Abstract
Objectives:
This retrospective study examined the relevance and prognostic factors of whole-course conformal radiotherapy (CRT) and late-course accelerated hyperfractionation radiotherapy (LCAFRT) for esophageal squamous cell carcinoma (ESCC).
Methods:
A total of 110 patients with ESCC received whole-course CRT and LCAFRT between May 2004 and January 2015. All patients received conventional CRT of 2 Gy per day, up to 30–40 Gy, followed by LCAFRT using reduced fields at 1.5 Gy/fraction twice a day, up to 24–39 Gy, for a total dose of 60–69 Gy.
Results:
The median follow-up was 85 months. The whole groups 1-, 3-, and 5-year survival rates were 81.8%, 46.4%, and 41.8%, respectively. The local control rates for the whole group at 1, 3, and 5 years were 82.7%, 70.0%, and 68.2%, respectively. There were no significant differences among survival rates and local control rates between the 3D-CRT and intensity-modulated radiotherapy (IMRT) groups. The main reactions to acute radiotherapy were acute radiation tracheitis, esophagitis, and pneumonia. The tumor location and TNM stage were independent prognostic factors for overall survival.
Conclusion:
The results showed that whole-course CRT and LCAFRT for ESCC can 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.
Advances in knowledge:
Whole-course CRT and LCAFRT for ESCC can improve the survival and local control rate compared with previous studies from the 2DRT era. It might provide another treatment for patients with inoperable ESCC or refusing surgery.
Introduction
Esophageal carcinoma (EC) is one of the most common gastrointestinal cancers in the world. 1 The incidence 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 worldwide, 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 an average age-standardized incidence of about 100/100,000 people. 5 Radiotherapy (RT) is one of the main treatment methods for ESCC, especially for inoperable patients or those unwilling to undergo surgery. In the past, conventional fractionated RT was the main method of RT, but its efficacy was limited, and the 5-year survival rate was about 10%. 6 The development of late-course accelerated hyperfractionation RT (LCAFRT), especially in China, improved the EC curative effect. 7,8 Nevertheless, most clinical trials used two-dimensional RT (2DRT) and the number of patients treated remains small. Based on the development of conformal RT (CRT) technology in recent years, this study aimed to review 110 patients with ESCC who received whole-course CRT and LCAFRT to evaluate the effectiveness of LCAFRT in ESCC and analyze its treatment failure mode.
Methods
Study design
This retrospective study was approved by our institutional ethics committee. The eligibility criteria were (1) initial treatment, (2)>18 years of age and Karnofsky performance status (KPS) scores ≥ 70, (3) confirmed to be ESCC by pathology, (4) clinical disease stages of I-IVa according to the sixth edition of the TNM staging standard provided by the Union for International Cancer Control (UICC) for EC, 9 and (5) ineligible for chemotherapy or refused chemotherapy. The exclusion criteria were (1) esophageal perforation or deep ulceration, (2) esophageal bleeding, or (3) distant metastases.
Data collection
Data were collected for 110 patients with ESCC who received whole-course CRT and LCAFRT in Chaozhou City People’s Hospital between August 2004 and January 2015. Pretreatment evaluation of all patients included a complete history and physical examination, baseline laboratory tests, liver and kidney function tests, fiberoptic esophagoscopy, esophageal barium meal, and chest-computed tomography (CT). All patients were treated by external irradiation using a 6 MV X-ray linear accelerator. Each patient underwent CT imaging for treatment planning. Then, the images were transferred to an RT planning system (Eclipse External Beam Planning, V. 6.5, Varian Medical System, Palo Alto, CA, USA). The target area was delineated by two associate chief physicians, and irradiation field design was based on the diagnosis by CT, esophageal barium meal, and fiberoptic esophagoscopy. The gross tumor volume (GTV) included primary esophageal tumor and regional-enlarged lymph nodes. The clinical target volume (CTV) was defined as the GTV expansion of 0.5–0.8 cm in the radial margin and 2–3 cm in the craniocaudal margin. The planning target volume was a CTV three-dimensional expansion of 0.5 cm. The organs at risk were also delineated, including the spinal cord, lungs, and heart. The RT plan was designed in 3–5 coplanar fields, including 65 cases of 3D-CRT and 45 cases of IMRT.
