PDF
Citation
Print
INTRODUCTION
Definitive chemoradiotherapy (dCRT) is the recommended treatment for unresectable esophageal squamous cell carcinoma.1 Despite this, the prognosis of patients who received definitive chemoradiotherapy (CRT) is still poor, with a median progression- free survival (PFS) of 7.4–12.0 months and overall survival (OS) of 9.0–34.0 months.2-5 The one-year, two-year, and three-year OS rates were 57%, 39%, and 40%, respectively.6 Local relapse and distant metastasis remain the leading cause of treatment failure.7 Thus, new treatment strategies are needed to improve the survival of patients with inoperable esophageal squamous cell carcinoma (ESCC).
Resistance to radiation is one of the important factors affecting the efficacy of radiotherapy. One of the causes of radiation resistance is tumor hypoxia.8 The blood vessels in tumors often have abnormal structures and functions, which are usually caused by the defects of endothelial cells and other structures.9 These abnormal blood vessels affect the oxygen supply of tumors and cause radiation resistance.10,11 Endostatin is an artificially synthesized antiangiogenesis drug with efficacy in some types of cancers, including lung, colorectal, soft tissue, and gastric cancers.12 Endostatin enhanced the radiosensitivity via tumor vasculature remodeling.8
This study examined the clinical outcomes and adverse effects in patients with unresectable ESCC treated with endostatin combined with definitive CRT.
SUBJECTS AND METHODS
1. Study design and included patients
The current study was a retrospective analysis of ESCC patients treated with a combination of endostatin and dCRT at the Sun Yat-Sen University Cancer Center between February 2015 and June 2020. The Ethics Committee of Sun Yat-sen University Cancer Center approved this study on May 29th, 2020 (approval ID: 2020-FXY-147).
The inclusion criteria of patients were as follows: 1) newly diagnosed and histologically proven ESCC13, 2) ≥18 years at the start of treatment, 3) tumor unsuitable for radical esophagectomy14, and 4) treated with endostatin combined with definitive CRT. The exclusion criteria were as follows: 1) previous history of other malignancies, 2) treatment of recurrent esophageal carcinoma, 3) metastatic esophageal carcinoma (except for the invasion of the celiac trunk or supraclavicular lymph nodes), or 4) received another type of antiangiogenic therapy.
3. Chemotherapy
The patients received concurrent chemotherapy or induction chemotherapy. The chemotherapy regimens included liposomal paclitaxel plus nedaplatin, paclitaxel plus 5-fluorouracil plus nedaplatin, docetaxel plus 5-fluorouracil plus nedaplatin, according to the National Comprehensive Cancer Network (NCCN) guidelines.14
5. Follow-up
The first follow-up was two to three months after the end of treatment. The follow-up was conducted every three to four months in the first two years. After two years, follow-up was conducted every six to 12 months. The last follow-up was in December 2022.
6. Observational clinical outcomes
The basic information of patients was recorded, including age, sex, location of the tumor, T stage, N stages, and clinical stage. The TNM and clinical stages were restaged based on the eighth edition of the AJCC TNM classification system. The treatment characteristics, including the radiation dose and chemotherapy regimens, were also recorded.
The clinical outcomes, including tumor response and adverse events, were followed and recorded. The tumor responses were evaluated by endoscopy and a CT scan three months after the completion of therapy. The tumor responses were assigned as follows: (1) complete response (CR)―all target lesions disappeared; (2) partial response (PR)―the total diameter of all target lesions was reduced by ≥30%; (3) stable disease (SD)—the decrease in the target lesions did not reach PR and the increase in the target lesions did not reach PD; (4) progressive disease (PD)—the total diameter of all target lesions increased by ≥20%.19 The objective response rate (ORR)=CR+PR. The disease control rate (DCR)=CR+PR+SD.
The most common adverse events were esophagitis, heart damage, pneumonitis, hematologic toxicity, and skin damage. The adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.20
A relapse or progression in the primary tumor or regional lymph nodes was considered to be locoregional failure. Tumor metastasis to a distant site was defined as distant failure. Any of the above conditions occurring during the follow-up was considered failure.
The OS and PFS were recorded. The OS was defined as the interval from initiation of treatment to death or end of follow-up or loss to follow-up. The PFS was defined as the interval from initiation of treatment to failure, end of follow-up, or loss to follow-up.
7. Statistical analysis
The data were analyzed statistically using GraphPad Prism software (version 9.2.0; GraphPad Software, Boston, MA, USA). The continuous and categorical variables are reported as medians (range) and frequencies (%), respectively. The Kaplan–Meier method was used to evaluate the OS and PFS. The influence of factors on the survival risk was estimated using the Cox proportional hazards model. The influence of factors on the ORR and DCR was estimated using the logistic regression model. P-values <0.05 were considered significant.
