Salvage treatment for lymph node recurrence after radical resection of esophageal squamous cell carcinoma

In China, surgical resection is the preferred treatment for resectable esophageal cancer. However, the 5-year overall survival rates of these patients are low, ranging from 31 to 55% [1, 2]. In addition, 43%~ 53% of patients who undergo surgery experience local recurrence and/or distant metastasis, and the median time to recurrence ranges from 10 to 12 months. The most common local recurrence sites are anastomotic, supraclavicular lymph nodes and mediastinal lymph nodes [1, 3, 4]. Treatments for local recurrence include chemoradiotherapy, radiotherapy, surgery, chemotherapy and stringent supportive care. A retrospective study by Kosuga et al. [5]indicated that lymphadenectomy, radiotherapy, and chemoradiotherapy were effective salvage treatments. Lymphadenectomy has been reported to be feasible for postoperative cervical lymph node recurrence [6‐8]. Radiotherapy administered locally was also found to be a promising option to control lymph node recurrence after curative resection [9‐11]. Given that chemoradiotherapy is effective in mounting local control and reducing distant recurrence by promoting radiosensitivity, while eliminating micrometastases, several studies have verified the effectiveness of concurrent chemoradiotherapy [12‐14]. However, the prevailing data on this treatment is not conclusive and many therapeutic strategies for postoperative lymph node recurrence after esophageal cancer are controversial. Herein, we determined the prognostic factors of patients with esophageal squamous cell carcinoma with regional lymph node recurrence after radical surgery and the efficacy of radiotherapy with or without chemotherapy for lymph node recurrence in such patients.

Our results showed that radiotherapy, with or without chemotherapy, is an effective and feasible salvage treatment for lymph node recurrence after radical resection of ESCC. The 1-year, 3-year, and 5-year OS rates were 83.0, 40.1, and 35.1%, with the median OS of 18 months. In the radiotherapy group, the 3-year survival rate was 47.5%, the response rate was 73.2% and the median OS was 22 months. In patients who received concurrent chemoradiotherapy, the 3-year survival rate, the response rate and the median OS were 41.9, 91.4% and 16 months, respectively. Grade 3 toxicity was low (18%) and there were no treatment-related deaths that occurred. In the multivariate analysis of OS, age was characterized as a significant independent prognostic factor(P = 0.034). Similar to previous studies, our results are robust. In the study of Ma et al. [10], 98 patients were randomly enrolled to undergo either three-dimensional conformal radiotherapy alone (group A) or concurrent chemoradiotherapy (group B). All patients received a radiation dose of 62-70Gy and the patients in group B received a weekly low dose of cisplatin (30 mg/m²). The median OS and 3-year survival rates of group B (35 months and 46.9%, respectively) were greater than those of group A (19 months and 28.6%, respectively). Our overall 3-year OS rates (47.5%) were greater than those (28.6%) reported by Ma et al. [10] in the RT group, while they were similar in the CCRT group. In addition, researchers found that neither of the treatment modalities brought about any improvements to the 5-year survival rates. VMAT was commonly used in our study. Clinical research and methodological studies relating to the treatment of esophageal cancer have shown that IMRT or VMAT are better than 3DCRT with respect to improved target coverage and conformality, in addition to reduced radiation exposure to adjacent organs [25, 26].This may be the reason why our results were favorable. Previous studies suggested that synergistic effects of concurrent chemoradiotherapy can improve survival. Jingu et al. [24] reported the long-term results of CCRT for postoperative lymph node recurrence in their prospective phase II study. A total of 30 patients were treated for post-operative LR with RT (60Gy) combined with concurrent chemotherapy consisting of two cycles of nedaplatin and 5-fluorouracil. The 3-year OS was 38.4%, with an MST of 21.0 months. Yamashita et al. [22] also reported similar findings in a study that involved 237 patients who received RT or CCRT. The 3-year OS was 39.7% with CCRT and 20.8% with RT alone (p<0.05). In her study, 83% of patients received CCRT, among which, 5-fluorouracil and cisplatin/ nedaplatin were used in 167patients. In the present study, Platinum or fluorouracil monotherapy were predominantly used; it may reduce the toxicity compared to reported studies. Despite the controversy in concurrent chemotherapy regimens that are suitable for postoperative lymph node recurrence, the FP regimen produced excellent results for recurrent lymph nodes reported by Zhang et al. [13] Studies on CCRT for patients with locoregional recurrent esophageal carcinomas are limited in countries with the exception of Asia. Baxi el at [27]. treated 14 patients with both adenocarcinoma and SCC. All patients received 58–60Gy, with either cisplatin, fluorouracil, or both. Similar to our results, the median OS was 16 months and the 2-year OS was 21%. Jeene el at [28]. investigated salvage treatment for an isolated lymph node recurrence after curative resection in 22 patients. Treatment consisted of 50.4Gy combined with weekly concurrent paclitaxel and carboplatin therapy. The study reported a median OS was 33 months, which, is better than the findings from the present study. In western countries, it is more common to use neoadjuvant chemoradiotherapy followed by surgery as a standard for the radical treatment of esophageal cancer. However, the dose or the area of re-irradiation may be limited, especially on those infield recurrences. In those studies, adenocarcinomas were mostly the cancers effecting the participants. Although, there was no agreement on prognosis between adenocarcinomas and SCC. In addition, the recurrence at the site of the anastomosis has been reported prognostically unfavorable in those two studies. In this study, the differences in recurrent lymph node size might have been one reason for the difference in the survival periods. The median size of 8.14cm³ in the CCRT group was significantly greater than that of 4.15 cm³ in the radiotherapy group. Previous studies stated that small recurrent lymph nodes have a better prognosis [10]. There was no other difference between the two groups, including radiation dose (median 60Gy in both groups), interval to recurrence, region of lymph node recurrence, and postoperative staging. Controversies remain regarding the treatment strategy for lymph node recurrence after radical resection in esophageal cancer. Radiotherapy or chemoradiotherapy may be selected as salvage treatment considering the good survival results and low toxicity reported in this study. However, lymph node recurrence, anastomotic recurrence, and distant metastasis occurred even after salvage treatment. Given the presence of micrometastasis, further prospective studies should be carried out to determine populations that have high risk of metastasis so that they may receive intensive therapy.

