External beam radiotherapy plays an important role in relieving the symptoms of esophageal cancer and maintaining quality of life of patients, but its effects are limited. Most patients have recurrence or metastasis within 2 years after radiotherapy [4, 7, 8]. Without active intervention, the survival and prognosis of patients with disease progression are often poor, and most die within 1 year [9]. Although many researchers are actively exploring the best salvage treatment for LRESCC, there is still no consensus. Many studies have confirmed the positive role of chemotherapy in the initial treatment of ESCC [10], but the role of chemotherapy in the re-irradiation therapy of ESCC is not clear. The clinical efficacy of recurrent ESCC salvage radiotherapy is significantly affected by the radiation dose [11]. Up to date, the optimal dose of salvage radiotherapy is still unclear.
Recently, a study of the effect of dose-escalated radiotherapy on ESCC showed that, in patients who achieved complete response, radiotherapy dose was increased to > 59.4 Gy after standard concurrent chemoradiotherapy (50.4 Gy), which significantly improved local control, 5-year recurrence-free survival rate and 5-year OS rate [12]. Previously, some studies have indicated that the survival rate of LRESCC can be significantly prolonged when the dose of re-irradiation is > 50 Gy [4, 13]. Kobayashi et al. pointed out that 60 Gy was an appropriate salvage dose for LRESCC after surgery [14]. Another study from Japan pointed out that patients with LRESCC with a radiation history should be given higher doses of radiotherapy [15]. These studies suggest that increasing the dose of radiotherapy for recurrent esophageal cancer may be beneficial to prolong survival. However, there is no report on whether higher doses of re-irradiation between 50 and 60 Gy would benefit more patients with LRESCC with radiation history.
This study is believed to be the first to compare the effects of 50 Gy and 60 Gy re-irradiation dose on the survival of patients with LRESCC with radiation history. Our results showed that most patients (68/125, 54.4%) had recurrence within 2 years after initial (chemo)radiotherapy, which was consistent with previous reports [4, 8, 13, 16]. Jingu et al. reported that the 3-year survival rate and median survival time of 33 patients with LRESCC receiving 60 Gy (range, 18–70 Gy) re-radiotherapy were 17.8% and 16 months, respectively [15]. Hong et al. reported that the median survival time of recurrent ESCC patients receiving 50 Gy (range, 21–70 Gy) re-radiotherapy was 10 months[17]. This is close to our survival results. In the present study, the 1- and 3-year survival rates and median survival time were 61.2% and 19.4% and 18 months in the HD group, respectively. The 1- and 3-year survival rate and median survival time were 48.3% and 10.3% and 11 months in the LD group, respectively. Radiotherapy dose is an important factor affecting survival, which was clearly demonstrated in our results. The median survival time of patients receiving radiation alone in the HD group was 15 months, which was significantly higher than 9 months in the LD group. Increasing the dose of radiation showed an encouraging outcome. Our results are also better compared with those of other studies[4, 13, 15]. The reason may be that higher doses of radiation were more beneficial for tumor control. Therefore, we recommend higher doses of radiation for patients with recurrent ESCC after radiotherapy.
Few studies have addressed the role of chemotherapy in re-radiotherapy for recurrent ESCC. Chen et al. reported that the 1-, 2- and 3-year survival rates of 36 LRESCC patients receiving re-irradiation with concurrent chemotherapy (paclitaxel + cisplatin) were 51.7%, 21.4% and 12.2%, respectively [4]. Katano et al. reported that the median survival time of six patients who underwent concurrent chemotherapy with nedaplatin and tegafur with re-radiotherapy was 13.6 months[6]. As of now, the role of chemotherapy in re-radiotherapy for recurrent ESCC is still unclear. In subgroup analysis, our results showed that chemotherapy combined with radiotherapy could increase survival rate. In the LD group, the median survival time for chemoradiotherapy was 14 months, which was consistent with the results reported by Katano et al. [6]. However, in the HD group, chemoradiotherapy did not show better efficacy than radiotherapy alone, and other studies have reported the same [17]. Our results suggest that chemotherapy can increase the survival rate of re-radiotherapy for ESCC, especially when patients are exposed to lower radiation doses. This may be related to the fact that chemotherapy increases the tumor control rate at low rather than high dose of radiotherapy.
In this study, the most common toxicity of the whole cohort was esophagitis. Although the incidence of esophagitis in the HD group was higher than in the LD group (68.7% vs 58.6%), the difference was not significant. A previous study showed that the incidence of severe acute esophagitis in patients with thoracic radiotherapy was 15–25%[18]. Grade 3 or higher acute esophagitis was rare in the two groups in this study. Hematological toxicity and gastrointestinal reactions were also common, and only hematologic toxicity was significant between the two groups. In this study, the incidence of radiation pneumonitis was lower than in previous studies[19]. Grade 1–2 radiation pneumonitis occurred in six (10.3%) and eight (11.9%) patients in the LD and HD groups, respectively, and the symptoms was controllable. We recorded eleven patients with severe treatment-related toxicity, including bleeding, esophageal perforation, and esophageal fistula, and eight of eleven were found in the LD group. This may be related to the NRI of ≤ 24 months in most patients (36/58, 62.1%) in the LD group. Current results indicated that a higher re-irradiation dose was safe.