Whole-Course Conformal Radiotherapy Combined with Late-Course Accelerated Hyperfractionation Radiotherapy for Esophageal Squamous Cell Carcinoma: A Report of 110 Cases

Purpose: This retrospective study was designed to analyze the effect and prognostic factors of whole-course conformal radiotherapy and late-course accelerated hyperfractionation radiotherapy (LCAFRT) for esophageal squamous cell carcinoma (ESCC). Methods and materials: A total of 110 patients with ESCC received whole-course conformal radiotherapy and LCAFRT in Chaozhou City People’s hospital between May 2004 and January 2015. All patients received conventional conformal radiotherapy of 2 Gy per day up to 30–40 Gy, followed by accelerated hyperfractionation conformal radiotherapy using reduced elds at 1.5 Gy/fraction twice a day up to 24– 39 Gy, with a total dose of 60–69 Gy. Results: Median follow-up was 85 months (2–170 months). The one-, three-, and ve-year survival rates were 81.82%, 46.36%, and 41.82%, respectively. The median survival time was 31.8 months. The local control rates for the whole group at 1, 3, and 5 years were 82.73%, 70%, and 68.18%, respectively. There were no signicant differences among 1-, 3-, and 5-year survival rates and local control rates between the three-dimensional conformal radiotherapy group and intensity-modulated radiotherapy group. The main reactions to acute radiotherapy were acute radiation tracheitis, esophagitis, and pneumonia. Multivariate analysis showed that the tumor location and TNM stage were independent prognostic factors. Conclusion: The results from this study showed that whole-course conformal radiotherapy and LCAFRT for ESCC can further improve survival and local control with a tolerable acute reaction compared to previous studies. Local recurrence and distant metastasis are the main failure modes of treatment.


Introduction
Esophageal carcinoma (EC) is one of the most common gastrointestinal cancers in the world. 1 The incidence rate of EC in different countries or regions is quite different. In North America and Europe the main histological type of EC is adenocarcinoma, while esophageal squamous cell carcinoma (ESCC) is the most common type in Asia, Africa, and South America. 2 The incidence of EC in China accounts for 50% of cases around the world, and most of them are ESCCs. 3,4 There are obvious regional differences in EC in China. High incidence areas are mainly concentrated in the Taihang Mountains. Furthermore, this cancer is particularly prevalent in the Chaoshan area of Southeastern China, with the average agestandardized incidence of about 100/100,000 people. 5 Radiotherapy is one of the main treatment methods for ESCC, especially for inoperable patients or those unwilling to undergo surgery. In the past, conventional fractionated radiotherapy was the main method of radiotherapy, but its e cacy was limited and the ve-year survival rate was at about 10%. 6 With the development of late-course accelerated hyperfractionation radiotherapy (LCAFRT) for EC, especially in China, its curative effect has been fully con rmed. 7,8 However, most of the seminal clinical trials have utilized two-dimensional radiotherapy (2DRT) and the number of cases remains small. Since the development of conformal radiotherapy technology in recent years, we conducted a retrospective evaluation of 110 patients with ESCC who Page 3/13 received whole-course conformal radiotherapy and LCAFRT in order to further verify the e cacy of LCAFRT in ESCC and analyze its treatment failure mode.

Materials
The study was approved by our institutional ethics commmittee. Data were collected for 110 patients with EC who received whole-course conformal radiotherapy and LCAFRT in Chaozhou City People's  Table 1. Methods All patients were treated by external irradiation with 6-mV X-ray linear accelerator. Each patient underwent CT imaging for treatment planning. Then, the images were transferred to a radiotherapy planning system (Eclipse). The target area was delineated by two associate chief physicians, and irradiation eld design was based on the diagnosis by CT, esophageal barium meal, and beroptic esophagoscopy. The gross tumor volume (GTV) included esophageal primary tumor and regional enlarged lymph nodes. The clinical target volume (CTV) was de ned as the GTV expansion of 0.5-0.8 cm in the radical margin and 2-3 cm in the cranio-caudal margin. The planning target volume is CTV three-dimensional expansion of 0.5 cm.
The organs at risk were also sketched, including the spinal cord, lungs, and heart. The radiotherapy plan was designed in 3-5 coplanar elds, including 65 cases of 3D-CRT and 45 cases of IMRT. All patients received conventional conformal radiotherapy of 2 Gy per day up to a dose of 30-40 Gy. It was followed by accelerated hyperfractionation conformal radiotherapy using reduced elds at 1.5 Gy/fraction twice daily with a minimum interval of 6 hours up to a dose of 24-39 Gy, with a total dose of 60-69 Gy.
End points in this analysis were overall survival, local control, and acute and late radiotherapy responses.
Statistical analysis was performed using SPSS 22.0. Kaplan-Meier survival curves were used to analyze survival and local control rates.

