Postoperative Radiotherapy in Pathological T2-3N0M0 Thoracic Esophageal Squamous Cell Carcinoma: Interim Report of a Prospective, Phase III, Randomized Controlled Study.
胸段食管鳞癌病理 T2-3N0M0 术后放疗: 一项前瞻性、 ⅲ 期、随机对照研究的中期报告。
- 作者列表："Deng W","Yang J","Ni W","Li C","Chang X","Han W","Zhou Z","Chen D","Feng Q","Liang J","Lv J","Wang X","Wang X","Deng L","Wang W","Bi N","Zhang T","Li Y","Gao S","Xue Q","Mao Y","Sun K","Liu X","Fang D","Wang D","Li J","Zhao J","Shao K","Li Z","Chen X","Han L","Wang L","He J","Xiao Z
BACKGROUND:The role of postoperative radiotherapy in pathological T2-3N0M0 esophageal squamous cell carcinoma is unknown. We aimed to evaluate the efficacy and safety of postoperative radiotherapy in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma. MATERIALS AND METHODS:Patients aged 18-72 years with pathological stage T2-3N0M0 esophageal squamous cell carcinoma after radical surgery and without neoadjuvant therapy were eligible. Patients were randomly assigned to surgery alone or to receive postoperative radiotherapy of 50.4 Gy in supraclavicular field and 56 Gy in mediastinal field in 28 fractions over 6 weeks. The primary endpoint was disease-free survival. The secondary endpoints were local-regional recurrence rate, overall survival, and radiation-related toxicities. RESULTS:From October 2012 to February 2018, 167 patients were enrolled in this study. We analyzed 157 patients whose follow-up time was more than 1 year or who had died. The median follow-up time was 45.6 months. The 3-year disease-free survival rates were 75.1% (95% confidence interval [CI] 65.9-85.5) in the postoperative radiotherapy group and 58.7% (95% CI 48.2-71.5) in the surgery group (hazard ratio 0.53, 95% CI 0.30-0.94, p = .030). Local-regional recurrence rate decreased significantly in the radiotherapy group (10.0% vs. 32.5% in the surgery group, p = .001). The overall survival and distant metastasis rates were not significantly different between two groups. Grade 3 toxicity rate related to radiotherapy was 12.5%. CONCLUSION:Postoperative radiotherapy significantly increased disease-free survival and decreased local regional recurrence rate in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma with acceptable toxicities in this interim analysis. Further enrollment and follow-up are warranted to validate these findings in this ongoing trial. IMPLICATIONS FOR PRACTICE:The value of adjuvant radiotherapy for patients with node-negative esophageal cancer is not clear. The interim results of this phase III study indicated that postoperative radiotherapy significantly improved disease-free survival and decreased local-regional recurrence rate in patients with pathological T2-3N0M0 thoracic esophageal squamous cell carcinoma compared with surgery alone with acceptable toxicities. The distant metastasis rates and overall survival rates were not different between the two groups. Adjuvant radiotherapy should be considered for pathologic T2-3N0M0 thoracic esophageal squamous cell carcinoma. Prospective trials to identify high-risk subgroups are needed.
