
==== Front
PeerJ
PeerJ
PeerJ
PeerJ
2167-8359
PeerJ Inc. San Diego, USA

18065
10.7717/peerj.18065
Oncology
Radiology and Medical Imaging
Radical chemoradiotherapy for superficial esophageal cancer complicated with liver cirrhosis
Bao Hejing 12
Bao Hehong 3467242060@qq.com

Lin Liping 12linliping@pyhospital.com.cn

Wang Yuhuan 4
Zhang Longbin 5
Zhang Li 5
Zhang Han 5
Liu Lingxiang 12
Cao Xiaolong 12
1 Department of Oncology, The Affiliated Panyu Center Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
2 Cancer Institute of Panyu, Guangzhou, China
3 Department of Psychosomatic Medicine, Chongqing University Three Gorges Hospital, Wanzhou, Chongqing, China
4 Department of Oncology, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
5 Department of Oncology, Chongqing University Three Gorges Hospital, Wanzhou, Chongqing, China
Zhang Xin
11 9 2024
2024
12 e1806517 4 2024
19 8 2024
© 2024 Bao et al.
2024
Bao et al.
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits using, remixing, and building upon the work non-commercially, as long as it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

Background

Although chemoradiotherapy is an effective treatment for esophageal cancer, its feasibility in esophageal cancer with cirrhosis remains largely unclear.

Methods

We retrospectively studied 11 patients with superficial esophageal cancer with liver cirrhosis (Child-Pugh score ≤8) who underwent radical chemoradiotherapy from four centers, and the overall survival rate, local control rate and adverse events at 1 and 3 years were explored.

Results

The median age of the included patients was 67 years (Inter-Quartile Range 60–75 years). Complete response was observed in most patients (n = 10, 90.9%), and the remaining patient was unevaluable. The 1- and 3-year overall survival and local control rates were 90.9% and 90.9%, and 72.7% and 63.6%, respectively. Hematotoxicity was a common adverse reaction, and seven patients developed radiation esophagitis, with grade 3–4 observed in two cases. All cases of radiation dermatitis (n = 4) and radiation pneumonia (n = 2) were grade 1–2. Gastrointestinal bleeding occurred in two patients, including one with grade 1–2 bleeding, and one died.

Conclusion

Radical chemoradiotherapy is a potential treatment option for patients with superficial esophageal cancer complicated with cirrhosis. However, it can increase the risk of bleeding, which warrants prompt recognition and intervention.

Radical chemoradiotherapy
Superficial esophageal cancer
Liver cirrhosis
Retrospective study
Natural Science Foundation of Chongqingcstc2021jcyj-msxmX0950 Panyu Central Hospital projectPY-2023-024 Health Science and Technology Project of Guangzhou20241A011114 This work was supported by the Natural Science Foundation of Chongqing (cstc2021jcyj-msxmX0950), the Panyu Central Hospital project (PY-2023-024) and the Health Science and Technology Project of Guangzhou (20241A011114). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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pmcIntroduction

Esophageal cancer (EC) is a common malignant digestive tract tumor with a poor prognosis and high mortality (Rogers et al., 2022; Li et al., 2023). Notwithstanding that the past decade has witnessed unprecedented medical advances, including combination strategies, the 5-year survival rates for patients with esophageal cancer remain relatively low (Waters & Reznik, 2022; Xu et al., 2024; Dai et al., 2024). It is well-established that Asia has a high incidence of liver cirrhosis, and since liver cirrhosis and esophageal cancer have common risk factors, such as alcohol and smoking, the incidence of esophageal malignancies in patients with cirrhosis is high. In this respect, studies have shown that esophageal cancer and liver cirrhosis coexist in approximately 7.0% of patients (Bassegoda et al., 2022; Asti et al., 2018; Fujisaki et al., 2022).

T1a and T1b esophageal squamous cell carcinomas (ESCCs) are designated superficial esophageal neoplasms (SENs) regardless of lymph node or distant organ metastasis (Noh et al., 2020). Endoscopic submucosal dissection (ESD) has gained broad recognition as a treatment for SEN to avoid esophagectomy (Kawachi et al., 2022; Chen, 2022). However, due to the technical complexity of esophageal ESD, there is a significant risk of bleeding (2.1%) and perforation (5%) (Ishihara, 2022; Kim et al., 2023). Severe delayed bleeding may also occur after ESD (Lin, Lin & Gong, 2021). The use of ESD in patients with cirrhosis has been associated with a higher risk of complications due to coagulopathy, decreased platelet count, and/or co-presence of esophageal varices (Kolb et al., 2021). Accordingly, some endoscopists consider the coexistence of cirrhosis and SEN a contraindication for ESD treatment. The incidence of lymph node metastasis (including vascular invasion) after surgical resection in T1b-SM1 ESCC patients ranged from 8.3% to 53.1% (Akutsu et al., 2013; Li et al., 2013). Several studies have reported on adjuvant chemotherapy and postoperative adjuvant radiotherapy in pT1a-MM/pT1b-SM1 ESCC patients after ESD, demonstrating the significant role of chemoradiotherapy in the treatment of early esophageal cancer (Koterazawa et al., 2018; Yoshimizu et al., 2018; Nishibuchi et al., 2020; Zhang et al., 2020; Lu et al., 2024).

Esophagectomy is usually recommended when esophageal tumors involve the submucosa (Min et al., 2018). However, cirrhosis patients are at high risk of perioperative complications and death due to impaired liver function, with mortality rates reaching 45% for esophageal surgery and other extrahepatic surgery (Yamada et al., 2006). Alternatively, some patients receive chemoradiotherapy, depending on patient comorbidities, tumor location, and metastasis (Emi et al., 2022). Several cases of cT1bN0M0 esophageal cancer patients that underwent RT have recently been reported (Kawamoto et al., 2022; Kodaira et al., 2010). Chemoradiotherapy (CRT) outcomes revealed a non-inferiority trend in overall survival (OS) of cT1bN0M0 EC patients compared to surgery (Lyu et al., 2022; Suzuki et al., 2022).

Although the life expectancy of patients with liver cirrhosis combined with esophageal varices is shortened, with the development of esophageal cancer treatment methods, it is recommended to intervene in such patients, especially for those with well-compensated cirrhosis and those who may choose liver transplantation (Tapper & Parikh, 2023). For patients with esophageal cancer who cannot undergo endoscopic or surgical treatment, radiotherapy can also achieve a high disease control rate and is an alternative treatment option (Ai et al., 2024; Jiang et al., 2024; McPhail et al., 2024). To our knowledge, there are still few literatures on local treatment methods, drug treatment methods and outcomes of patients with esophageal cancer combined with cirrhosis. There is no report on the feasibility of chemoradiotherapy for esophageal cancer in the context of cirrhosis. To assist clinicians in treating this challenging patient group, we conducted a retrospective analysis of the outcomes of chemoradiotherapy for esophageal cancer in the context of cirrhosis, aiming to evaluate the efficacy and safety of chemoradiotherapy in patients with compensated cirrhosis and esophageal varices.

