A comparison of the survival outcome of paclitaxel liposome-based chemoradiotherapy with or without rhEndostatin for unresectable esophageal squamous cell carcinoma: a retrospective study

doi:10.21203/rs.3.rs-5320299/v1

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A comparison of the survival outcome of paclitaxel liposome-based chemoradiotherapy with or without rhEndostatin for unresectable esophageal squamous cell carcinoma: a retrospective study

https://doi.org/10.21203/rs.3.rs-5320299/v1

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Objectives

. This study aimed to compare the survival outcomes of paclitaxel liposome-based chemoradiotherapy, with or without rhEndostatin, in patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC).

Methods.

Patients with ESCC treated with paclitaxel liposome-based definitive chemoradiotherapy (dCRT), with or without rhEndostatin, between February 2015 and June 2020 were included. Patients received induction chemotherapy followed by concurrent radiochemotherapy, with or without rhEndostatin. The chemotherapy regimen consisted of paclitaxel liposome-based treatments. RhEndostatin was administered at a dose of 30 mg/d from day 1 to day 5 of each chemotherapy cycle. Total radiotherapy dose was 66–68 Gy, delivered in fractions of 2.0-2.2 Gy/d. Follow-up continued until December 2023. The primary endpoints were 3-year progression-free survival (PFS) and 3-year overall survival (OS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and toxicity.

Results

A total of 80 patients were included, with 34 in the dCRT group and 46 in the E + dCRT group. The 3-year PFS was 26.47% (95% confidence interval [CI], 13.19–41.81) in the dCRT group and 56.29% (95% CI, 40.79–69.20) in the E + dCRT group (Hazard ratio (HR), 0.50; 95% CI, 0.28–0.89, P = 0.012). Patients in the E + dCRT group had a superior 3-year OS compared to those in the dCRT group (80.44% [95% CI, 65.77–89.30] vs. 47.06% [95% CI, 29.83–62.52]; HR, 0.40; 95% CI, 0.21–0.72; P = 0.003). The ORR was 91.18% in the dCRT group and 95.65% in the E + dCRT group. The most common grade 3–4 toxicities were leukopenia, neutropenia, and thrombocytopenia.

Conclusion

The addition of rhEndostatin to paclitaxel liposome-based dCRT may improve clinical outcomes for patients with unresectable ESCC while maintaining manageable toxicities. However, further prospective randomized controlled studies are necessary to confirm the survival benefits of this treatment strategy.

esophageal squamous cell carcinoma

chemoradiotherapy

anti-angiogenesis

rhEndostatin

survival outcomes

Esophageal cancer is one of the most common cancers worldwide, with the seventh highest incidence rate and the sixth highest mortality rate[1]. Esophageal cancers are histologically categorized into two distinct types: squamous cell carcinoma (SCC) and adenocarcinoma. These two forms exhibit significant differences in their etiology, pathology, location within the esophagus, treatment options, and prognosis[2]. Squamous cell carcinoma (SCC) is the most prevalent type in Asia. Definitive chemoradiotherapy (dCRT) is the recommended treatment for unresectable esophageal squamous cell carcinoma (ESCC)[3]. However, the prognosis of patients who receive dCRT remains poor, with a 3-year overall survival (OS) rate of 62.3%-69.5%[4]. Local relapse and distant metastasis remain the main causes of treatment failures[5]. New treatment strategies are needed to improve the survival of patients with unresectable ESCC.

Radiation resistance is one of the key factors affecting the clinical outcomes of radiotherapy. One of the causes of radiation resistance is tumor hypoxia[6]. The blood vessels in tumors are often abnormal in structure and function due to defects in endothelial cells and other components[7]. These abnormal blood vessels affect the oxygen supply to the tumor, leading to radiation resistance[8, 9]. RhEndostatin is a synthetic antiangiogenic drug that has shown efficacy in various cancers, including lung cancer, colorectal cancer, soft tissue sarcoma, and gastric cancer[10]. It has been indicated that rhEndostatin enhances radiosensitivity through tumor vasculature remodeling[6]. A previous study showed that dCRT combined with rhEndostatin and oxaliplatin resulted in high efficacy with tolerable toxicities in esophageal cancer, with an overall response rate (ORR) of 83.8% and a 2-year OS rate of 39.6%[11].