背景: 术后放疗在食管鳞癌病理 T2-3N0M0 作用尚不清楚。本研究旨在评价胸段食管鳞癌病理 T2-3N0M0 术后放射治疗的有效性和安全性。 材料与方法: 年龄 18 ~ 72 岁，病理分期为 T2-3N0M0 食管鳞癌根治术后未接受新辅助治疗的患者。患者随机分为单纯手术或术后放疗，锁骨上野 50.4 Gy，纵隔野 56 Gy，共 28 次，疗程 6 周。主要终点是无病生存率。次要终点是局部区域复发率、总生存期和放射相关毒性。 结果: 从 2012年10月到 2018年2月，共有 167 例患者入选本研究。我们分析了 157 例随访时间超过 1 年或已死亡的患者。中位随访时间为 45.6 个月。术后放疗组 3 年无病生存率分别为 75.1% (95% 可信区间 [CI] 65.9-85.5) 和 58.7% (95% CI 48.2-71.5) 在手术组中 (风险比 0.53，95% CI 0.30-0.94，p =. 030)。放疗组局部区域复发率显著降低 (10.0% vs.手术组 32.5%，p =.001)。两组的总生存率和远处转移率无显著差异。与放疗相关的 3 级毒性发生率为 12.5%。 结论: 术后放疗可显著提高病理 T2-3N0M0 胸段食管鳞癌患者的无病生存率，降低局部区域复发率，毒性反应可接受。在这项正在进行的试验中，需要进一步的入组和随访来验证这些发现。 对实践的启示: 辅助放疗对淋巴结阴性食管癌患者的价值尚不清楚。这项 III 期研究的中期结果表明，与单纯手术相比，术后放疗可显著改善病理 T2-3N0M0 胸段食管鳞癌患者的无病生存率和降低局部-区域复发率。可接受的毒性。两组的远处转移率和总生存率无差异。胸段食管鳞癌病理 T2-3N0M0 应考虑辅助放疗。需要前瞻性试验来确定高危亚组。
METHODS::Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main Methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression ofRAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.
METHODS::Cancer stem-like cells are rare immortal cells within tumor, which are thought to play important roles in ionizing radiation (IR) therapy-resistance. Quercetin is a natural flavonoid with potential anti-cancer properties without significant cytotoxicity in normal tissues. In this study, we demonstrated that quercetin-IR combination treatment exhibited more dramatic anti-cancer effect than either quercetin or IR treatment alone via targeting colon cancer stem cells (CSCs) and inhibiting the Notch-1 signaling. These effects were further verified by in vivo studies which showed remarkable decrease of the CSCs markers and the expression of Notch-1 signaling proteins in human colon cancer xenografts in nude mice. Co-treatment with quercetin and low dose of radiation significantly reduced the expressions of all five proteins of γ-secretase complex in HT-29 and DLD-1 cells. In addition, ectopic expression of the Notch intracellular domain (NICD) partly reversed the inhibition effects by the combination therapy. In conclusion, our results indicated that the combination of quercetin (20 μM) and IR (5Gy) might be a promising therapeutic strategy for colon cancer treatment by targeting colon cancer stem-like cells and inhibiting the Notch-1 signaling. In future studies, we intend to further explore the potential therapeutic efficacy of the quercetin-radiation combination treatment in clinical trials.
METHODS:OBJECTIVES:Long-term prevention of metastatic disease remains a challenge in locally advanced rectal cancer, and robust pretreatment prognostic factors for metastatic progression are lacking. We hypothesized that detecting circulating tumor-specific DNA (ctDNA) based on hypermethylation of the neuropeptide Y gene (meth-ctDNA) could be a prognostic marker in the neoadjuvant setting; we examined this in a secondary, explorative analysis of a prospective trial. MATERIALS AND METHODS:Serum samples were prospectively collected in a phase III trial for locally advanced rectal cancer. Positivity for and fractional abundance of meth-ctDNA in baseline samples were estimated. Overall survival (OS) and the rate of distant metastases were compared between meth-ctDNA positive and negative patients; other prognostic factors were controlled for in multivariate Cox regression. Importance of quantitative load was examined by considering the fractional abundance of meth-ctDNA relative to total circulating DNA. RESULTS:Baseline serum samples were available for 146 patients. In total, 30 patients had presence of meth-ctDNA, with no correlation with cT (P=0.8) or cN (P=0.6) stages. Median follow-up was 10.6 years for OS and 5.1 years for freedom from distant metastases. Patients with meth-ctDNA had significantly worse 5-year OS (47% vs. 69%), even when controlling for other prognostic factors (hazard ratio=2.08; 95% confidence interval, 1.23-1.51). This seemed mainly driven by disparity in the rate of distant metastases (55% vs. 72% at 5 y, P=0.01); hazard ratio=2.20 (95% confidence interval, 1.19-4.07, P=0.01) in multivariate analysis. Increased quantitative load was highly significant for worse outcomes. CONCLUSIONS:Meth-ctDNA could be a potential prognostic marker in the neoadjuvant setting and may, if validated, identify patients at increased risk of distant metastases.