Methods

Patient selection

We reviewed the medical records, radiotherapy plans and diagnostic images of EC patients who underwent radiotherapy/chemoradiotherapy (RT/CCRT) at Guangzhou Panyu Central Hospital, Chongqing University Three Gorges Hospital, Southern Medical University Nanfang Hospital, and Sun Yat-Sen University Cancer Center from January 2014 to December 2021. The inclusion criteria were as follows: (I) esophageal squamous cell carcinoma confirmed by pathology; (II) The Eastern Cooperative Oncology Group (ECOG) performance score was 0–2; (III) cT1N0M0 Cancer based on the Eighth Edition of the Tumour, Node, Metastasis (TNM) classification of the International Union Against Cancer (UICC); (IV) Compensatory cirrhosis (Child-Pugh score ≤8). All patients were pathologically diagnosed by biopsy, and staging was confirmed by computed tomography (CT) scan or positron emission tomography/computed tomography, esophagogastroduodenoscopy and Lugol staining, and endoscopic ultrasound (EUS). Exclusion criteria include other concurrent malignancies, difficult-to-treat infections and serious comorbidities such as diabetes. The present study was approved by the ethics committees of the Ethics Committee of Panyu Central Hospital (PYRC-2023-188). Patients provided informed written consent at the time of data collection.

Chemoradiotherapy

All enrolled patients underwent CT imaging for tumor localization. In cases that were difficult to identify with CT imaging, a titanium clip was placed during gastroscopy to facilitate tumor localization (Case 3-Figs. 1A–AH). The patient was placed in the supine position with arms hanging down on both sides of the body. The thermoplastic film was fixed in place, and the slice thickness was 5 mm for contrast-enhanced CT. CT was conducted to identify the upper and lower boundaries of esophageal tumors or the titanium clips in cases where the lesion could not be observed. According to the International Committee on Radiometric Unit Points, selective lymph node irradiation (ENI) was used to cover bilateral supraclavicular and mediastinal lymph node areas, or affected field irradiation (IFI), including primary tumors with margins of 2 to 4 cm. The linear accelerator was used to deliver 6 or 10 MV-X external irradiation, and IMRT radiotherapy was administered to all patients. The normal tissue tolerance dose limits were set as follows: the maximum dose to the spinal cord was less than 38 Gy, heart V30 <20%, V5 <40%, V20 <20%, and V30 <10% for both lungs. The subsequent treatment plan was developed by physicists in accordance with the prescribed dose requirements. The daily dose of RT was 1.8–2.0 Gy, 5 days a week, and the total dose was 50.4 to 60 Gy.

10.7717/peerj.18065/fig-1 Figure 1 Gastroscopic images of Case 1 before and during treatment.

(A and B) During gastroscopy, a large erosion area, partially coarse and covered with white keratinized tissue, was observed in the esophagus 25–30 cm away from the incisors. (C and D) During gastroscopy, esophageal masses were labeled with titanium clips that were inserted at the upper and lower margins of the lesions. (E and F) Several linear and nodular varicose veins can be seen from the middle and lower esophagus to the cardia surface with negative red-wale signs. (G and H) Repeat endoscopy after radiotherapy showed that titanium clips were inserted in the original esophageal lesion with rough localized mucosa, and no ulcers or masses were observed.

All patients received chemotherapy combined with radiotherapy except those in poor general condition (ECOG = 2). The chemotherapy regimen consisted of S-1, 70 mg/m2 daily, taken orally on days 1 to 14 and 29 to 42; 5-fluorouracil 700 mg/m2 on days 1–4, every 4 weeks, plus cisplatin 70 mg/m2 on day 1, every 4 weeks. Alternatively, paclitaxel 50 mg/m2 and carboplatin (target area under curve 2 mg/ml/min) were administered on the first day, four times per week.

This study used the Monaco treatment planning system to characterize patient images and outline the gross tumor volume (GTV) and clinical target volume (CTV). The thickness of CT sections was 5 mm, and the skin, esophageal varices, and liver of patients were delineated. After the outline of the organs was delineated, the GTV, CTV, esophageal varices volume (EVV) and liver volume were directly calculated using the volume estimation function of the software. A dose-volume histogram (DVH) of the measurement curve was generated to record V20, V30 and V40 of esophageal varices.

Evaluation and statistical analysis

In the present study, complete response (CR) was defined as the absence of the primary tumor and irregular erosive, ulcerative, or significantly elevated lesions observed during endoscopy and/or the absence of malignant cells in the biopsy specimen (Kim et al., 2015). Local control rates and the time from the start of radiotherapy until the patient died from any cause were assessed. Adverse events were classified according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI CTCAE, Version 4.0). Kaplan-Meier survival analysis was used to calculate the 1- and 3-year overall survival and local control rates.

Results

Clinical and therapeutic characteristics of patients

Table 1 shows the clinical and therapeutic characteristics of the included patients (n = 11). The median age of patients included was 67 years (range 60–75 years), with male predominance (n = 8, 72.7%) and most patients older than 65 years (n = 7, 63.6%) and having hepatitis B or C-related cirrhosis (n = 8, 72.7%). Seven patients (63.6%) reported regular alcohol consumption. The ECOG score was 0–1 in most cases (n = 9, 81.8%). The median albumin, total bilirubin, international normalized ratio (INR) value and platelet count were 36.1 g/L (IQR, 33.5–39.3), 1 mg/dL (IQR, 0.8–1.35), 1.01 (IQR, 0.94–1.15), and 120 × 109/L (IQR, 90–181), respectively. The included patients presented with stages T1a (n = 6, 54.5%) and T1b (n = 5, 45.5%). The tumors were located in the upper (n = 2, 18.2%), middle (n = 6, 54.5%) and lower (n = 3, 27.3%) thorax. Synchronous chemotherapy included S-1 (n = 4, 36.4%), cisplatin plus 5-FU (PF) (n = 1, 9.1%), and taxanes and cisplatin (TP) (n = 4, 36.4%). The radiotherapy dose range was 50.4–60 Gy. Five (45.5%) patients were treated with ENI, and six (54.5%) with IFI.

10.7717/peerj.18065/table-1 Table 1 Baseline characteristics.