Follow-up
As of February 1, 2020, the median follow-up was 85 months (2-170 months), ve cases were lost, and the follow-up rate was 93.6%.

Radiation reaction and complications
The acute toxicities were mainly acute radiation tracheitis, esophagitis, and pneumonia, which could be tolerated without affecting the treatment. The incidence of acute reactions in the IMRT group was lower than that in the 3D-CRT group. The late complications were mainly esophageal stenosis and pulmonary brosis ( Table 2).

Patterns of death and failure
The pattern of death is shown in Table 3. A total of 79 patients died before the follow-up date. The main causes of death were local regional failure and distant metastasis. There were 37 cases of local failure (including distant metastasis) in the whole group, accounting for 46.8% of the dead cases and including 30 cases of regional recurrence and seven cases of local lesions that were not controlled well. There were 30 cases of distant metastasis (including local failure) in the whole group, accounting for 38.0% of the dead cases and including 24 cases of distant organ metastasis and six cases of distant lymph node metastasis.

Analysis of prognostic factors
The multivariate analysis results showed that the tumor location and TNM stage were independent prognostic factors (Table 4).  12 Zhao KL et al. have analyzed 201 ESCC patients treated by LCAFRT. Their results have shown that 1-, 3-, and 5-year overall survival rates were 73%, 34%, and 26%, respectively, while 1-, 3-, and 5-year local control rates were 77%, 58%, and 56%, respectively. Their treatment resulted in similar local control and survival rates when using standard chemotherapy plus RT, such as was delivered in the RTOG 85 − 01 and 94-05. 13 Several other studies [14][15][16] have also indicated that the curative effect of LCAFRT was better than that of CFRT.
However, the use of continuous accelerated hyperfractionated radiotherapy 17 20 In the present study, the ve-year local control and survival rates were 68.18% and 41.82%, respectively. Compared to the previous studies, this method offers obvious advantages, which might be due to the fact that conformal radiotherapy elevated the local irradiation dose and homogeneity. The e cacy of 3D-CRT technique or intensity-modulated radiation therapy (IMRT) is similar, but the incidence of radiotherapy-related adverse reactions due to IMRT is lower. The results of multivariate analysis showed that the prognosis of patients with lesions located in the lower thoracic segment and with TNM stage III and IV were poor. In the analysis of the causes of death, local uncontrolled regional recurrence and distant metastasis were still the main causes of death. IMRT may thus be more advantageous for local control.
Overall, the present results revealed that the survival rate for patients with esophageal cancer treated by whole-course conformal radiotherapy and LCAFRT was signi cantly higher than that for patients treated with conventional technology. IMRT had more advantages in local control and fewer radiotherapy-related adverse reactions. These results need to be further con rmed using prospective studies.

Conclusions
The results from this study showed that whole-course conformal radiotherapy and LCAFRT for ESCC can further improve survival and local control with a tolerable acute reaction compared to previous studies. Local recurrence and distant metastasis are the main failure modes of treatment.

Declarations
Ethical Approval and Consent to participate The study was approved by our institutional ethics commmittee.

Consent for publication
Not applicable.

Availability of supporting data
Not applicable.

Funding
This study was supported by Chaozhou Science and Technology Bureau (2018GY38). Local control rate for the whole group.

Figure 2
Survival rate for the whole group. Local control and survival rates for the 3D-CRT and IMRT groups.