All 110 patients first received conventional-fractionated conformal radiotherapy (3D-CRT in 65 patients and IMRT in 45 patients) at a fraction of 2 Gy/ time, once a day. The first stage dose was 30–40 Gy. Then, all patients received LCAFRT (the same 65 patients received 3D-CRT and 45 patients received IMRT) with a divided dose of 1.5 Gy twice a day, 6 h apart, and the second stage dose was 24–39 Gy. The total dose was 60–69 Gy. In the LCAFRT session, the radiation fields were reduced over the superior and inferior ends of the primary esophageal tumor with 2 cm margins, whereas the width of the fields remained the same. The CTV-PTV definition for LCAFRT was the same as for CRT. IMRT was a regular IMRT program. The dose-volume limit of TPS was 95% target volume (i.e., PTV volume) to receive 100% of the dose during the whole treatment process (including the second stage of IMRT hyperfractionated radiotherapy), which is a unified international standard. The selection of IMRT and 3D-CRT was mainly based on the physicians’ experience and judgment.
The following data were collected: sex, age, KPS scores, tumor location, tumor length, TNM stages, RT modes, radiation side effects, and complications.
Outcomes
The patients were followed up once a year. As of February 1, 2020, the median follow-up was 85 months (2–170 months), five cases were lost, and the follow-up rate was 93.6%. The primary endpoints were overall survival and local control rates for the whole group. Local control referred to the control rate of primary esophageal lesions and local lymphatic drainage area. The secondary endpoints were differences in survival and local control rates between the 3D-CRT and IMRT groups, radiation side effects, and complications.
Statistical analysis
Statistical analysis was performed using SPSS 22.0 (IBM, Armonk, NY, USA). All rates were estimated by the Kaplan-Meier model. Differences between groups were compared using the log-rank test. All p values < 0.05 were considered statistically significant.
Results
This study included 110 patients (46–83 years of age; median age: 65 years) with ESCC who received whole-course CRT and LCAFRT (Figure 1). Their baseline characteristics are summarized in Table 1.
Figure 1.
Study flowchart.
Table 1.
Patient clinical characteristics
| Feature | N | % |
|---|---|---|
| No. of patients | 110 | |
| Sex | ||
| Male | 82 | 74.5 |
| Female | 28 | 25.5 |
| Age (years) | ||
| ≤60 | 51 | 46.4 |
| >60 | 59 | 53.6 |
| Median | 65 | |
| Range | 46–83 | |
| Tumor location | ||
| Cervical | 4 | 3.6 |
| Upper-thoracic | 38 | 34.6 |
| Middle-thoracic | 47 | 42.7 |
| Lower-thoracic | 21 | 19.1 |
| Length (cm) | ||
| <7 cm | 70 | 63.6 |
| ≥7 cm | 40 | 36.4 |
| TNM stage | ||
| I | 2 | 1.8 |
| II | 48 | 43.6 |
| III | 44 | 40.0 |
| IVa | 16 | 14.6 |
| Radiotherapy mode | ||
| 3D-CRT | 65 | 59.1 |
| IMRT | 45 | 40.9 |
3D-CRT: three-dimensional conformal radiotherapy; IMRT: intensity-modulated radiotherapy;TNM: tumor-node-metastasis.
Local control and survival rates
The local control rate for the whole group at 1, 3, and 5 years was 82.7%, 70.0%, and 68.2%, respectively (Figure 2). The survival rate for the whole group at 1, 3, and 5 years was 81.8%, 46.4%, and 41.8%, respectively. The median survival was 31.8 months (Figure 3). The 1-, 3-, and 5 year survival rates for the 3D-CRT and IMRT groups were 81.5%, 44.6%, and 41.5%, vs 82.2%, 48.9%, and 42.2%, respectively (p = 0.826). The local control rates were 83.1%, 67.7%, and 64.6% vs 84.4%, 73.3%, and 73.3%, respectively (p = 0.203). There were no significant differences between the two groups (Figure 4).
Figure 2.
Local control rate for the whole group.
Figure 3.
Survival rate for the whole group.
Figure 4.
Local control and survival rates for the 3D-CRT and IMRT groups.
