Patterns of Failure after Radical Surgery among Patients with Thoracic Esophageal Squamous Cell Carcinoma: Implications for the Clinical Target Volume Design of Postoperative Radiotherapy

et al. (2014) Patterns of Failure after Radical Surgery among Patients with Thoracic Esophageal Squamous Cell Carcinoma: Implications for the Clinical Target Volume Design of Postoperative Radiotherapy. PLoS ONE 9(5): e97225. doi:10.1371/journal.pone.0097225 Patterns of Failure after Radical Surgery among Patients with Thoracic Esophageal Squamous Cell Carcinoma: Implications for the Clinical Target Volume Design of Postoperative Radiotherapy Qi Liu 0 Xu-Wei Cai 0 Bin Wu 0 Zheng-Fei Zhu 0 Hai-Quan Chen 0 Xiao-Long Fu 0 Andreas-Claudius Hoffmann, West German Cancer Center, Germany 0 1 Department of Radiation Oncology, Fudan University Shanghai Cancer Center , Shanghai , P.R. China , 2 Department of Oncology, Shanghai Medical College, Fudan University , Shanghai , P.R. China , 3 Department of Radiology, Fudan University Shanghai Cancer Center , Shanghai , P.R. China , 4 Department of Thoracic Surgery, Fudan University Shanghai Cancer Center , Shanghai , P.R. China Background: This study evaluated patterns of treatment failure (especially locoregional failure; LRF) after radical esophagectomy and proposes a clinical target volume (CTV) for postoperative radiotherapy (PORT) among patients with thoracic esophageal squamous cell carcinoma (SCC). Methods: All patients who were followed up in our center after radical esophagectomy between 2007 and 2011 were retrospectively enrolled. The patterns of first discovered failure were assessed, and LRFs (including anastomotic and regional lymph node recurrences) were evaluated to determine whether our proposed PORT CTV encompassed these areas. The clinicopathologic factors predictive of lymphatic recurrence type were analyzed. Results: Of the 414 patients who underwent surgery and were followed up over the study, 207 experienced recurrent or metastatic diseases. The median time to progression was 11.0 months. Of the 173 patients with locoregional recurrence, nodal failure recurred in 160; supraclavicular and superior mediastinal lymph nodes had the highest metastasis rates. All 233 recurrent sites across the 160 patients were located in a standard CTV area, including the bilateral supraclavicular areas, the entire mediastinum, and the left gastric lymphatic drainage region. A total of 203 sites (87.2%) were located in either the bilateral supraclavicular areas or the entire mediastinum, and 185 sites (79.4%) were located in either the bilateral supraclavicular areas or the upper mediastinum. A multivariate analysis revealed the lymph node metastatic ratio (LNMR) and tumor differentiation were risk factors for nodal failure. Conclusions: Locoregional recurrence (especially lymph node recurrence) was the most common and potentially preventable type of initial treatment failure after curative surgery among patients with thoracic esophageal SCC. The proposed PORT CTV covered most LRF sites. The lymphatic drainage regions for PORT are selective, and the supraclavicular and superior mediastinal areas should be considered. However, the value of PORT and the extent of CTV should be investigated in further prospective studies. - . These authors contributed equally to this work. Surgery is the most important initial treatment for patients with thoracic esophageal squamous cell carcinoma (SCC). However, the recurrence rate of SCC is as high as 40%50% after radical surgery [1], and locoregional recurrence is the major cause of treatment failure [2,3], even among patients with a pathologically complete response to neoadjuvant chemoradiotherapy [4]. van Hagen et al. [5] indicated that overall survival (OS) and local tumor control could be improved using neoadjuvant chemoradiotherapy, which is already used at many institutions. This standard suggests that postoperative radiotherapy (PORT) should not play an important role in SCC treatment. However, SCC comprises more than 90% of the esophageal cancer cases in East Asia, and tumors located in the upper and middle thoracic esophagus are most commonly observed. In these cases, neoadjuvant radiotherapy often increases the difficulties associated with surgery due to tissue edema and hemorrhage. In addition, patients in China generally prefer surgery to neoadjuvant chemoradiation as their initial treatment. Therefore, evaluating the efficacy of adjuvant radiotherapy is essential. To date, no randomized trial has evaluated the survival advantages of PORT alone; thus, adjuvant radiotherapy is not currently recommended in the National Comprehensive Cancer Network (NCCN) treatment guidelines. According to multiple retrospective analyses, the addition of postoperative chemoradiotherapy has been associated with survival benefits among patients with locoregional esophageal carcinoma [6]. Xiao et al. [7] reported that PORT improves the survival rates of patients with positive lymph nodes and reduces the incidences of intrathoracic recurrence and supraclavicular lymph node metastasis among all patients. Chen et al. [8] retrospectively analyzed 945 patients and found similar results. Xu et al. [9] retrospectively analyzed 725 patients and reported an association between improved OS and PORT (36.6%43.6%, p = 0.018) among patients with lymph nodes positive for stage III ESCC. A large, population-based review using the Surveillance Epidemiology and End Results database also supported the use of postoperative radiation for stage III SCC and adenocarcinoma of the esophagus [10]. PORT should be strongly considered for certain patients with esophageal SCC; however, selecting patients for adjuvant radiotherapy (RT) can be problematic. In addition, the appropriate clinical target volume (CTV) for prophylactic RT is generally disputed, particularly with regard to the extent of the lymphatic drainage region based on axial image scans. Increased knowledge of the patterns of recurrence and metastasis after radical surgery would help to determine the irradiation targets for PORT. Accurate recurrence locations based on CT images can provide more information when contouring target volume. This retrospective study analyzed the recurrence and metastases of thoracic esophageal SCC after radical resection based on CT scans to evaluate the risk factors that influence its recurrence patterns and provides a reference to determine appropriate PORT. Patients To be included in this study, patients must have met the following criteria: (1) radical R0 resection (complete removal of the entire tumor with clear histological margins) to treat esophageal SCC confirmed by pathological findings; (2) pathological stage T14aN0-3M0; (3) no prior therapy or PORT; and (4) initial regional recurrence identified using routine computed tomography (CT) scanning during the follow-up period. The exclusion criteria were (1) a histological diagnosis of adenocarcinoma or another histological type; (2) an esophagectomy with a one-field lymphadenectomy or non-lymphadenectomy; (3) fewer than 12 removed lymph nodes; and (4) previous malignancies. Patients (...truncated)