To determine whether the addition of rhEndostatin to dCRT can improve the prognosis of patients with unresectable locally advanced ESCC, we conducted this retrospective study to compare the survival outcomes of paclitaxel liposome-based chemoradiotherapy with or without rhEndostatin in these patients.

Study design and included patients

The current study was a retrospective analysis of ESCC patients treated with paclitaxel liposome-based definitive chemoradiotherapy (dCRT) with or without rhEndostatin at the Sun Yat-Sen University Cancer Center between February 2015 and June 2020. This study was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center on May 29, 2020 (approval ID: 2020-FXY-147). The sample size was determined by the number of patients who met the inclusion criteria.

The inclusion criteria were: 1) newly diagnosed and histologically proven ESCC [12]; 2) ≥ 18 years at the start of treatment; 3) the tumor was not suitable for radical esophagectomy [13]; 4) received at least one cycle of rhEndostatin treatment; 5) treated with paclitaxel liposome-based regimens; 6) received definitive radiotherapy. The exclusion criteria were: 1) previous history of other malignancies; 2) treatment for recurrent esophageal carcinoma; 3) metastatic esophageal carcinoma (except for invasion of the celiac trunk or supraclavicular lymph nodes); 4) received other types of antiangiogenic therapy; 5) received non paclitaxel liposome-based regimens; 6) received palliative radiotherapy or adjuvant radiotherapy.

Radiotherapy

Intensity-modulated radiation therapy (IMRT) was utilized for radiotherapy. The primary tumor and the involved lymph nodes were defined as the gross tumor volumes (GTVs). Lymph nodes with a short diameter > 5 mm in the tracheoesophageal sulcus or > 10 mm in the mediastinum, or those that the radiologist believed to be invaded by the tumor, were considered involved lymph nodes[14]. Target volumes and organs at risk (OARs) were contoured based on CT scans, esophagoscopy findings, and/or FDG-PET/CT scans when available. The clinical target volume (CTV) was defined as described in a previous study[15]. The total radiation dose for GTV was 66–68 Gy in 32–33 fractions, and the dose for CTV was 44–46 Gy in 22–23 fractions.

Dose distribution according to the dose-volume histogram was as follows: (1) 95% of the planning target volume (PTV) received the prescribed dose; (2) the 95% isodose curve covered 99% of the PTV; and (3) the maximum dose (Dmax) to the PTV did not exceed 110% of the prescribed dose. Dose limitations to the OARs were as follows: (1) the mean dose (Dmean) to the lungs was ≤ 13 Gy; (2) the percentage of lung volume receiving ≥ 20 Gy (V20) was ≤ 28%; (3) Dmean to the heart was < 30 Gy; and Dmax to the spinal cord was ≤ 45 Gy[16]. Radiotherapy was halted if the patient developed grade 2 hematological toxicity or grade 4 non-hematological toxicity. If the toxicity persisted for more than two weeks, radiotherapy was terminated.

Chemotherapy

All patients received two cycles of induction chemotherapy followed by two cycles of concurrent chemotherapy. The chemotherapy regimens were paclitaxel liposome-based. Induction chemotherapy: paclitaxel liposome (175 mg/m²) on day 1 + cisplatin (25 mg/m²) on days 1 to 3; or paclitaxel liposome (175 mg/m²) on day 1 + nedaplatin (25 mg/m²) on days 1 to 3. Concurrent chemotherapy: paclitaxel liposome (135 mg/m²) on day 1 + cisplatin (25 mg/m²) on days 1 to 3; or paclitaxel liposome (135 mg/m²) on day 1 + nedaplatin (25 mg/m²) on days 1 to 3. Chemotherapy cycles were repeated every three weeks.

