkpoint inhibitors.

In the text

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