Long-term complete response in stage IVa esophageal squamous cell carcinoma treated with chemoradiotherapy and modulated electro-hyperthermia: A case report

Abstract

BACKGROUND

Unresectable locally advanced esophageal squamous cell carcinoma accompanied by severe systemic compromise, such as cachexia, infection, and anemia, is associated with extremely poor prognosis. Achieving durable complete remission in these patients remains uncommon. Adjunctive hyperthermia has been proposed to enhance the efficacy of chemoradiotherapy, but clinical evidence supporting long-term outcomes remains limited.

CASE SUMMARY

We report the case of a 51-year-old man with stage IVa (cT4N3M0) esophageal squamous cell carcinoma complicated by cachexia, severe anemia, and pneumonia. Following stabilization with intensive supportive care, including infection control, nutritional support, and blood transfusion, the patient underwent definitive concurrent chemoradiotherapy delivered by volumetric modulated arc therapy with cisplatin and 5-fluorouracil. Adjunctive modulated electro-hyperthermia was administered during radiotherapy. Treatment was completed without interruption, resulting in a complete response confirmed by endoscopy and computed tomography, and further supported by histopathological evaluation demonstrating a pathological complete response. The patient has remained disease-free for more than five years of follow-up.

CONCLUSION

Multimodal therapy combined with intensive supportive care may enable durable remission in selected patients with advanced esophageal squamous cell carcinoma.

Key Words: Esophageal squamous cell carcinoma; Chemoradiotherapy; Modulated electro-hyperthermia; Cachexia; Long-term complete response; Case report

Core Tip: This case report describes a patient with stage IVa esophageal squamous cell carcinoma complicated by severe cachexia, pneumonia, and anemia who achieved durable complete remission exceeding five years after definitive chemoradiotherapy combined with adjunctive electrohyperthermia. Despite multiple poor prognostic factors, aggressive multimodal therapy together with early intensive supportive care enabled successful treatment completion and long-term disease control. This case highlights the potential role of electrohyperthermia as an adjunct to chemoradiotherapy in improving outcomes in selected high-risk patients with advanced esophageal cancer with histopathological confirmation of complete response.

INTRODUCTION

Esophageal cancer is frequently diagnosed at an advanced stage and is associated with poor survival outcomes. According to data from the Taiwan Cancer Registry, the overall 5-year survival rate for esophageal cancer was only 16.8% from 2008 to 2014[1]. The prognosis is even worse in patients presenting with severe systemic conditions such as cachexia, infection, anemia, or deteriorated performance status, in whom survival is often limited to only several months[2,3]. However, treatment outcomes remain unsatisfactory in patients with multiple unfavorable prognostic factors[4]. In recent years, adjunctive hyperthermia has gained increasing attention as a potential strategy to enhance the effects of radiotherapy and chemotherapy by improving tumor perfusion, oxygenation, and radiosensitivity[5]. Nevertheless, clinical evidence demonstrating durable long-term remission associated with hyperthermia-based multimodal therapy remains limited. Here, we report a patient with stage IVa esophageal squamous cell carcinoma complicated by severe cachexia, pneumonia, and anemia who achieved a durable complete response exceeding five years following definitive chemoradiotherapy combined with adjunctive modulated electro-hyperthermia (mEHT) and intensive supportive care. This case highlights the potential role of multimodal treatment strategies in achieving long-term remission in selected high-risk patients.

CASE PRESENTATION

Chief complaints

A 51-year-old man presented with progressive dysphagia, persistent vomiting, profound fatigue, and marked weight loss.

History of present illness

The patient, a painting worker with a long history of heavy alcohol consumption, experienced progressive dysphagia and vomiting over several months, accompanied by severe unintentional weight loss. At presentation, his body weight was 40 kg with a height of 169 cm, corresponding to a body mass index (BMI) of 14.0 kg/m². He also reported generalized weakness and reduced oral intake. Chest computed tomography (CT) revealed a large esophageal mass with associated pneumonia and suspected tracheoesophageal fistula (TEF) formation, prompting hospital admission for further evaluation and management.

History of past illness

The patient had no known history of chronic systemic diseases, malignancy, or prior radiotherapy or chemotherapy. There was no history of diabetes mellitus, cardiovascular disease, chronic liver disease, or renal dysfunction.

Personal and family history

The patient reported long-term alcohol consumption. There was no known family history of esophageal cancer or other malignancies. No relevant hereditary diseases were reported.