RhEndostatin treatment: Patients who received at least one cycle of rhEndostatin treatment were assigned to the E + dCRT group. The dose of rhEndostatin was 30 mg/day, administered from day 1 to day 5 of each chemotherapy cycle. The treatment schedule is shown in Fig. 1.

Follow-up

The first follow-up occurred 2–3 months after the end of treatment. Subsequent follow-ups were conducted every 3 months for the first two years. After two years, follow-ups were conducted every 6 to 12 months. Follow-up examinations included physical examinations, CT scans, endoscopy, routine blood tests, and laboratory tests. The final follow-up was in December 2023.

Data collection and clinical outcomes

Basic patient information was recorded, including age, sex, tumor location, T stage, N stage, and clinical stage. According to the 8th edition of the AJCC TNM classification system, TNM and clinical stages were restaged based on baseline CT scans and endoscopy findings.

The primary endpoints were 3-year progression-free survival (PFS) rate and 3-year overall survival (OS) rate. PFS was defined as the time from treatment initiation to disease recurrence, progression, loss to follow-up, end of follow-up, or death (whichever occurred first). OS was defined as the time from treatment initiation to death, loss to follow-up, or end of follow-up (whichever occurred first).

Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and toxicity. Tumor responses were categorized as: (1) Complete response (CR): all target lesions disappeared; (2) Partial response (PR): the total diameter of all target lesions reduced by ≥ 30%; (3) Stable disease (SD): the decrease in target lesions did not reach PR and the increase did not reach PD; (4) Progressive disease (PD): the total diameter of all target lesions increased by ≥ 20%[17]. ORR was defined as CR + PR, and DCR was defined as CR + PR + SD.

Toxicity was evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (NCI-CTCAE v5.0).

Bia controls

To reduce the bias caused by the imbalance of patient characteristics, we compared the patient characteristics of the two groups of patients. If the patient characteristics of the two groups of patients were not balanced, we further conducted subgroup analysis. To reduce recall bias, we used data in the medical records whenever possible. Patient-reported data was used only when the medical record data was incomplete.

Statistical analysis

Statistical analyses were performed using GraphPad Prism software (version 9.2.0, GraphPad Software, Boston, MA, USA). Continuous variables were reported as medians (range). Categorical variables were presented as frequencies (%) and tested using the Chi-square test or Fisher's exact test. The Kaplan-Meier method was used to evaluate OS and PFS, and differences were tested using the log-rank test. If Results with P values < 0.05 were considered statistically significant.

Patient characteristics

A total of 107 ESCC patients received definitive chemoradiotherapy (dCRT) with or without rhEndostatin at SYSUCC between February 2015 and June 2020. Of these, 48 received dCRT and 58 received dCRT with rhEndostatin (E + dCRT). Fourteen patients in the dCRT group and twelve in the E + dCRT group were excluded due to incomplete information, not completing the treatment regimen, unknown efficacy, or receiving a non-paclitaxel liposome-based regimen. In total, eighty patients were included in the final analysis, with 34 patients in the dCRT group and 46 patients in the E + dCRT group. The enrollment flowchart is shown in Fig. 2.

The median age was 64 years (range, 48–92) in the dCRT group and 59 years (range, 42–74) in the E + dCRT group. Eighteen patients (52.94%) in the dCRT group and thirty-five patients (76.09%) in the E + dCRT group were under 65 years old. The proportion of patients under 65 years old was significantly higher in the E + dCRT group. There were no statistically significant differences in gender, stage, and tumor location between the two groups (Table 1).