RESULTS
1. Patient characteristics
Fifty-eight patients were included in the analysis. The median age was 58.5 (range, 39–82) years, and 43 (74.14%) patients were under 65 years old. Forty-six (79.31%) patients were male. One patient had stage I disease, and another had stage II disease. Forty-five (77.59%) patients were diagnosed with stage III, and five (8.62%) were diagnosed with stage IV. The disease stage of six (10.34%) patients was unknown. The tumors were located at the cervical, upper thoracic, middle thoracic, and lower thoracic in 12 (20.69%), 18 (31.03%), 19 (32.76%), and nine (15.52%) patients, respectively. All patients received at least one dose of endostatin therapy during induction chemotherapy or concurrent chemoradiotherapy. During induction therapy, 20 (34.48%), 29 (50.00%), and six (10.34%) patients received one, two, and three doses of endostatin, respectively. In the schedule of concurrent therapy, 19 (32.76%), 14 (24.14%), and 10 (17.24%) patients received one, two, and at least three doses of endostatin, respectively. The chemotherapy regimen of 55 (94.83%) patients was liposomal paclitaxel plus nedaplatin. Table 1 lists the patient characteristics.
2. Tumor response
All patients completed induction and concurrent chemoradiotherapy without interruption or delayed longer than seven days. Twenty-seven (46.55%), 21 (36.21%), one (1.72%), and five (8.62%) patients achieved CR, achieved PR, had SD, and developed PD, respectively. Four (7.90%) patients were not evaluable because data were missed. The ORR and DCR were 82.76% (95% confidence interval [CI] 70.57–91.41%) and 84.48% (95% CI 72.58–92.65%), respectively (Table 2). After excluding the three patients not receiving liposomal paclitaxel plus nedaplatin (one CR, one PR, and one SD) and reanalyzing the efficacy, the ORR and DCR were 83.64% and 84.64%, respectively (Supplementary Table 1).
Logistic regression was conducted to explore the factors influencing the ORR and DCR. The ORR and DCR were not influenced by gender, age, tumor location, clinical stage, or the endostatin dose used during induction and concurrent therapy (Table 3).
3. Survival
When the follow-up was ended, the median OS and PFS of patients were not reached. The one-, two- and three-year OS rates were 91.83% (95% CI 79.41–96.89%), 86.43% (95% CI 71.89–93.76%), and 73.86% (95% CI 62.35–85.36%), respectively. The one-, two- and three-year PFS rates were 74.09% (95% CI 59.40–84.15%), 62.16% (95% CI 46.51– 74.41%), and 61.95% (95% CI 35.16–66.34%), respectively (Fig. 1 and Table 4). The median OS and median PFS were not reached in patients who received liposomal paclitaxel+ nedaplatin. The one-, two- and three-year OS rates were 93.81% (95% CI 81.86–97.98%), 85.69% (95% CI 70.49– 93.41%), and 75.59% (95% CI 64.31–86.86%), respectively. The one-, two- and three-year PFS rates were 75.23% (95% CI 60.33–85.19%), 62.78% (95% CI 46.76–75.19%), and 51.85% (95% CI 34.67–66.67%), respectively (Supplementary Table 2 and Supplementary Fig. 1).
The Cox proportional hazards model was conducted to explore the factors influencing the survival risk and progression- free survival risk. Age, gender, tumor location, clinical stage, and endostatin dose did not affect the survival and progression-free survival risks (Table 5).
4. Failure pattern analysis
Eighteen (31.03%) patients experienced treatment failure. Among these patients, nine (50.00%), six (33.33%), and two (5.56%) were locoregional failure, only distant metastasis, and locoregional failure and distant failure, respectively.
5. Adverse events
Table 6 lists the toxicities related to treatments. At least one treatment-related adverse event occurred in 57 patients. The most common any-grade adverse events were hematologic toxicity (41.38% for leukopenia, 50.00% for neutropenia, 70.69% for anemia, and 37.93% for thrombocytopenia), hypoalbuminemia (43.10%), pneumonia (75.86%), and esophagitis (89.66%). The most common grade 3 and 4 adverse events were leukopenia (10.34%), neutropenia (8.62%), anemia (12.07%), thrombocytopenia (8.62%), pneumonia (12.07%), and esophagitis (31.03%). One patient developed an esophageal perforation. No patients died of treatment-related toxicities.
DISCUSSION
This study examined the efficacy and safety of endostatin combined with dCRT for ESCC. The results indicated that the endostatin combined with dCRT was effective, with an ORR and DCR of 82.76% and 84.48%, respectively. The treatment- related toxicities were acceptable. The most common grade 3 and 4 adverse events were reversible hematological toxicity, pneumonia, and esophagitis.