Physical examination

On admission, physical examination revealed a cachectic appearance and pale conjunctivae. No jaundice or palpable cervical lymphadenopathy was noted. Vital signs were stable. Cardiopulmonary and abdominal examinations were otherwise unremarkable.

Laboratory examinations

Initial laboratory investigations demonstrated severe anemia with a hemoglobin level of 7.6 g/dL and leukocytosis with a white blood cell count of 13470/μL. Serum albumin was decreased at 3.2 g/dL. Renal and hepatic function tests, as well as electrolyte levels, were within normal limits.

Imaging examinations

Contrast-enhanced chest CT revealed a large soft-tissue mass (approximately 9.3 cm × 4.5 cm) involving the mid-to-lower third of the esophagus, accompanied by paratracheal and paraesophageal lymphadenopathy. Consolidation and abscess formation consistent with pneumonia, along with a suspected TEF, were also observed (Figure 1). Positron emission tomography/CT demonstrated intense fluorodeoxyglucose uptake in the primary esophageal tumor and involved mediastinal lymph nodes, without evidence of distant metastasis (Figure 2).

Figure 1 Initial chest computed tomography showing esophageal tumor and pneumonia. Contrast-enhanced axial computed tomography scan demonstrates a large soft-tissue mass involving the mid- to lower-third esophagus (white arrow), with associated paratracheal and paraesophageal lymphadenopathy. Consolidation and abscess formation suggestive of pneumonia (yellow arrow) with a suspicious tracheoesophageal fistula are also observed.

Figure 2 Baseline positron emission tomography/computed tomography confirming locoregional disease without distant metastasis. Axial fused positron emission tomography/computed tomography image shows hypermetabolic activity at the primary esophageal tumor site and involved mediastinal lymph nodes (arrows), without evidence of distant metastatic disease.

Upper gastrointestinal endoscopy revealed a protruding tumor measuring approximately 3 cm in longitudinal length, located 30 cm from the incisors. Endoscopic biopsy yielded three fragments of gray-white soft tissue, each measuring up to 0.3 cm × 0.2 cm × 0.1 cm in aggregate. Histopathological evaluation demonstrated features consistent with high-grade squamous intraepithelial neoplasia (at least squamous cell carcinoma in situ). Microscopically, the squamous epithelium exhibited full-thickness architectural and cytologic atypia, characterized by nuclear enlargement, hyperchromasia, pleomorphism, and loss of normal maturation (Figure 3). Definitive stromal invasion was not identified due to the limited depth of the biopsy. Focal areas suspicious for subepithelial connective tissue invasion were noted. The presence of keratin pearl formation further supported squamous differentiation.

Figure 3 Histopathological features of esophageal squamous cell carcinoma prior to treatment. Hematoxylin and eosin-stained sections from endoscopic biopsy specimens were examined. A: Low-power view (× 40): Multiple small, fragmented pieces of esophageal mucosa are shown. The limited tissue size (0.3 cm × 0.2 cm × 0.1 cm) constrains evaluation of deeper structures; B: Medium-power view (× 100): The squamous epithelium exhibits complete loss of normal stratification and maturation, with atypical cells occupying the entire layer; C: High-power view (× 200): Neoplastic squamous cells exhibit prominent hyperchromatic nuclei and pleomorphism, involving the full thickness of the epithelium. These features are diagnostic of at least high-grade squamous intraepithelial neoplasia (squamous cell carcinoma in situ); D: High-power view (× 400): Focal areas show keratin pearl formation, supporting squamous differentiation. While subepithelial stromal invasion is suspected, a definitive diagnosis of invasive carcinoma is precluded by the limited depth of the specimen. These findings are consistent with squamous cell carcinoma in situ with features suspicious for early invasion.

FINAL DIAGNOSIS

Based on the definitive clinical and radiological findings, the tumor was staged as cT4N3M0 (Stage IVa) according to the American Joint Committee on Cancer 8^th edition. The T4 classification was primarily supported by CT findings of esophageal wall disruption and the suspected TEF, which were clinically prioritized over the superficial biopsy findings (Figure 1). The N3 status was determined by multiple enlarged, fluorodeoxyglucose-avid mediastinal lymph nodes involving the paratracheal and paraesophageal regions (Figure 2). This discrepancy between the superficial biopsy (carcinoma in situ) and the advanced clinical stage reflects the limited sampling depth of the endoscopic procedure for such a massive lesion.