Table 1

Patient characteristics
	dCRT N = 34		E + dCRT N = 46
	n	%	n	%	P value
Age					0.0304^‡
Median(range)	64(48–92)				59(42–74)
< 65	18	52.94	35	76.09
>=65	16	47.06	11	23.91
Gender					0.2862^‡
Male	23	67.65	36	78.26
Female	11	32.35	10	21.74
Stage					0.4346^†
II	4	11.76	2	4.35
III	28	82.35	39	84.78
IV	2	5.88	5	10.87
Tumor location
Cervical	7	20.59	12	26.09	0.6066^†
Thoracic	27	79.41	34	73.91
^‡ Chi-square, ^† Fisher's exact test

Clinical outcomes

Overall, 31 patients (91.18%) in the dCRT group and 44 patients (95.65%) in the E + dCRT group had a response after completing the treatment. Nineteen patients achieved a complete response (CR) and twelve patients had a partial response (PR) in the dCRT group, while 29 patients achieved a CR and 15 patients had a PR in the E + dCRT group (Table 2).

Table 2

Tumor response assessment*
	dCRT N = 34		E + dCRT N = 46		HR
	n	%	n	%	HR
PFS
Progress or death	27	79.41	24	52.17
Percentage of patients alive and without progress at 3 year (95% CI)	26.47(13.19–41.81)		56.29 (40.79–69.20)		0.50 (0.28–0.89)
Median PFS (95% CI)	20.04 (4.90–80.30)		42.03 (5.33–93.87)
OS
Darth	25	73.53	16	34.78
Percentage of patients alive at 3 year (95% CI)	47.06 (29.83–62.52)		80.44 (65.77–89.30)		0.40 (0.21–0.75)
Median OS (95% CI)	34.24 (7.37–80.30)		NR
Fail pattern
Locoregional failure^†	13	38.24	8	17.39
Distant metastasis	16	47.06	17	36.96
Response
CR	19	55.88	29	63.04
PR	12	35.29	15	32.61
SD	2	5.88	0	0
PD	1	2.92	2	4.35
ORR	31	91.18	44	95.65
DCR	33	95.45	46	93.75
*According to CT scan and endoscopy
^† Fisher's exact test, p < 0.05
CR: complete remission; PR: partial remission; SD: stable disease; PD: progression disease; Objective response rate (ORR) = CR + PR, disease control rate (DCR) = CR + PR + SD.

At the final follow-up on December 15, 2023, the median follow-up was 22.9 months in the dCRT group and 38.8 months in the E + dCRT group. A total of 30 of the 80 patients were alive and 9 patients were lost to follow-up at the final follow-up. All patients who were alive or lost to follow-up had follow-up records of more than 36 months. We recorded 27 events of disease progression or death in the dCRT group and 24 events in the E + dCRT group. The 3-year PFS was 26.47% (95% confidence interval [CI], 13.19–41.81) in the dCRT group, compared to 56.29% (95% CI, 40.79–69.20) in the E + dCRT group (Hazard ratio [HR] for progression or death, 0.50; 95% CI, 0.28–0.89, P = 0.012) (Table 2 and Fig. 3A).

There were 25 deaths in the dCRT group and 16 deaths in the E + dCRT group. Patients in the E + dCRT group had better 3-year OS than those in the dCRT group (80.44% [95% CI, 65.77–89.30] vs. 47.06% [95% CI, 29.83–62.52]; HR for death, 0.40; 95% CI, 0.21–0.72; P = 0.003) (Table 2 and Fig. 3B).

Due to the difference in age distribution between the two groups, we compared the survival of patients aged over 65 and under 65 years old separately. In the population aged > 65 years, the E + dCRT group showed better 3-year OS (81.82% [95% CI, 44.74–89.30] vs. 37.50% [95% CI, 15.42–59.77]; HR for death, 0.21; 95% CI, 0.07–0.58; P = 0.021) and a trend of better 3-year PFS (62.34% [95% CI, 27.75–84.01] vs. 25.00% [95% CI, 7.75–47.16]; HR for disease progression or death, 0.39; 95% CI, 0.15–0.98; P = 0.058) compared to the dCRT group (Fig. 3C and 3D). In the population aged ≤ 65 years, patients in the E + dCRT group also showed a trend of better 3-year PFS (54.29% [95% CI, 36.61–68.98] vs. 33.33% [95% CI, 13.65–54.54]; HR for disease progression or death, 0.58; 95% CI, 0.27–1.22; P = 0.114) and 3-year OS (80.00% [95% CI, 62.58–89.92] vs. 55.56% [95% CI, 30.51–74.75]; HR for death, 0.54; 95% CI, 0.23–1.23; P = 0.102) compared to those in the dCRT group (Fig. 3E and 3F).