Radiation side effects 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 side-effects in the IMRT group was lower than in the 3D-CRT group. The late complications were mainly esophageal stenosis and pulmonary fibrosis (Table 2).
Table 2.
Radiation side effects and complications
| Side effects of radiotherapy | N (%) | 3D-CRT (%) | IMRT (%) |
|---|---|---|---|
| Acute reactions | |||
| Bronchitis | 45 (40.9) | 29 (44.6) | 16 (35.6) |
| Grade I | 14 (12.7) | 9 (13.8) | 5 (11.1) |
| Grade II | 20 (18.2) | 12 (18.5) | 8 (17.8) |
| Grade III | 11 (10.0) | 8 (12.3) | 3 (7.7) |
| Esophagitis | 69 (62.7) | 44 (67.7) | 25 (55.6) |
| Grade I | 22 (20.0) | 14 (21.5) | 8 (17.8) |
| Grade II | 30 (27.3) | 19 (29.2) | 11 (24.4) |
| Grade III | 12 (10.9) | 8 (12.3) | 4 (8.9) |
| Grade IV | 5 (4.5) | 3 (4.6) | 2 (4.4) |
| Pneumonitis | 22 (20.0) | 15 (23.1) | 7 (15.6) |
| Grade I | 15 (13.6) | 9 (13.8) | 6 (13.3) |
| Grade II | 6 (5.5) | 5 (7.7) | 1 (2.2) |
| Grade III | 1 (0.9) | 1 (1.5) | 0 |
| Late complications | |||
| Esophageal stenosis | 8 (7.3) | 5 (7.7) | 3 (6.7) |
| Grade II | 5 (4.6) | 3 (4.6) | 2 (4.4) |
| Grade III | 3 (2.7) | 2 (3.1) | 1 (2.2) |
| Pulmonary fibrosis | 4 (3.6) | 3 (4.6) | 1 (2.2) |
| Grade I | 3 (2.7) | 2 (3.1) | 1 (2.2) |
| Grade II | 1 (0.9) | 1 (1.5) | 0 |
D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.
Clinical outcomes: patterns of failure and cause of death
The death pattern is shown in Table 3. A total of 79 patients died during follow-up. 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 patients who died; these 37 patients included 30 cases of regional recurrence and seven cases of local lesions that were not controlled well. There were 30 distant metastasis cases (including local failure) in the whole group, accounting for 38.0% of the patients who died; these 30 patients included 24 cases of distant organ metastasis and six cases of distant lymph node metastasis.
Table 3.
Causes of death
| Reasons of death | N (%) | 3D-CRT (%) | IMRT (%) |
|---|---|---|---|
| Local uncontrolled or | |||
| regional recurrence | 37 (33.6) | 25 (38.5) | 12 (26.7) |
| Distant metastasis | 30 (27.3) | 20 (30.8) | 10 (22.2) |
| Hemorrhage | 2 (1.8) | 1 (1.5) | 1 (2.2) |
| Other diseases | 7 | 4 | |
| Unknown | 3 | 2 | 1 |
D-CRT, three-dimensional conformal radiotherapy; IMRT, intensity-modulated radiotherapy.
Analysis of prognostic factors
The multivariable analysis results showed that the tumor location and TNM stage were independent prognostic factors for overall survival (Table 4).
Table 4.
Multivariable analysis for overall survival
| B | SE | Wald | df | Sig. | Exp(B) | 95% CI for Exp(B) | ||
|---|---|---|---|---|---|---|---|---|
| Lower | Upper | |||||||
| Sex | 0.149 | 0.254 | 0.345 | 1 | 0.557 | 1.161 | 0.706 | 1.909 |
| Age | −0.304 | 0.24 | 1.601 | 1 | 0.206 | 0.738 | 0.461 | 1.181 |
| TNM | −1.531 | 0.289 | 28.068 | 1 | 0 | 0.216 | 0.123 | 0.381 |
| Lesion location | −0.561 | 0.269 | 4.347 | 1 | 0.037 | 0.571 | 0.337 | 0.967 |
| Lesion length | −0.234 | 0.24 | 0.949 | 1 | 0.33 | 0.791 | 0.494 | 1.267 |
CI: confidence interval; TNM: tumor-node-metastasis.