TREATMENT

Pneumonia was effectively treated with intravenous antibiotics. Anemia was corrected through blood transfusions, achieving hemoglobin levels above 10 g/dL. Nutritional support was initiated via gastrostomy tube feeding combined with appetite stimulants. Following clinical stabilization, the patient underwent definitive concurrent chemoradiotherapy. Radiotherapy was delivered using volumetric modulated arc therapy. An initial dose of 41.4 Gy in 23 fractions was administered to the gross tumor and elective regional lymphatic, including the mediastinum, supraclavicular fossa, and upper abdomen. Subsequently, the gross tumor and involved lymphadenopathy received a boost to a total dose of 59.4 Gy in 33 fractions (Figure 4). Dose constraints for organs at risk were maintained in accordance with standard protocols. Concurrent chemotherapy consisted of four cycles of the PF4 regimen, comprising cisplatin (110 mg) on day 1 and 5-fluorouracil (1150 mg) daily for four days per cycle.

Figure 4 Radiotherapy planning images demonstrating gross tumor and planning target volumes. A-C: Representative axial (A), sagittal (B), and coronal (C) views from volumetric modulated arc therapy radiotherapy treatment planning are shown. The gross tumor volume and involved lymphadenopathy regions were delineated for a sequential boost irradiation (green line), delivering a total dose of 59.4 Gy in 33 fractions, while maintaining dose constraints for surrounding normal organs. The cyan line represents the planning target volume; D: Three-dimensional reconstruction of the target volumes.

Adjunctive mEHT was administered twice weekly during radiotherapy using the Oncotherm EHY-2000+ system. The patient lay on the water bed in supine position and the machine delivered capacitive heating by radiofrequency of 13.56 MHz. The treatment was performed with a power output of 80 W, and the standing wave ratio was maintained between 1.02 and 1.05 to ensure optimal impedance matching. Over the eight sessions, the thermal energy delivered to the esophageal tumor and lymphadenopathy regions averaged 290.9 kJ per session (range: 282.1-324.9 kJ), utilizing a 20 cm diameter electrode. Each one-hour session was initiated within one hour following radiotherapy, showing good treatment tolerability.

During treatment, grade 1 mucositis, esophagitis, nausea and vomiting were noted. Chemotherapy related anemia (grade 1 to grade 3) was corrected by blood transfusions. The patient completed the entire course of therapy without interruptions, supported by ongoing nutritional therapy throughout the treatment period.

OUTCOME AND FOLLOW-UP

The initial post-treatment response was evaluated by endoscopy at approximately 2.2 months after the completion of concurrent chemoradiotherapy. The examination revealed a 3-cm long healing ulcer located between 32 and 35 cm from the incisors (Figure 5).

Figure 5 Follow-up endoscopy and imaging after treatment completion. Endoscopic and radiological follow-up after multimodal treatment. A: Endoscopic view at approximately 2.2 months post-chemoradiotherapy showed a healing ulcer without evidence of residual tumor; B: Follow-up endoscopy at 58 months post-chemoradiotherapy revealed no signs of local recurrence; C: Follow-up computed tomography scan at approximately 2.5 months post-chemoradiotherapy, showing significant tumor regression and resolution of pneumonia; D: Follow-up computed tomography scan at 60 months (5 years) post-chemoradiotherapy, confirming a sustained complete response and progression-free status.