Upon analyzing the data, we found that 13 patients in the E + dCRT group were diagnosed in 2020, whereas only one patient in the dCRT group was diagnosed in 2020, indicating an imbalance between the two groups. Therefore, we conducted a further analysis of the subgroup of patients who were diagnosed before 2020. In this subgroup of patients, we found that the 3-year PFS and 3-year OS in the E + dCRT group were better than in the dCRT group (For PFS, 54.09% [95% CI, 35.73–69.29] vs. 30.30% [95% CI, 15.86–46.12]; HR for disease progression or death, 0.53; 95% CI, 0.29–0.97; P = 0.037; For OS, 75.76% [95% CI, 57.33–87.06] vs. 48.49% [95% CI, 30.83 − 64.06]; HR for death, 0.53; 95% CI, 0.29–1.00; P = 0.049) (Fig. 3G and 3H).

Failure pattern

Progression in the primary tumor or regional lymph nodes was considered locoregional failure. Thirteen patients (38.24%) in the dCRT group and eight patients (17.39%) in the E + dCRT group experienced locoregional failure. Sixteen patients (47.06%) in the dCRT group and seventeen patients (36.96%) in the E + dCRT group had distant metastasis. Patients in the E + dCRT group had a significantly lower rate of locoregional failure than those in the dCRT group (P = 0.043). However, the distant metastasis rate between the two groups did not show a significant difference (P > 0.05).

Adverse events

During the treatment, 11 patients in the dCRT group and 19 patients in the E + dCRT group experienced grade 3–4 adverse events. Leukopenia (26.47% in the dCRT group and 21.74% in the E + dCRT group) was the most common grade 3–4 event, followed by neutropenia (23.53% in the dCRT group and 21.74% in the E + dCRT group) and thrombocytopenia (20.59% in the dCRT group and 17.39% in the E + dCRT group). The most common adverse event of any grade was pneumonia (70.59% in the dCRT group and 71.74% in the E + dCRT group), followed by esophagitis (64.71% in the dCRT group and 71.74% in the E + dCRT group). Other adverse events are listed in Table 3.

Table 3

Adverse events
	dCRT N = 34				E + dCRT N = 46
	Any grade		Grade3-4		Any grade		Grade 3–4
	n	%	n	%	n	%	n	%
leukopenia	19	55.88	9	26.47	23	50.00	10	21.74
neutropenia	13	38.24	8	23.53	15	32.61	10	21.74
anemia	28	82.35	6	17.65	31	67.39	7	8.70
thrombocytopenia	15	44.12	7	20.59	20	43.48	8	17.39
Elevated ALT	6	17.65	0	0	7	15.22	1	2.17
Elevated AST	5	14.71	0	0	9	19.57	1	2.17
hypoalbuminemia	9	26.47	0	0	12	26.09	1	2.17
esophagitis	22	64.71	2	5.88	33	71.74	6	13.04
pneumonia	24	70.59	2	5.88	33	71.74	3	6.52
hemorrhage	0	0	0	0	0	0	0	0
perforation	0	0	1	1	0	0	1	2.17
nausea	16	47.06	0	0	22	47.83	0	0
vomiting	9	26.47	0	0	10	21.74	0	0

The current study aimed to retrospectively compare the survival outcomes of paclitaxel liposome-based chemoradiotherapy with or without rhEndostatin in patients with unresectable locally advanced ESCC. The results showed that patients who received paclitaxel liposome-based chemoradiotherapy combined with rhEndostatin had higher 3-year PFS and OS rates. The locoregional failure rate was also lower in the E + dCRT group, suggesting that the survival benefit of adding rhEndostatin may be due to better locoregional control of the tumor. The treatment-related toxicities were manageable. The most common grade 3 and grade 4 adverse events were reversible hematological toxicity, pneumonia, and esophagitis.

