Daxuan Hao

Combining radiation with autophagy inhibition enhances suppression of tumor growth and angiogenesis in esophageal cancer

Radiotherapy is an effective treatment for esophageal cancer; however, tumor resistance to radiation remains a major biological problem. The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation. The effects of the autophagy inhibitor 3-methyladenine (3-MA) on radiosensitivity were tested in the EC9706 human esophageal squamous cell carcinoma cell line by colony formation assay. Furthermore, the synergistic cytotoxic effects of 3-MA and radiation were assessed in a tumor xenograft model in nude mice. Mechanistic studies were performed using flow cytometry, immunohistochemistry and western blot analysis. The results of the present study demonstrated that radiation induced an accumulation of autophagosomes and 3-MA effectively inhibited radiation-induced autophagy. Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo. The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation. In addition, autophagy inhibition increased apoptosis and reduced tumor cell proliferation. The combination of radiation and autophagy inhibition resulted in a significant reduction in tumor volume and vasculature in the murine model. The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma.

First-line epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma

We proposed to compare the outcomes of first‐line epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR‐TKI) alone with EGFR‐TKI plus whole‐brain radiotherapy (WBRT) for the treatment of brain metastases (BM) in patients with EGFR‐mutated lung adenocarcinoma. A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study. Among the 132 patients, 72 (54.5%) harbored a deletion in exon 19, 97 (73.5%) showed multiple intracranial lesions, and 67 (50.8%) had asymptomatic BM. Seventy‐nine patients (59.8%) were treated with EGFR‐TKI alone, 53 with concomitant WBRT. The intracranial objective response rate was significantly higher in the EGFR‐TKI plus WBRT treatment group (67.9%) compared with the EGFR‐TKI alone group (39.2%) (P = 0.001). After a median follow‐up of 36.2 months, 62.1% of patients were still alive. The median intracranial TTP was 24.7 months (95% CI, 19.5–29.9) in patients who received WBRT, which was significantly longer than in those who received EGFR‐TKI alone, with the median intracranial TTP of 18.2 months (95% CI, 12.5–23.9) (P = 0.004). There was no significant difference in overall survival between WBRT and EGFR‐TKI alone groups, (median, 48.0 vs 41.1 months; P = 0.740). The overall survival is significantly prolonged in patients who had an intracranial TTP exceeding 22 months compared to those who developed intracranial progression <22 months after treatment, (median, 58.0 vs 28.0 months; P = 0.001). For EGFR‐mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a higher response rate of BM and significant improvement in intracranial progression‐free survival compared with EGFR‐TKI alone.

Neoadjuvant chemoradiotherapy versus chemotherapy and surgery for patients with locally advanced esophageal squamous cell carcinoma

Background: Neoadjuvant chemoradiotherapy (nCRT) and surgery has been recommended as the standard treatment for locally advanced esophageal carcinoma in western countries. However, neoadjuvant chemotherapy (nCT) rather than nCRT is preferred for a large cohort of patients with locally advanced esophageal squamous cell carcinoma (ESCC) in China to reduce postoperative morbidity. This study aimed to compare the efficacy and postoperative morbidity of nCRT and nCT in patients with locally advanced ESCC. Methods: A total of 111 patients with locally advanced ESCC (T2-4aN0-1M0) received neoadjuvant treatment at our institution from January 2009 to January 2014. Among them, 53 cases received one cycle of nCT with concurrent radiotherapy while the remaining 58 received two cycles of chemotherapy alone before surgery. Results: Pathologic complete response (pCR) was observed in 15 patients in the nRCT group (28.3%) and 8 patients in the nCT group (13.8%, P=0.060). Postoperative morbidity was 32.1% in the nRCT group and 37.9% in the nCT group (P=0.660). Disease-free survival (DFS) rates at 1, 2, 3 years were 73.1%, 66.7%, 53.6% in the nRCT group, and 73.7%, 60.4%, 52.2% in the nCT group, respectively (P=0.848). Overall survival (OS) rates at 1, 2, 3 years were 88.5%, 78.0%, 59.5% in the nRCT group, and 89.5%, 72.9% and 56.2% in the nCT group, respectively (P=0.749). Conclusions: NRCT may achieve higher pCR rate than nCT without increasing the odds of postoperative morbidity, but the survival was similar between two treatment groups.

Neoadjuvant nimotuzumab plus chemoradiotherapy compared to neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy for locally advanced esophageal squamous cell carcinoma

Neoadjuvant therapy improves long-term locoregional control and overall survival after surgical resection for esophageal cancer, and neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT) are commonly used in clinical practice. Nimotuzumab is a humanized monoclonal antibody against epidermal growth factor receptor (EGFR), the efficacy of nimotuzumab added to nCRT for esophageal cancer is uncertain. We conducted this retrospective study in which combining neoadjuvant treatment of nimotuzumab with chemoradiotherapy (Nimo-nCRT) is compared with nCRT and nCT for patients with potentially resectable locally advanced esophageal squamous cell carcinoma. One hundred ninety-five patients received neoadjuvant therapy and 172 (88.2%) underwent esophagectomy. Surgical resection was performed in 94.4% after Nimo-nCRT, versus 92.5% after nCRT and 83.5% after nCT (P = 0.026). The R0 resection rate was 100% after Nimo-nCRT, 95.9% after nCRT and 92.6% after nCT (P = 0.030). Pathological complete response (pCR) was achieved in 41.2% after Nimo-nCRT, versus 32.4% after nCRT and 14.8% after nCT (P = 0.0001). Lymph-node metastases were observed in 29.4% in the Nimo-nCRT group, versus 21.6% in the nCRT group and 35.8% in the nCT group (P = 0.093). More patients in the Nimo-nCRT and nCRT group developed grade 3 esophagitis compared to those in the nCT group, P = 0.008. There was no difference in surgical complications between the treatment groups. nCRT results in improved R0 resection, higher pCR rate, and a lower frequency of lymph node metastases compared to nCT, adding nimotuzumab to nCRT is safe and appears to facilitate complete resection and increase the pCR rate.

Neoadjuvant or adjuvant chemoradiation therapy for stage II-III esophageal squamous cell carcinoma.

202 Background: Esophageal cancer is the eighth most common cancer worldwide, and especially in China is the fourth most common cause of death. Clinical trials have explored the value of neoadjuvant or adjuvant chemoradiation in potentially resectable esophageal squamous cell carcinoma (ESCC); however, these studies have produced conflicting results. This retrospective study was performed to investigate whether patients with resectable stage II/III ESCC should receive neoadjuvant or adjuvant therapy in addition to surgery. Methods: A review of stage II/III ESCC patients who underwent esophagectomy and either neoadjuvant or adjuvant chemoradiation was performed. Patients who underwent neoadjuvant therapy were treated with one cycle of chemotherapy consisted of cisplatin and fluorouracil concurrently with radiotherapy (40Gy/20f), adjuvant therapy consisted of two cycles of chemotherapy concurrently with radiotherapy (46-50Gy/23-25f, 5 days/week). Results: A total of 122 patients met inclusion criteria, of w...