	Liver cirrhosis (n = 11)	
Age, years		
≥65 yr	7 (63.6%)	
<65 yr	4 (36.4%)	
Sex		
Female	3 (27.3%)	
Male	8 (72.7%)	
Drinker	7 (63.6%)	
ECOG score		
0-1	9 (81.8%)	
2	2 (18.2%)	
Laboratory tests, mean level of		
Albumin, g/L (IQRrange)	36.1 (33.5–39.3)	
Total bilirubin, mg/dL (IQRrange)	1 (0.8–1.35)	
INR (IQRrange)	1.01 (0.94–1.15)	
Platelet count × 109/L (IQRrange)	120 (90–181)	
T stage		
T1a	6 (54.5%)	
T1b	5 (45.5%)	
Tumor location		
Upper thoracic	2 (18.2%)	
Middle thoracic	6 (54.5%)	
Lower thoracic	3 (27.3%)	
Concurrent chemotherapy		
None	2 (18.2%)	
S-1	4 (36.4%)	
PF	1 (9.1%)	
TP	4 (36.4%)	
Total radiation dose		
50.4 Gy	5 (45.5%)	
60 Gy	6 (54.5%)	
Radiation field		
ENI	5 (45.5%)	
IFI	6 (54.5%)	
Note:

Data are n (%). ECOG, Eastern Cooperative Oncology Group; IQR, Inter-Quartile Range; INR, international normalized ratio; T, tumor; ER, endoscopic resection; RT, additional radiotherapy; CCRT, concurrent chemoradiotherapy; S-1, tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; PF, 5-fluorouracil and cisplatin; TP, paclitaxel with carboplatin; ENI, elective nodal irradiation; IFI, involved-field irradiation.

Treatment efficacy in patients

The median GTV volume was 28.7 cm3 (IQR, 22.45–32.2 cm3), the median CTV volume was 148 cm3 (IQR, 135.8–156.45 cm3), the median EVV volume was 11 cm3 (IQR, 9.1–12.85 cm3), and the median liver volume was 1,050 cm3 (IQR, 988.95–1,101.6 cm3). Most patients presented with EVV V20 at 0–50% (n = 7), followed by EVV V20 at 50–75% (n = 3) and >75% (n = 1). Consistently, most patients presented with EVV V30 of 0–50% (n = 8), followed by EVV V30 at 50–75% (n = 3) and >75% (n = 1). Finally, most patients exhibited EVV V40 at 0–50% (n = 8), followed by EVV V40 at 50–75% (n = 3) and >75% (n = 1) (Table 2). In Figs. 2A–2F, Case 1 is depicted with a tumor in the mid-thoracic segment and varicose veins partially overlapping the target area. Case 2, whose tumor was in the lower thoracic segment and whose varicose veins extended beyond the target range, is depicted in Figs. 3A–3F. Figures 4A–4F shows Case 3, whose tumor was in the upper thoracic segment, with minimal overlap between varicose veins and the target area. Figures S1A, S1B illustrates the dose-volume histogram of Cases 1 and 2.

10.7717/peerj.18065/table-2 Table 2 Treatment and best overall response.

Patients	GTV, cm3	CTV, cm3	EVV, cm3	Cause of liver cirrhosis	Child-Pugh class(score)	The stage of esophageal varices	Liver volume, cm3	EVV, V20	EVV, V30	EVV, V40	
1	29.7	154.3	8.3	Hepatitis B	B (7)	GII	1,240.0	41.5%	37.98%	37.8%	
2	33.0	158.8	19.7	Hepatitis B	A (5)	GIII	1,192.0	93.14%	91.53%	91.53%	
3	19.6	123.4	7.1	Alcoholic Hepatitis	A (6)	GI	1,071.5	21.02%	20.76%	20.37%	
4	28.7	142.3	12.3	Alcoholic Hepatitis	B (7)	GI	1,091.2	46.7%	45.53%	45.27%	
5	31.6	157.7	9.2	Hepatitis B	A (5)	GII	977.6	72.16%	71.64%	71.23%	
6	20.5	148.0	9.0	Hepatitis B	A (6)	GI	886.3	40.89%	38.76%	37.98%	
7	21.0	132.3	15.2	Hepatitis C	B (7)	GII	987.8	65.22%	63.87%	63.1%	
8	35.0	160.5	11.2	Hepatitis B	A (5)	GI	1,112.0	50.12%	47.56%	47.11%	
9	23.9	135.6	9.5	Alcoholic Hepatitis	A (5)	GI	1,002.6	39.8%	37.55%	36.67%	
10	28.0	136.0	11.0	Hepatitis B	A (6)	GI	1,050.0	31.22%	30.62%	30.23%	
11	32.8	155.2	13.4	Hepatitis B	B (7)	GII	990.1	27.3%	26.57%	26.2%	
Note:

Data are n (%). GTV, Gross tumorvolume; CTV, Clinical target volume; EVV, esophageal varices volume.

10.7717/peerj.18065/fig-2 Figure 2 Monaco system target image of Case 1.

Blue represents skin, green represents GTV, pink represents CTV, red represents liver, and yellow represents EVV. (A) Front view. (B) Left lateral view. (C) Posterior view. (D) Front and inferior view. (E) Right lateral view. (F) Posterior and inferior view.

10.7717/peerj.18065/fig-3 Figure 3 Monaco system target image of Case 2.

(A) Front view. (B) Left lateral view. (C) Posterior view. (D) Front and inferior view. (E) Right lateral view. (F) Posterior and inferior view.

10.7717/peerj.18065/fig-4 Figure 4 Monaco system target image of Case 3.

(A) Front view. (B) Left lateral view. (C) Posterior view. (D) Front and inferior view. (E) Right lateral view. (F) Posterior and inferior view.

The median follow-up period for the entire cohort was 36 months (IQR, 24–43.5 months). Most patients achieved CR (n = 10), and one patient died from massive variceal bleeding. The 1- and 3-year overall survival and local control rates were 90.9% (95% CI [59–100%]) and 90.9% (95% CI [59–100%]), and 72.7% (95% CI [48–98%]) and 63.6% (95% CI [39–94%]), respectively (Fig. S2).

Treatment-related adverse events

Hematotoxicity was a common adverse reaction, which could be mainly characterized as a decrease in leukocytes and platelets (grade 1–2, n = 4), a decrease in neutrophils (grade 1–2, n = 5), a decrease in lymphocytes (grade 1–2, n = 6), as well as a severe decrease in lymphocytes (grade 3–4, n = 1). Different degrees of radiation esophagitis (n = 7) were observed, with only two cases with grade 3–4. There were four cases of radiation dermatitis and two cases of radiation pneumonia, all of which were grade 1–2.

There were two patients with gastrointestinal bleeding: one experienced grade 1–2 bleeding, and the other died due to bleeding (Case 2) (Table 3). Case 2 was a 64-year-old man who developed gastrointestinal bleeding half a month after the end of radiotherapy and passed away after ineffective rescue. Case 7 also experienced gastrointestinal bleeding after radiotherapy. After endoscopic and drug treatment, hemostasis was achieved, and the patient attained CR (Figs. S3A–S3D).

10.7717/peerj.18065/table-3 Table 3 Treatment-related adverse events.