In the study, the age distribution differed between the two groups of patients, so we analyzed the subgroups of patients aged over 65 and under 65 years old separately. For patients aged over 65 years, the addition of rhEndostatin showed a survival benefit. Patients aged under 65 years also showed a trend of benefit from the addition of rhEndostatin, but the difference did not achieve statistical significance, possibly due to the small sample size.

In the E + dCRT group, thirteen patients were diagnosed in 2020, while only one was diagnosed in the dCRT group. Patients diagnosed after 2020 were more likely to receive immunotherapy after disease progression than those diagnosed before 2020. To reduce bias caused by inconsistent treatment regimens after disease progression, we excluded patients diagnosed after 2020 and compared the survival outcomes again. The results remained consistent, showing that the addition of rhEndostatin improved survival outcomes.

In patients with unresectable locally advanced ESCC, dCRT is the standard therapy. However, the prognosis remains poor. The 1-year, 3-year, and 5-year overall survival rates are 65%, 28%, and 25%, respectively. Approximately 40–60% of patients experience disease recurrence after dCRT[18–20]. In a recently published study, patients who received concurrent chemoradiotherapy with S-1 achieved a 2-year survival rate of 53.2%[21]. In a phase I/II study, patients were treated with dose-escalated radiotherapy in combination with chemotherapy using PET/CT-based planning. The 1-year, 2-year, and 3-year survival rates were 77%, 53%, and 41%, respectively[22]. The unsatisfactory clinical outcomes suggest that further effective treatment regimens should be explored to improve the prognosis of EC.

A phase III randomized clinical trial, RTOG 0436, evaluated the effect of adding cetuximab to dCRT with paclitaxel and cisplatin for patients with EC. The 2- and 3-year overall survival rates were 45% and 34% for the dCRT plus cetuximab group versus 44% and 28% for the dCRT group (HR = 0.90; 95% confidence interval, 0.70–1.16; P = 0.47)[23]. The addition of cetuximab to dCRT did not improve survival for patients with unresectable EC. A phase II trial evaluated the efficacy of bevacizumab and erlotinib combined with preoperative chemoradiation therapy with paclitaxel, carboplatin, and 5-FU. Twenty-nine percent of patients completed neoadjuvant treatment and received surgery. Twenty-nine percent and 35% of patients achieved pCR and partial pathologic remission, respectively. The addition of bevacizumab and erlotinib failed to show survival benefit or improved pCR rate compared with similar regimens[5].

Recombinant human endostatin (rhEndostatin) is an anti-angiogenic agent targeting new vessel endothelial cells in tumors. RhEndostatin shows antitumor activity when used in combination with chemotherapy[24]. A phase II study assessed the efficacy and safety of dCRT using oxaliplatin and rhEndostatin in patients with inoperable ESCC. The study included 37 ESCC patients. The CR, PR, and ORR rates were 27.0%, 56.8%, and 83.8%, respectively. The median OS was 18.5 months and the 2-year OS rate was 39.6%. The median PFS was 11.5 months and the 2-year PFS rate was 20.2%. Five patients developed grade 3–4 hematological toxicity, eight patients had grade 3–4 esophagitis toxicity, and four patients had grade 3–4 pneumonitis[11].

The current retrospective study showed similar response rates in the dCRT group (91.18%) and the rhEndostatin plus dCRT group (95.65%). The 3-year PFS and 3-year OS in both groups also appeared to be better than those in patients treated with rhEndostatin combined with dCRT and oxaliplatin. The high response rate and better survival outcomes in our study may be partially due to the high radiotherapy dose. Patients in the current study received radiotherapy at a dose of 66–68 Gy, while patients treated with rhEndostatin combined with dCRT and oxaliplatin received a dose of 60 Gy. Another reason for the good outcome may be that the patients in this study received a more aggressive chemotherapy regimen. It should be noted that the chemotherapy regimens used in the current study were double-drug regimens (paclitaxel liposome and cisplatin or nedaplatin), while the chemotherapy regimen in the previous phase II study was a single-drug regimen.