dCRT is the standard therapy in patients with unresectable locally advanced esophageal carcinoma (EC), but the prognosis is poor. The one-, three-, and five-year overall survival rates were 65%, 28% and 25%, respectively. Approximately 40–60% of patients experienced disease recurrence after dCRT.2,21,22 In a recently published study, patients who received concurrent chemoradiotherapy with S-1 achieved a two-year survival rate of 53.2%.23 In a phase I/II study, the patients were treated with dose-escalated radiotherapy in combination with chemotherapy and PET/CT-based planning. The one-, two-, and three-year survival rates were 77%, 53%, and 41%, respectively.24 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 effects of adding cetuximab to dCRT with paclitaxel and cisplatin for patients with EC. The two- and three-year overall survival rates for the dCRT plus cetuximab group were 45% and 34%, respectively, versus 44% and 28% for the dCRT group, respectively (HR 0.90, 95% CI 0.70–1.16; p=0.47).25 Adding cetuximab to dCRT did not improve the survival rate of 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, and 29% and 35% of patients achieved pCR and partial pathologic remission, respectively. Adding bevacizumab and erlotinib failed to show a survival benefit or improved pCR rate compared with a similar regimen.7
Recombinant human endostatin (rhEndostatin) is an antiangiogenic agent targeting new vessel endothelial cells in tumors. rhEndostatin shows antitumor activity when combined with chemotherapy.26 A phase II study assessed the efficiency and safety of dCRT using oxaliplatin and rhEndostatin in 37 patients with inoperable ESCC. The CR, PR, and ORR rates were 27.0%, 56.8%, and 83.8%, respectively. The median OS was 18.5 months, and the two-year OS rate was 39.6%. The median PFS was 11.5 months, and the two-year PFS rate was 20.2%. Five, eight, and four patients developed grade 3–4 hematological toxicity, grade 3–4 esophagitis toxicity, and grade 3-4 pneumonitis, respectively.27 The current retrospective analysis revealed consistent results with an ORR and DCR of 82.76% and 84.48%, respectively. The median OS and PFS were not achieved. The three-year OS and PFS rates were 73.86% (95% CI 62.35–85.36%) and 61.95% (95% CI 35.16– 66.34%), respectively. The OS and PFS appeared to be better than those treated with rhEndostatin combined with dCRT using oxaliplatin, but the toxicity was similar. The high survival rate in the present study may be partly 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 using 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. Most chemotherapy regimens used in the current study were a doublet-drug regimen, while the chemotherapy regimen in the previous phase II study was a single-drug regimen. One of the adverse events of antiangiogenic drugs was hemorrhage.28 In solid cancer patients treated with bevacizumab, another antiangiogenic drug, the incidence of bleeding events was 30–70%.28 In a phase II trial, no bleeding event was reported in nasopharyngeal carcinoma patients treated with a combination of rhEndostatin and chemoradiation. In the current study, ESCC patients were treated with rhEndostatin and chemoradiation, and no bleeding event was recorded. On the other hand, the incidence of grade 3–4 radiation pneumonia was 12.07%, which was higher than previously reported.27 The patient’s pulmonary function should be assessed carefully before treatment, and respiratory symptoms should be closely monitored during treatment.
A previous retrospective study enrolled patients with esophageal cancer who received definitive CRT. The radiotherapy dose was 66–68 Gy, and the chemotherapy regimens included paclitaxel/nedaplatin, paclitaxel/5-fluorouracil/nedaplatin, and docetaxel/5-fluorouracil/nedaplatin, which were similar to the treatment protocols used in the current study, with or without recombinant human endostatin (rhEndostatin). Subgroup analysis showed that in the group without rhEndostatin, the three-year PFS and OS were 53.5% and 61.1%, respectively, indicating poorer outcomes than the rhEndostatin group, where the three-year PFS and OS were 64.3% and 78.6%, respectively.15 Compared to the group without rhEndostatin, a trend toward improved outcomes was observed, but these differences did not reach statistical significance. In the present study, the combination of rhEndostatin with definitive CRT resulted in a three-year PFS and OS of 61.95% and 73.86%, respectively, which are consistent with a previous report. Nevertheless, further prospective randomized controlled trials are required to validate these findings due to the single-arm design of this study and the absence of a control group.
The current analysis indicated that a combination of rhEndostatin with dCRT may improve the prognosis of patients with unresectable ESCC with acceptable toxicities. Nevertheless, the current study had some limitations. First, this study was a retrospective analysis, which inherently carries the risk of recall and selection bias. Despite the explicit inclusion and exclusion criteria in the enrollment process, the patients were selected based on their eligibility for endostatin and dCRT at the authors’ institution. In addition, the treatment protocols, including chemotherapy regimens and radiotherapy doses, varied across patients included in the study, which may have affected the consistency and generalizability of the results. Second, the tumor responses were assessed by endoscopy and CT, but a pathological examination was not performed. Third, the number of patients in this analysis was insufficient to draw any firm conclusions, and the absence of a control group makes it challenging to draw definitive conclusions regarding the impact of endostatin. Prospective randomized controlled trials will be needed to confirm the findings of the current study.
Combining rhEndostatin with dCRT in ESCC patients achieved high response, PFS, and OS rates. The toxicity was acceptable. Nevertheless, additional prospective randomized controlled study trials will be needed to confirm the efficacy of this treatment strategy.
SUPPLEMENTARY MATERIAL
Supplementary material is available at the Korean Journal of Gastroenterology website (https://www.kjg.or.kr/).
XML Download