Treatment-related adverse events	Grade 1–2	Grade 3–4	Grade 5	
Fatigue	2 (18.2%)			
Nausea	3 (27.3%)			
Vomiting	3 (27.3%)			
Anorexia	2 (18.2%)			
Diarrhea	3 (27.3%)			
Anemia	3 (27.3%)			
White blood cell decreased	4 (36.4%)			
Neutrophil count decreased	5 (45.5%)			
Lymphocyte count decreased	6 (54.5%)	1 (9.1%)		
Platelet count decreased	4 (36.4%)			
Esophageal stricture	2 (18.2%)			
Hemorrhage	1 (9.1%)		1 (9.1%)	
Radiation esophagitis	5 (45.5%)	1 (9.1%)		
Radiation pneumonitis	1 (9.1%)			
Radiodermatitis	3 (27.3%)			
Note:

Data are n (%).

Discussion

It is well-established that there is a risk of subclinical lymph node metastasis in esophageal tumors involving musculo-mucosal (m3) or submucosal (sm) disease (Mönig et al., 2018). Radical esophagectomy combined with prolonged lymph node dissection remains the standard of care treatment for pT1b disease, even if the lymph nodes are clinically negative (Fedorova & Watson, 2021). In this regard, a single-center study Valmasoni et al. (2017) reviewing patients with esophageal cancer and cirrhosis (n = 73) who underwent surgery found a higher 90-day complication rate and mortality than patients without cirrhosis (n = 146). Patients with cirrhosis also experienced a significantly higher incidence of respiratory events (p = 0.013), infections (p = 0.005), and severe anastomotic complications (p = 0.046), with no difference in 5-year survival. Another meta-analysis (Schizas et al., 2020) included 12 observational studies reporting 1,938 patients who underwent surgery for esophageal cancer and found that patients with cirrhosis were more likely to develop postoperative pulmonary complications, ascites, and anastomotic fistula within 30 days after esophageal cancer surgery. Although patients with cirrhosis had a higher 30-day mortality rate (OR: 3.04; 95% CI [1.71–5.39]), mortality at 90 days or late mortality was unaffected.

While surgical treatment does not seem to impact long-term survival, the high complication (83–87%) and mortality (17–30%) rates in cirrhotic patients undergoing esophageal resection suggest ESD combined with CCRT represents a viable alternative for those with esophageal submucosal lesions and cirrhosis (Suzuki et al., 2022). Radical chemoradiotherapy is an alternative early superficial esophageal cancer treatment option (Nemoto et al., 2006), with a reported overall survival rate comparable to radical surgery due to the advantages of organ preservation. However, the local failure rate (up to 30%) and morbidity associated with dose escalation are major limitations of this strategy (Emi et al., 2022). Therefore, ER combined with CRT holds much promise for the conservative management of esophageal lesions involving pT1a m3 or pT1b. ER ensures local control and confirms the depth of invasion, while auxiliary CRT consolidates local control in the presence of positive margins or deep lesions and improves progression-free survival by treating lymph nodes in areas at risk of tumor invasion.

It is widely acknowledged that endoscopic mucosal resection (EMR) or ESD can achieve a good local tumor control rate in cases of early esophageal cancer. A retrospective study Tsou et al. (2016) evaluated 40 patients with SENs treated with ESD. The non-cirrhotic group included 32 patients, and the cirrhotic group included eight patients, of whom four patients had esophageal varices. R0 removal rates were 77.8% and 94.3% in the cirrhotic and non-cirrhotic groups, respectively (p = 0. 16). Intraoperative bleeding was more common in patients with cirrhosis than those without cirrhosis (18.2% vs. 0%, p = 0.045). None of the patients experienced esophageal perforation, postoperative bleeding, or ESD-related death. Another study Choi et al. (2022) reviewed 437 patients, including 15 with cirrhosis, and showed no difference in overall (88.2% vs. 97.0%) and radical (64.7% vs. 78.9%) excision rates between cirrhosis and non-cirrhosis groups (p = 0.105 and p = 0.224, respectively). Bleeding was more common in patients with cirrhosis (p = 0.054) and was successfully controlled by endoscopy in all cases. Endoscopic submucosal resection of early esophageal squamous cell carcinoma in cirrhotic patients has rarely been reported in the literature (Wang et al., 2022).

At present, few cases of the application of chemoradiotherapy in early esophageal malignancies complicated with cirrhosis have been reported in the literature (Kam et al., 2018). The severity of esophageal varices in cirrhosis is mainly determined by endoscopic visualization. Significant inroads in technology have been achieved in recent years. The radiotherapy target delineation system enables the evaluation of the organ volume and the dose of organs at risk. Multiple superficial esophageal cancers were found by endoscopy in a 55-year-old cirrhotic patient (Maruyama et al., 2003). Due to the patient’s pancytopenia, radiotherapy was performed. After 16 radiotherapy sessions, the patient was hospitalized due to hematemesis. Finally, the patient completed radiotherapy with a total dose of 66 Gy and attained CR. Eight months after treatment, the patient showed no signs of relapse. An additional case (Katano, Yamashita & Nakagawa, 2019) was reported in a 63-year-old Japanese male with alcoholic cirrhosis and superficial esophageal squamous cell carcinoma, who underwent endoscopic submucosal dissection with pathological stage pT1bN0M0. The patient also received chemoradiotherapy and was followed up for 30 months without recurrence.

As for radiotherapy for early esophageal cancer, a study Koide et al. (2017) included 20 patients with stage T1aN0M0 who received radical radiotherapy or chemoradiotherapy due to contraindications for endoscopic treatment, and all patients achieved CR. The 1-, 3- and 5-year overall and disease-specific survival rates were 100% and 100%, 83% and 100%, and 67% and 100%, respectively. Relapse occurred in eight patients, but no recurrence was observed after salvage therapy. The patients with early esophageal cancer in this study included patients with T1b disease complicated with cirrhosis, accounting for the lower overall survival rate compared to the above studies. Patients with esophageal cancer and cirrhosis pose unique challenges in terms of treatment options due to limitations in surgical and endoscopic techniques. Therefore, radical chemoradiotherapy has emerged as a viable alternative treatment option.

In our case series, the incidence of radiation esophagitis was relatively high (mostly grade I-II), which improved after timely drug treatment. Similar outcomes were observed for radiation dermatitis and radiation pneumonia. No perforation or cicatricial stenosis was found in the 11 patients. There were two cases of gastrointestinal bleeding after radiotherapy, of which one case had a good prognosis. After timely endoscopic hemostasis and drug therapy, the tumor was no longer visible upon endoscopy during follow-up. However, the other patient died due to variceal bleeding. The patient had post-hepatitis B cirrhosis in the past and underwent a splenectomy due to uncontrollable portal hypertension. The cirrhosis was well controlled in the past 5 years, and early esophageal cancer was later found. EVVV20, V30 and V40 were all over 90%. Half a month after the completion of radiotherapy, the patient had black stools. However, the patient did not pay attention and seek medical treatment in time. When the patient had hematemesis and was sent to the emergency department, the patient had already suffered from hemorrhagic shock and eventually died despite rescue efforts.