Discussion
In this study, 110 patients were analyzed to reveal the relevance of whole-course CRT combined with LACFRT in patients with ESCC. The results showed that whole-course CRT and LCAFRT for ESCC can further improve survival and local control with tolerable acute side effects compared with the previous studies that used conventional 2DRT technology.
RT is considered an effective alternative to surgery for the treatment of patients with EC. 10 Although the landmark RTOG 85–01 trial established CCRT as the standard therapy for EC, its side effects were serious. 11 Previous studies have found that the efficacy of conventional fractionated RT is unsatisfactory, the repopulation of surviving tumor cells during RT is an important cause of treatment failure, and unconventional fractionated RT can better inhibit the accelerated proliferation of tumor cells. 12 Based on this concept, LCAFRT for EC has been widely utilized. In the 2DRT era, Shi et al reported that compared to CFRT, LCAFRT could increase the 5-year survival rate of EC patients from 15 to 34%. 7 Zhao et al analyzed 201 ESCC patients treated by LCAFRT. Their results showed that the 1-, 3-, and 5-year overall survival rates were 73%, 34%, and 26%, respectively, while the 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 14–16 also indicated that the curative effect of LCAFRT was better than that of CFRT. However, continuous accelerated hyperfractionated RT 17 or LCAFRT combined with chemotherapy 8,15 does not significantly increase efficacy due to toxicity. With the continuous update of RT equipment in recent years, the CRT technique has been adopted instead of the conventional RT method. Few studies have shown the efficacy of LACFRT. Wang et al used 3D-CRT to treat 98 patients with EC, including 48 cases with LCAFRT. The result showed that the 1-, 2-, and 3-year local control and survival rates for LACFRT were 81.3%, 62.5%, and 50.0 and 79.2%, 56.3%, and 43.8%, respectively. However, the radiation side effects were greater in LACFRT. 18 Zhang et al showed that the therapeutic effect of whole-course 3D-CRT combined with LCAFRT for EC is superior to conventional RT, with the 1, 2, and 3-year tumor local control and overall survival rates of 87.8%, 75.5%, and 63.3 and 85.7%, 71.4%, and 46.7%, respectively. 19 In the present study, the 5-year local control and survival rates were 68.2 and 41.8%, respectively. Compared to the previous studies, this method offers obvious advantages, which might be because CRT elevated the local irradiation dose and homogeneity. The efficacy of the 3D-CRT technique or IMRT is similar, but the incidence of RT-related adverse reactions due to IMRT is lower. The results of the multivariable analysis showed that the prognosis of patients with lesions located in the lower thoracic segment and with TNM stage III and IV was poor. In analyzing the causes of death, local uncontrolled regional recurrence and distant metastasis were still the main causes of death. IMRT might thus be more advantageous for local control.
The present study has some limitations. First, this was a retrospective cohort study, and no causal inference could be determined. Second, because this was a single-center study, the number of cases was small, which might introduce bias.
In summary, the present study revealed that the survival rate of patients with EC treated by whole-course CRT and LCAFRT was significantly higher than in patients treated with conventional technology. IMRT had more advantages in local control and fewer RT-related adverse reactions.
In conclusion, whole-course CRT and LCAFRT might be a treatment option for patients with inoperable EC or those unwilling to undergo the treatment procedure. These results need to be further confirmed using prospective studies.
Footnotes
Acknowledgment: We thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.
Funding: This study was supported by the Chaozhou Science and Technology Bureau (2018GY38).
Ethical approval and consent to participate: The study was approved by our institutional ethics committee.
Author contribution: Study design: SUN Jian-yong and ZHANG Yao-hong. Data acquisition: SUN Jian-yong and CHEN Jing-bin. Statistical analysis and data interpretation: SUN Jian-yong and HUANG Wei-ju.
Contributor Information
Jianyong Sun, Email: 99785849@qq.com, Oncology Department Chaozhou City People’s Hospital, Guangdong, China .
Weiju Huang, Email: Huangweiju62@163.com, Oncology Department Chaozhou City People’s Hospital, Guangdong, China .
Jingbin Chen, Email: 15816586880@139.com, Oncology Department Chaozhou City People’s Hospital, Guangdong, China .
Yaohong Zhang, Email: 39899398@qq.com, Oncology Department Chaozhou City People’s Hospital, Guangdong, China .
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