As for prognostic factors, age was characterized as a significant independent prognostic factor (P = 0.034); younger patients had a shorter survival time. Consistent with our findings, both Nemoto el at [9]. and Jingu el at [29].reported that younger patients had a worse prognosis. Biological behavior of tumors in younger patients may be aggressive. Thence, cancer screening is recommended to be early performed. In the present study, there were no other factors observed to be significantly associated with prognosis. Although some common prognostic factors including single lymph node recurrence, single regional lymph node recurrence, and small lymph node have been reported to be associated with better prognosis [10, 12, 14, 30].

The survival rate was not significantly different for a radiation dose that was higher or less than 60Gy (p = 0.888), although patients who received a higher dose had a longer survival time (median OS of 21 months) than those who received a lower dose (median OS of 16 months). In our case, all patients accepted intensity modulated radiotherapy, which could possibly be the reason for our encouraging finding. Raoul et al. [31] reported a median survival time of 10.7 months in patients combined chemotherapy with cisplatin and 5-FU with an RT dose of 60Gy. The low survival rate was associated with factors such as 2DCRT radiotherapy and multiple region recurrences. Kawamoto et al. [12] reported a favorable result with the median OS of 22 months after using a radiation dose of 60-66Gy. Given the advancements in radiotherapy technology, Zhang et al. [23] showed that doses higher than 60Gy significantly improved the progression-free survival and overall survival (median OS of 16.3 months, p = 0.041). However, due to the small size of their sample, and the lack of multivariate analysis, their findings may have been affected by bias. In the study run by Ma et al. [10], 98 patients received a radiation dose of 62-70Gy. They reported exciting finding of a median OS of 35 months in the concurrent chemotherapy group and that of 19 months in the radiotherapy group. Despite the numerous reported dose-related studies so far, the optimal dose for local recurrence after esophageal cancer surgery is yet to be agreed on. A high dose above 60Gy may be suitable with no associated patient deaths.

The present study has several limitations associated with its retrospective design. This study could not demonstrate a survival benefit between salvage RT and CCRT compared to the previous reports. In the present study, various chemotherapy regimens were used, but platinum or fluorouracil monotherapies were mainly used. Recent studies have suggested the TP or FP regimens can increase the survival time of recurrent esophageal cancer [12, 21, 29]. There were some selection biases: small sample size, the selection of primary therapy was different among surgeons, as well as the heterogeneity of the combined chemotherapy regimen, recurrent time, RT dose and RT technology.

Our results suggest that radiotherapy with or without concurrent chemotherapy is an effective and feasible salvage treatment for postoperative lymph node recurrence after occurrence of esophageal squamous cell carcinoma. In view of the shortcomings aforementioned, further research is necessary to identify recurrent esophageal cancer in patients who should be treated with radiotherapy or chemoradiotherapy.