Similarly, the risk of bleeding also increases with other treatment strategies. The risk of bleeding in ESD for treating precancerous lesions of the upper gastrointestinal tract in patients with cirrhosis is 13.1–50%, requiring endoscopic hemostasis (Tan et al., 2023; Repici et al., 2012). The incidence of bleeding in this study was 18.2%, which did not exceed the incidence of delayed bleeding in ESD-treated patients with cirrhosis. However, one patient died, which may be related to the patient’s failure to seek medical treatment in time. Based on the analysis of the causes of increased bleeding risk in the cases reported in this study, it was found that the relative positional overlap between the tumor and varicose veins was large in the two bleeding patients, which seemed to increase their bleeding risk. However, there was no previous literature reporting the causal relationship between the two. The overlap of the radiation field and the position of varicose veins as a radiotherapy contraindication also lacks evidence. Overall, the impact of the relationship between the radiation field and the position of varicose veins on the bleeding risk awaits further studies with larger sample sizes for analysis. For dose limitations of organs at risk, especially EV V20-V40, the results indicated that it was relatively safe below 50%, while treatment should be cautious when V20-V40 exceeded 50%.

Other treatment options for esophageal cancer with cirrhosis include radiofrequency ablation (RFA). Interestingly, a study Wang et al. (2017) investigated the efficacy and safety of RFA in early ESCNs with cirrhosis and esophageal varices. Six of the eight patients achieved CR, while the two remaining cases had residual squamous epithelioma. After additional focal RFA treatment, all patients achieved CR at 12 months. No tumor progression or recurrence occurred during a median follow-up period of 21.6 months (13–42 months), but the incidence of adverse events was significantly higher than in patients without cirrhosis. At present, no consensus has been reached on the treatment and follow-up methods for this special patient population. Based on the literature, various approaches have been employed, encompassing surgical operation, endoscopic resection, radical chemoradiotherapy, RFA (Wang et al., 2017; Cheng, Shiu & Ko, 2024) alone or combined therapy.

During the follow-up, local recurrence occurred in three cases in our study. Subsequently, some patients received surgery and some received radiotherapy again. It has been reported in the literature that although salvage surgery has the potential for cure, the high mortality rate, anastomotic fistula and pulmonary complications limit the number of candidate patients for salvage surgery (Markar et al., 2015). Endoscopic resection, if complete resection of locally residual/recurrent cancer can be achieved, is a minimally invasive and effective alternative to esophageal resection (Tani et al., 2023; Ego et al., 2021). It has been reported that chemotherapy, radiotherapy or combined methods can provide survival benefits for salvage treatment of recurrent esophageal cancer, but there is still no consensus at present (Xiang et al., 2023; Xu et al., 2019). Simple chemotherapy is the first choice for systemic treatment of patients with metastatic disease or multiple-site recurrence. However, salvage systemic chemotherapy after local recurrence and metastasis is not very satisfactory, with an estimated median overall survival of only 5 months (Sudo et al., 2013).

However, our study still has some limitations. This is a retrospective study with a relatively small number of cases and a short follow-up time. This is due to the small number of patients with liver cirrhosis combined with early esophageal cancer and even fewer patients receiving CCRT treatment. In addition, the application of radiation doses in clinical practice, different tumor locations, etc. also affect the results. The differences in chemotherapy regimens of patients also affect the results. However, this study first reports the value of CCRT treatment in early esophageal malignancies combined with cirrhosis. This study collected data from multiple centers, and the patients were from areas with high incidences of esophageal cancer and cirrhosis, which has certain advantages.

Conclusions

In summary, we retrospectively analyzed the efficacy and safety of radiotherapy and chemotherapy in early esophageal malignancies complicated with cirrhosis from four centers. We also explored strategies to prevent adverse events, especially variceal bleeding. Importantly, the organ dose at risk for esophageal varices was investigated. In conclusion, radical chemoradiotherapy is feasible for patients with esophageal cancer complicated with cirrhosis.

Supplemental Information

10.7717/peerj.18065/supp-1 Supplemental Information 1 Data.

10.7717/peerj.18065/supp-2 Supplemental Information 2 DVH plots of cases 1(A) and 2(B).

10.7717/peerj.18065/supp-3 Supplemental Information 3 Kaplan-Meier survival analysis showed the 1-year and 3-year overall survival and local control rates.

Endoscopic treatment of gastrointestinal bleeding in Patient No. 7.

10.7717/peerj.18065/supp-4 Supplemental Information 4 Figure S3.

(A-B) Bleeding from varicose veins in the fundus of the stomach and cardia was observed under electronic gastroscopy. 10ml hardener and 1.5ml tissue glue (Goruba 2) were injected in the 2 o’clock direction of the bleeding vein. (C-D) Local hemostasis at the injection site was achieved after endoscopic compression.

The authors are grateful to all staff at the study center who contributed to this study.

Additional Information and Declarations

Competing Interests

Author Contributions

Ethics

Data Availability

The authors declare that they have no competing interests.

Hejing Bao conceived and designed the experiments, performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Hehong Bao conceived and designed the experiments, performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Liping Lin conceived and designed the experiments, performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Yuhuan Wang performed the experiments, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Longbin Zhang performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Li Zhang performed the experiments, analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Han Zhang analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Lingxiang Liu analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

Xiaolong Cao analyzed the data, prepared figures and/or tables, authored or reviewed drafts of the article, and approved the final draft.

The following information was supplied relating to ethical approvals (i.e., approving body and any reference numbers):

This study was approved by the Ethics Committee of Panyu Central Hospital (PYRC-2023-188).