One of the adverse events of anti-angiogenic drugs is bleeding[25]. In solid cancer patients treated with bevacizumab, another anti-angiogenic drug, the incidence of bleeding events ranged from 30–70%[25]. In a phase II trial, no bleeding events were reported in nasopharyngeal carcinoma patients treated with a combination of rhEndostatin and chemoradiation. In our current study, ESCC patients were treated with rhEndostatin and chemoradiation, and no bleeding events were recorded. Between 5.88% and 6.52% of the patients experienced grade 3–4 radiation pneumonia, similar to previous reports[11].

Immunotherapy has become a standard treatment strategy for advanced ESCC[26]. In the current study, most of the patients were diagnosed between 2015 and 2019, when immunotherapy had not yet been approved for esophageal cancer in China. Anti-angiogenic therapy combined with immunotherapy has been proven to improve prognosis in non-small cell lung cancer[27]. Whether the combination of rhEndostatin and immunotherapy plus dCRT can further improve the prognosis of ESCC is worth further exploration.

The current retrospective study indicated that the addition of rhEndostatin to paclitaxel liposome-based dCRT may improve clinical outcomes for patients with unresectable ESCC with manageable toxicities. However, some limitations existed in the current study. Firstly, tumor responses were assessed by endoscopy and CT scan, but not by pathological examination. Pathological biopsy is only performed when there is suspicion of disease recurrence/progression. Thus, the CR rate may be overestimated. Secondly, the sample size was determined by the number of patients who met the inclusion criteria, rather than by rigorous statistical calculations, so there may not be sufficient power to draw firm conclusions. Thirdly, the study is a retrospective analysis, which may have recall bias.

The addition of rhEndostatin to paclitaxel liposome-based dCRT may improve clinical outcomes for patients with unresectable ESCC, with manageable toxicities. However, further prospective randomized controlled studies are needed to confirm the survival benefit of this treatment strategy.

Data Sharing Statement

The datasets included in the current research are available from the corresponding authors on reasonable request.

Ethical Statement

The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of Sun Yat-Sen University Cancer Center and individual consent for this retrospective analysis was waived.

Patient and Public Involvement

Patients or the public WERE NOT involved in the design, or conduct, or reporting, or dissemination plans of our research

Conflicts of Interest

The authors have no conflicts of interest to declare.

Funding

The study received funding from Basic and Applied Basic Research Foundation of GuangDong Province (No. 2020A1515110923) and Clinical Research Foundation of The Seventh Affiliated Hospital, Sun Yat-sen University (No. ZSQYLCKYJJ202015).

Author Contribution

(I) Conception and design: XF. Pan, MY. Zhu, M. Wei, S. Huang, JJ. Xu and Q. Li. (II) Administrative support: JJ. Xu and Q. Li. (III) Provision of study materials or patients: XF. Pan, MY. Zhu, M. Wei, S. Huang, and JJ. Xu. (IV) Collection and assembly of data: XF. Pan, MY. Zhu, M. Wei, S. Huang and JJ. Xu. (V) Data analysis and interpretation: XF. Pan, JJ. Xu and Q. Li. (VI) Manuscript writing: All authors. (VII) Final approval of manuscript: All authors.

Acknowledgement

We thank all colleagues of the Sun Yat-sen University Cancer Center, for their assistance for this research.

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A comparison of the survival outcome of paclitaxel liposome-based chemoradiotherapy with or without rhEndostatin for unresectable esophageal squamous cell carcinoma: a retrospective study

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Abstract

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Introduction

Materials & Methods

Study design and included patients

Radiotherapy

Chemotherapy

Follow-up

Data collection and clinical outcomes

Bia controls

Statistical analysis

Results

Patient characteristics

Clinical outcomes

Failure pattern

Adverse events

Discussion

Conclusion

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