Histopathological examination of the post-treatment endoscopic biopsy specimens showed fragments of esophageal mucosa with normal squamous epithelium and active inflammation. The subepithelial connective tissue demonstrated a mixed inflammatory infiltrate, predominantly composed of neutrophils and lymphocytes. These findings are consistent with post-treatment inflammatory changes. No evidence of residual dysplasia or malignant squamous epithelial cells was identified in the examined specimen. These findings support the absence of residual tumor at the primary site (Figure 6). The pathological findings were consistent with the endoscopic and radiological assessments, collectively supporting the achievement of a clinical and pathological complete response. At approximately 2.5 months post-chemoradiotherapy, follow-up CT imaging demonstrated significant regression of the primary esophageal tumor and complete resolution of the pneumonia (Figure 5). Long-term surveillance has continued to demonstrate a sustained complete response, as confirmed by the latest endoscopic follow-up at approximately 58 months post-chemoradiotherapy, which showed no signs of local recurrence (Figure 5). A milestone follow-up CT scan at 60 months (5 years) post-chemoradiotherapy confirmed a sustained complete response and progression-free status (Figure 5). The patient’s nutritional and functional status improved remarkably during the follow-up period; his body weight increased from 40 kg (BMI: 14.0 kg/m²) at presentation to 52 kg (BMI: 18.2 kg/m²) by the initial post-treatment evaluation and has remained stable thereafter. He successfully regained full oral intake without dysphagia and returned to normal daily activities with an Eastern Cooperative Oncology Group performance status of 0. Long-term surveillance, including regular clinical evaluations and imaging studies, has consistently shown no evidence of local recurrence or distant metastasis. As of the latest clinical evaluation at day 1968, the patient remains disease-free with no late complications, such as esophageal stenosis or swallowing difficulties, related to chemoradiotherapy or hyperthermia. This exceptional outcome, with survival exceeding five years, stands in stark contrast to the historical 5-year overall survival rate of 16.8% for esophageal cancer. The patient’s treatment timeline, intervention and follow-up are summarized in Table 1.

Figure 6 Histopathological findings after treatment. Hematoxylin and eosin-stained sections from post-treatment endoscopic biopsy specimens were evaluated. A: Low-power view (× 40): Post-treatment biopsy showing preserved architecture of the esophageal mucosa with evidence of chronic inflammatory cell infiltration in the stroma. The arrow indicates a representative area for detailed evaluation; B: Medium-power view (× 100): Magnified view of the arrow-indicated area in (A). The squamous epithelium demonstrates regenerative changes with restoration of normal stratification and maturation. No evidence of expansile epithelial proliferation or tumor nests is observed; C: High-power view (× 200): Further magnification of the same region. The epithelial cells lack cytologic atypia, with normal nuclear-to-cytoplasmic ratios. No dysplastic or malignant features are identified; D: High-power view (× 400): Highest magnification of the arrow-indicated area. Post-treatment endoscopic biopsy specimen demonstrates subepithelial connective tissue with prominent inflammatory infiltrates composed predominantly of neutrophils and lymphocytes. No cytologic atypia or malignant squamous cells are identified in the examined field. These findings support the presence of a pathological complete response at the primary tumor site.

Table 1 Treatment timeline and interventions.

Day (date)	Intervention and clinical status
Day 0 (July 29, 2020)	Diagnosis and initial care: Diagnosis of stage IVa (cT4N3M0) esophageal squamous cell carcinoma complicated by pneumonia, cachexia (body mass index 14.0), and anemia. Initiation of intravenous antibiotics; blood transfusions to correct anemia
Day 5 (August 3, 2020)	Supportive care: Placement of gastrostomy tube and port-A; initiation of nutritional support
Day 14 (August 12, 2020)	Treatment initiation: Commencement of definitive concurrent chemoradiotherapy using volumetric modulated arc therapy and PF4 regimen (cisplatin/5-FU)
Day 14-58 (August 12-September 25, 2020)	Adjunctive therapy: Eight sessions of modulated electro-hyperthermia administered twice weekly using the Oncotherm EHY-2000+ system; mean thermal energy 290.9 kJ (range: 282.1-324.9 kJ)
Day 58 (September 25, 2020)	Completion of treatment: Successful completion of the full course of chemoradiotherapy and modulated electro-hyperthermia without interruptions
Day 126 (December 2, 2020)	Initial response evaluation: Endoscopy revealed a healing ulcer without malignancy (biopsy-proven). Patient’s weight increased from 40 kg to 52 kg (body mass index: 18.2)
Day 1968 (December 18, 2025)	Long-term follow-up (> 5 years): Latest follow-up via computed tomography scan and endoscopy confirmed ongoing disease-free status (complete response) with no late complications

DISCUSSION

This case illustrates an exceptional and durable complete response in a patient with multiple unfavorable prognostic factors, including advanced-stage esophageal squamous cell carcinoma (cT4N3M0). Such patients typically have extremely poor outcomes, and long-term survival is rarely reported. In this patient, however, aggressive multimodal therapy consisting of intensive supportive care, definitive chemoradiotherapy, and adjunctive mEHT resulted in sustained disease control exceeding five years.