The following information was supplied regarding data availability:

The data are available in the Supplemental File.
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References

Ai et al. (2024) Ai D Hao S Shen W Wu Q Zhang S Chen Y Liu Q Deng J Zhu H Chen K Mo M Gu D Liu Y Zhang Z Zhou G Hu J Zhang Z Ye J Zhao K Induction sintilimab and chemotherapy followed by concurrent chemoradiotherapy for locally advanced esophageal cancer: a proof-of-concept, single-arm, multicenter, phase 2 trial EClinicalMedicine 2024 69 102471 10.1016/j.eclinm.2024.102471 38356729
Akutsu et al. (2013) Akutsu Y Uesato M Shuto K Kono T Hoshino I Horibe D Sazuka T Takeshita N Maruyama T Isozaki Y Akanuma N Matsubara H The overall prevalence of metastasis in T1 esophageal squamous cell carcinoma: a retrospective analysis of 295 patients Annals of Surgery 2013 257 6 1032 1038 10.1097/SLA.0b013e31827017fc 23108117
Asti et al. (2018) Asti E Sozzi M Bonitta G Bernardi D Bonavina L Esophagectomy in patients with liver cirrhosis: a systematic review and Bayesian meta-analysis Journal of Visceral Surgery 2018 155 6 453 464 10.1016/j.jviscsurg.2018.03.014 29653854
Bassegoda et al. (2022) Bassegoda O Rivera-Esteban J Serra I Morillas R Broquetas T Vergara M Rodriguez A Aracil C Virolés S Carrión JA Pardo A Rodríguez-Tajes S Serra-Burriel M Pericàs JM Augustin S Ginès P Graupera I High frequency of acute decompensation and cancer in patients with compensated cirrhosis due to nonalcoholic fatty liver disease: a retrospective cohort study Hepatology Communications 2022 6 11 3212 3222 10.1002/hep4.2056 36073343
Chen (2022) Chen KN Commentary: endoscopic treatment is the key for superficial esophageal squamous cell neoplasia The Journal of Thoracic and Cardiovascular Surgery 2022 163 6 1962 1964 10.1016/j.jtcvs.2021.09.018 34600760
Cheng, Shiu & Ko (2024) Cheng HE Shiu SI Ko CW Systematic review and meta-analysis: the efficacy and safety of radiofrequency ablation for early superficial esophageal squamous cell neoplasia BMC Gastroenterol 2024 24 1 152 10.1186/s12876-024-03250-7 38698314
Choi et al. (2022) Choi YK Noh JH Kim DH Na HK Ahn JY Lee JH Jung KW Choi KD Song HJ Lee GH Jung HY Outcomes of endoscopic submucosal dissection for superficial esophageal neoplasms in patients with liver cirrhosis Clinical Endoscopy 2022 55 3 381 389 10.5946/ce.2021.242 35656629
Dai et al. (2024) Dai Y Xu Q Xia M Chen C Xiong X Yang X Wang W Hsa_circ_0001615 downregulation inhibits esophageal cancer development through miR-142-5p/β-catenin PeerJ 2024 12 6 e17089 10.7717/peerj.17089 38464761
Ego et al. (2021) Ego M Abe S Nakatani Y Nonaka S Suzuki H Yoshinaga S Oda I Kato K Honma Y Itami J Daiko H Saito Y Boku N Long-term outcomes of patients with recurrent squamous cell carcinoma of the esophagus undergoing salvage endoscopic resection after definitive chemoradiotherapy Surgical Endoscopy 2021 35 4 1766 1776 10.1007/s00464-020-07571-y 32356109
Emi et al. (2022) Emi M Hmai Y Yoshikawa T Hirohata R Osawa M Okada M Murakami Y Nishibuchi I Clinical outcomes of esophagectomy and chemoradiotherapy after endoscopic resection for superficial esophageal squamous cell carcinoma Anticancer Research 2022 42 5 2791 2795 10.21873/anticanres.15759 35489771
Fedorova & Watson (2021) Fedorova E Watson TJ Antireflux and endoscopic therapies for barrett esophagus and superficial esophageal neoplasia Surgical Clinics of North America 2021 101 3 391 403 10.1016/j.suc.2021.03.002 34048760
Fujisaki et al. (2022) Fujisaki S Takashina M Tomita R Sakurai K Takayama T Long-term survival of patient having advanced esophageal cancer with cirrhosis after overcoming anastomotic leakage, purulent osteomyelitis, cervical lymph node recurrence, and systemic edema-a surgical case Gan to kagaku ryoho. Cancer & Chemotherapy 2022 49 1 91 93 35046372
Ishihara (2022) Ishihara R Endoscopic diagnosis and treatment of superficial esophageal squamous cell cancer: present status and future perspectives Current Oncology 2022 29 2 534 543 10.3390/curroncol29020048 35200548
Jiang et al. (2024) Jiang N Zhang J Guo Z Wu Y Zhao L Kong C Song X Gu L Zhao Y Li S He X Ren B Zhu X Jiang M Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial Journal for ImmunoTherapy of Cancer 2024 12 1 e008229 10.1136/jitc-2023-008229 38199609
Kam et al. (2018) Kam TY Kountouri M Roth A Frossard JL Huber O Mönig S Zilli T Endoscopic resection with adjuvant chemo-radiotherapy for superficial esophageal squamous cell carcinoma: a critical review Critical Reviews in Oncology/Hematology 2018 124 61 65 10.1016/j.critrevonc.2018.02.011 29548487
Katano, Yamashita & Nakagawa (2019) Katano A Yamashita H Nakagawa K Successful definitive concurrent chemoradiotherapy in a patient with esophageal cancer and Child-Pugh B cirrhosis of the liver Journal of Cancer Research and Therapeutics 2019 15 1 255 257 10.4103/jcrt.JCRT_338_ 30880788
Kawachi et al. (2022) Kawachi H Oyama T Kojima T Kuribayashi S Makino T Matsuda S Doki Y Esophageal Cancer Practice Guidelines Preparation Committee. Endoscopic imaging modalities for diagnosing the invasion depth of superficial esophageal squamous cell carcinoma: a systematic review Esophagus 2022 19 3 375 383 10.1007/s10388-022-00918-5 35397101
Kawamoto et al. (2022) Kawamoto T Shikama N Mine S Sasai K Comparison of recurrence patterns and salvage treatments after definitive radiotherapy for cT1a and cT1bN0M0 esophageal cancer Frontiers in Oncology 2022 12 857881 10.3389/fonc.2022.857881 35898896
Kim et al. (2015) Kim DH Jung HY Gong EJ Choi JY Ahn JY Kim MY Choi KS Lee JH Choi KD Song HJ Lee GH Kim JH Park YS Baek S Endoscopic and oncologic outcomes of endoscopic resection for superficial esophageal neoplasm Gut and Liver 2015 9 4 470 477 10.5009/gnl13263 25473069