Early and aggressive supportive care played a pivotal role. Cancer-associated cachexia impairs tolerance to oncologic therapies, weakens immune function, and correlates with poor survival[6]. In this patient, enteral feeding via gastrostomy tube helped correct negative energy balance, preserved lean body mass, and stabilized performance status. Adequate caloric and protein intake throughout treatment minimized interruptions, supported hematologic recovery, and promoted mucosal healing. Post-treatment nutritional rehabilitation likely contributed to sustained remission.

Similarly, timely correction of anemia, common in advanced esophageal cancer, was critical. Hypoxia in anemic tumors compromises radiotherapy efficacy and worsens outcomes[7]. In this case, blood transfusions raised hemoglobin to therapeutic levels, optimizing tumor oxygenation and enhancing responsiveness to chemoradiotherapy.

Definitive chemoradiotherapy was delivered without delay, comprising volumetric modulated arc therapy-based radiotherapy and cisplatin/5-FU chemotherapy. Adjunctive mEHT was administered concurrently and may have contributed to treatment efficacy in conjunction with chemoradiotherapy and optimal supportive care. mEHT selectively targets malignant cells based on dielectric differences, inducing membrane-level heating and apoptosis while sparing normal tissue[8]. In addition to local cytotoxic effects, hyperthermia improves tumor perfusion and oxygenation, sensitizing tumor cells to both radiation and chemotherapy[9].

At the molecular level, hyperthermia is known to upregulate heat shock proteins (HSPs), particularly HSP70 and HSP90. These proteins act as danger-associated molecular patterns and immunologic adjuvants. They facilitate the release and cross-presentation of tumor-associated antigens by dendritic cells, promoting the activation and expansion of cytotoxic T lymphocytes[10,11]. In this patient, repeated sessions of local mEHT may have amplified antitumor immune responses beyond the irradiated field, supporting the observed systemic disease control.

Hyperthermia also exerts broader effects on the tumor microenvironment. By increasing vascular permeability and perfusion, it improves drug delivery and alleviates tumor hypoxia. Concurrently, it modulates immune cell dynamics - enhancing infiltration of effector T cells while suppressing immunosuppressive cell populations such as regulatory T cells and myeloid-derived suppressor cells. Hyperthermia may also induce a shift in cytokine profiles and promote the release of additional danger-associated molecular patterns, collectively transforming the tumor microenvironment from an immunosuppressive to an immunostimulatory state[12,13]. These effects may synergize with chemoradiotherapy and immune activation to promote durable tumor eradication. In this case, the achievement of a complete response was not only supported by imaging and endoscopic findings but also confirmed by histopathological evaluation of post-treatment biopsy specimens, which demonstrated the absence of residual malignant squamous cells. This pathological confirmation provides robust evidence of true tumor eradication at the primary site, strengthening the validity of the observed durable long-term disease-free survival. Importantly, histopathological confirmation of complete response is rarely reported in patients with advanced esophageal squamous cell carcinoma treated with definitive chemoradiotherapy, particularly in those with multiple adverse prognostic factors. This finding further underscores the potential contribution of multimodal therapy, including adjunctive mEHT, in achieving durable tumor control.

A meta-analysis demonstrated that combining hyperthermia with chemoradiotherapy significantly improved complete response rates, local control, and overall survival compared to chemoradiotherapy alone[14]. Recent retrospective and prospective studies further support the beneficial role of mEHT in managing various solid tumors, including esophageal cancer[15,16].

As a single case report, causal relationships between adjunctive therapies and outcome cannot be definitively established, and favorable tumor biology or exceptional treatment response may also have contributed. In this complex case, the integration of intensive supportive care, definitive chemoradiotherapy, and adjunctive mEHT created a biologically favorable environment that overcame an otherwise poor prognosis, resulting in durable long-term complete remission. This outcome highlights the potential of multidisciplinary, personalized strategies and suggests that even patients with severe systemic compromise may achieve sustained remission when aggressive supportive care enables uninterrupted definitive therapy.

CONCLUSION

This case demonstrates that durable long-term remission may be achievable in selected patients with advanced esophageal squamous cell carcinoma despite multiple poor prognostic factors. Multimodal therapy combined with intensive supportive care may facilitate treatment completion and contribute to sustained disease control.

ACKNOWLEDGEMENTS

We sincerely thank Dr Jiann-Der Wu of the Department of Pathology at Ditmanson Medical Foundation Chiayi Christian Hospital for his valuable assistance in providing histopathological slide images and expert pathological interpretation.