Kim et al. (2023) Kim M Kim TJ Kim GH Lee YC Lee H Min BH Lee JH Rhee PL Kim JJ Min YW Outcomes of primary esophagectomy and esophagectomy after endoscopic submucosal dissection for superficial esophageal squamous cell carcinoma: a propensity-score-matched analysis Cancers (Basel) 2023 15 23 5542 10.3390/cancers15235542 38067246
Kodaira et al. (2010) Kodaira T Fuwa N Tachibana H Nakamura T Tomita N Nakahara R Inokuchi H Mizoguchi N Takada A Retrospective analysis of definitive radiotherapy for patients with superficial esophageal carcinoma: consideration of the optimal treatment method with a focus on late morbidity Radiotherapy and Oncology 2010 95 2 234 239 10.1016/j.radonc.2010.01.005 20153906
Koide et al. (2017) Koide Y Kodaira T Tachibana H Tomita N Makita C Itoh M Abe T Muro K Tajika M Niwa Y Itoh Y Naganawa S Clinical outcome of definitive radiation therapy for superficial esophageal cancer Japanese Journal of Clinical Oncology 2017 47 5 393 400 10.1093/jjco/hyx021 28334837
Kolb et al. (2021) Kolb JM Wani S Soetikno R Edmundowicz SA Hammad H Endoscopic submucosal dissection for early esophageal and gastric neoplasia in decompensated cirrhosis with varices Endoscopy 2021 53 4 E128 E129 10.1055/a-1216-0148 32757192
Koterazawa et al. (2018) Koterazawa Y Nakamura T Oshikiri T Kanaji S Tanaka S Ishida T Yamashita K Matsuda T Morita Y Suzuki S Kakeji Y A comparison of the clinical outcomes of esophagectomy and chemoradiotherapy after noncurative endoscopic submucosal dissection for esophageal squamous cell carcinoma Surgery Today 2018 48 8 783 789 10.1007/s00595-018-1650-y 29532261
Li et al. (2013) Li B Chen H Xiang J Zhang Y Kong Y Garfield DH Li H Prevalence of lymph node metastases in superficial esophageal squamous cell carcinoma The Journal of Thoracic and Cardiovascular Surgery 2013 146 5 1198 1203 10.1016/j.jtcvs.2013.07.006 23988285
Li et al. (2023) Li L Jiang D Zhang Q Liu H Xu F Guo C Qin Z Wang H Feng J Liu Y Chen W Zhang X Bai L Tian S Tan S Xu C Song Q Liu Y Zhong Y Chen T Zhou P Zhao JY Hou Y Ding C Integrative proteogenomic characterization of early esophageal cancer Nature Communications 2023 14 1 1666 10.1038/s41467-023-37440-w
Lin, Lin & Gong (2021) Lin N Lin J Gong J Risk factors of postoperative stricture after endoscopic submucosal dissection for superficial esophageal neoplasms: a meta-analysis Medicine (Baltimore) 2021 100 51 e28396 10.1097/MD.0000000000028396 34941174
Lu et al. (2024) Lu H Bei Y Wang C Deng X Hu Q Guo W Zhang X A retrospective cohort study to observe the efficacy and safety of Endoscopic Submucosal Dissection (ESD) with adjuvant radiotherapy for T1a-MM/T1b-SM Esophageal Squamous Cell Carcinoma (ESCC) PLOS ONE 2024 19 2 e0298792 10.1371/journal.pone.0298792 38386660
Lyu et al. (2022) Lyu B Yin Y Zhao Y Yang X Gong J Zhang M Chai G Li Z Shi M Hui Z Zhao L Long-term clinical outcomes and safety analysis of superficial esophageal cancer patients treated with definitive or adjuvant radiotherapy Cancers (Basel) 2022 14 14 3423 10.3390/cancers14143423 35884483
Markar et al. (2015) Markar S Gronnier C Duhamel A Pasquer A Théreaux J du Rieu MC Lefevre JH Turner K Luc G Mariette C Salvage surgery after chemoradiotherapy in the management of esophageal cancer: is it a viable therapeutic option? Journal of Clinical Oncology 2015 33 33 3866 3873 10.1200/JCO.2014.59.9092 26195702
Maruyama et al. (2003) Maruyama K Nagai K Maruyama N Tanaka J Katsumoto Y Yokouchi H Nakaguchi K Furukawa J Kinuta M Sue F A case of multiple superficial esophageal cancers with liver cirrhosis successfully treated by radiotherapy Gan to Kagaku Ryoho. Cancer & Chemotherapy 2003 30 11 1706 1709 14619499
McPhail et al. (2024) McPhail S Barclay ME Swann R Johnson SA Alvi R Barisic A Bucher O Creighton N Denny CA Dewar RA Donnelly DW Dowden JJ Downie L Finn N Gavin AT Habbous S Huws DW Kumar SE May L McClure CA Morrison DS Møller B Musto G Nilssen Y Saint-Jacques N Sarker S Shack L Tian X Thomas RJ Wang H Woods RR You H Zhang B Lyratzopoulos G ICBP Module 9 Radiotherapy Group Use of radiotherapy in patients with oesophageal, stomach, colon, rectal, liver, pancreatic, lung, and ovarian cancer: an International Cancer Benchmarking Partnership (ICBP) population-based study The Lancet Oncology 2024 25 3 352 365 10.1016/S1470-2045(24)00032-9 38423049
Min et al. (2018) Min YW Lee H Song BG Min BH Kim HK Choi YS Lee JH Hwang NY Carriere KC Rhee PL Kim JJ Zo JI Shim YM Comparison of endoscopic submucosal dissection and surgery for superficial esophageal squamous cell carcinoma: a propensity score-matched analysis Gastrointestinal Endoscopy 2018 88 4 624 633 10.1016/j.gie.2018.04.2360 29750981
Mönig et al. (2018) Mönig S Chevallay M Niclauss N Zilli T Fang W Bansal A Hoeppner J Early esophageal cancer: the significance of surgery, endoscopy, and chemoradiation Annals of the New York Academy of Sciences 2018 1434 1 115 123 10.1111/nyas.13955 30138532
Nemoto et al. (2006) Nemoto K Yamada S Nishio M Aoki M Nakamura R Matsumoto Y Sasamoto R Saitoh Y Takayama M Mitsuhashi N Gomi K Kanesaka N Kobayashi M Ohnishi H Sasaki S Tamamura H Mitsumori M Nishimura Y Tsujino K Takemoto M Uchida N Yamamoto M Shioyama Y Hirakawa K Ono S JASTRO Study Group Results of radiation therapy for superficial esophageal cancer using the standard radiotherapy method recommended by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group Anticancer Research 2006 26 2B 1507 1512 16619565
Nishibuchi et al. (2020) Nishibuchi I Murakami Y Adachi Y Imano N Takeuchi Y Tkahashi I Kimura T Urabe Y Oka S Tanaka S Nagata Y Effectiveness of salvage radiotherapy for superficial esophageal Cancer after non-curative endoscopic resection Radiation Oncology 2020 15 1 133 10.1186/s13014-020-01582-8 32487186
Noh et al. (2020) Noh JH Gong EJ Kim DH Na HK Ahn JY Lee JH Jung KW Choi KD Song HJ Lee GH Jung HY Endoscopic submucosal dissection for superficial esophageal neoplasms in elderly patients: a single-center, large-scale, retrospective study Geriatrics & Gerontology International 2020 20 5 430 435 10.1111/ggi.13892 32133752
Repici et al. (2012) Repici A Pagano N Hassan C Cavenati S Rando G Spaggiari P Sharma P Zullo A Endoscopic submucosal dissection of gastric neoplastic lesions in patients with liver cirrhosis: a systematic review Journal of Gastrointestinal and Liver Diseases 2012 21 3 303 307 23012672
Rogers et al. (2022) Rogers JE Sewastjanow-Silva M Waters RE Ajani JA Esophageal cancer: emerging therapeutics Expert Opinion on Therapeutic Targets 2022 26 2 107 117 10.1080/14728222.2022.2036718 35119973
Schizas et al. (2020) Schizas D Giannopoulos S Vailas M Mylonas KS Giannopoulos S Moris D Rouvelas I Felekouras E Liakakos T The impact of cirrhosis on esophageal cancer surgery: an up-to-date meta-analysis The American Journal of Surgery 2020 220 4 865 872 10.1016/j.amjsurg.2020.02.035 32107011
Sudo et al. (2013) Sudo K Taketa T Correa AM Campagna MC Wadhwa R Blum MA Komaki R Lee JH Bhutani MS Weston B Skinner HD Maru DM Rice DC Swisher SG Hofstetter WL Ajani JA Locoregional failure rate after preoperative chemoradiation of esophageal adenocarcinoma and the outcomes of salvage strategies Journal of Clinical Oncology 2013 31 34 4306 4310 10.1200/JCO.2013.51.7250 24145339
Suzuki et al. (2022) Suzuki G Yamazaki H Aibe N Masui K Kimoto T Nagasawa S Watanabe S Seri S Asato A Shiozaki A Fujiwara H Konishi H Dohi O Ishikawa T Elsaleh H Yamada K Chemoradiation versus surgery for superficial esophageal squamous cell carcinoma after noncurative endoscopic submucosal dissection: comparison of long-term oncologic outcomes Radiation Oncology 2022 17 1 191 10.1186/s13014-022-02162-8 36401267
Tan et al. (2023) Tan Y Qing Y Liu D Gong J Endoscopic submucosal dissection for treatment of early-stage cancer or precancerous lesion in the upper gastrointestinal tract in patients with liver cirrhosis Journal of Clinical Medicine 2023 12 20 6509 10.3390/jcm12206509 37892646
Tani et al. (2023) Tani Y Ishihara R Matsuura N Okubo Y Kawakami Y Sakurai H Nakamura T Matsueda K Miyake M Shichijo S Maekawa A Kanesaka T Yamamoto S Takeuchi Y Higashino K Uedo N Michida T Endoscopic resection for local residual or recurrent cancer after definitive chemoradiotherapy or radiotherapy for esophageal squamous cell carcinoma Scientific Reports 2023 13 1 10451 10.1038/s41598-023-32667-5 37380631
Tapper & Parikh (2023) Tapper EB Parikh ND Diagnosis and management of cirrhosis and its complications: a review The Journal of The American Medical Association 2023 329 18 1589 1602 10.1001/jama.2023.5997 37159031
Tsou et al. (2016) Tsou YK Liu CY Fu KI Lin CH Lee MS Su MY Ohata K Chiu CT Endoscopic submucosal dissection of superficial esophageal neoplasms is feasible and not riskier for patients with liver cirrhosis Digestive Diseases and Sciences 2016 61 12 3565 3571 10.1007/s10620-016-4342-8 27770376
Valmasoni et al. (2017) Valmasoni M Pierobon ES De Pasqual CA Zanchettin G Moletta L Salvador R Costantini M Ruol A Merigliano S Esophageal cancer surgery for patients with concomitant liver cirrhosis: a single-center matched-cohort study Annals of Surgical Oncology 2017 24 3 763 769 10.1245/s10434-016-5610-8 27704371
Wang et al. (2017) Wang WL Chang IW Chen CC Chang CY Mo LR Lin JT Wang HP Lee CT A case series on the use of circumferential radiofrequency ablation for early esophageal squamous neoplasias in patients with esophageal varices Gastrointestinal Endoscopy 2017 85 2 322 329 10.1016/j.gie.2016.06.045 27365263
Wang et al. (2022) Wang J Liu Y He S Zhang Y Dou L Sun L Wang G Endoscopic submucosal dissection for early esophageal squamous cell carcinoma with esophageal-gastric fundal varices caused by liver cirrhosis: a case report Translational Cancer Research 2022 11 7 2433 2437 10.21037/tcr-21-2624 35966322
Waters & Reznik (2022) Waters JK Reznik SI Update on management of squamous cell esophageal cancer Current Oncology Reports 2022 24 3 375 385 10.1007/s11912-021-01153-4 35142974
Xiang et al. (2023) Xiang G Xu C Chai G Lyu B Li Z Wang B Shi M Zhao L Re-irradiation for local primary-recurrence esophageal squamous cell carcinoma treated with IMRT/VMAT Radiation Oncology 2023 18 1 114 10.1186/s13014-023-02265-w 37430276
Xu et al. (2024) Xu X Sun Z Liu Q Zhang Y Shen L Zhang C Lin H Hu B Rong L Chen H Wang X Zhao X Bai YR Ye Q Ma X Neoadjuvant chemoradiotherapy combined with sequential perioperative toripalimab in locally advanced esophageal squamous cell cancer Journal for ImmunoTherapy of Cancer 2024 12 3 e008631 10.1136/jitc-2023-008631 38458635
Xu et al. (2019) Xu X Wang Z Jiang S Shang Y Wu Y Evaluating the optimal re-irradiation dose for locally recurrent esophageal squamous cell carcinoma after definitive radiotherapy Radiation Oncology 2019 14 1 191 10.1186/s13014-019-1402-1 31684983
Yamada et al. (2006) Yamada K Murakami M Okamoto Y Okuno Y Nakajima T Kusumi F Takakuwa H Matsusue S Treatment results of chemoradiotherapy for clinical stage I (T1N0M0) esophageal carcinoma International Journal of Radiation Oncology* Biology* Physics 2006 64 4 1106 1111 10.1016/j.ijrobp.2005.10.015 16504758
Yoshimizu et al. (2018) Yoshimizu S Yoshio T Ishiyama A Tsuchida T Horiuchi Y Omae M Hirasawa T Asari T Chin K Fujisaki J Long-term outcomes of combined endoscopic resection and chemoradiotherapy for esophageal squamous cell carcinoma with submucosal invasion Digestive and Liver Disease 2018 50 8 833 838 10.1016/j.dld.2018.01.138 29477349
Zhang et al. (2020) Zhang Y Liu L Wang Q Guo L Ye L Zeng H Zeng X Yuan X Li Y Zhang Y Zhou E Hu B Endoscopic submucosal dissection with additional radiotherapy in the treatment of T1a esophageal squamous cell cancer: randomized controlled Trial Endoscopy 2020 52 12 1066 1074 10.1055/a-1198-5232 32668474
