Chang-Hua Yu

A randomized, controlled, multicenter study comparing intensity-modulated radiotherapy plus concurrent chemotherapy with chemotherapy alone in gastric cancer patients with D2 resection.

BACKGROUND AND PURPOSE The role of postoperative chemoradiotherapy in the treatment of patients with gastric cancer with D2 lymph node curative dissection is not well established. In this study, we compared postoperative intensity-modulated radiotherapy plus chemotherapy (IMRT-C) with chemotherapy-only in this patient population. MATERIALS AND METHODS We randomly assigned patients with D2 lymph node dissection in gastric cancer to IMRT-C or chemotherapy-only groups. The adjuvant IMRT-C consisted of 400 mg of fluorouracil per square meter of body-surface area per day plus 20mg of leucovorin per square meter of body-surface area per day for 5 days, followed by 45 Gy of IMRT for 5 weeks, with fluorouracil and leucovorin on the first 4 and the last 3 days of radiotherapy. Two 5-day cycles of fluorouracil and leucovorin were given 4 weeks after the completion of IMRT. Chemotherapy-only group was given the same chemotherapy regimens as IMRT-C group. RESULTS The median overall survival (OS) in the chemotherapy-only group was 48 months, as compared with 58 months in the IMRT-C group; the hazard ratio for death was 1.24 (95% confidence interval, 0.94-1.65; P=0.122). IMRT-C was associated with increases in the median duration of recurrence-free survival (RFS) (36 months vs. 50 months), the hazard ratio for recurrence was 1.35 (95% confidence interval, 1.03-1.78; P=0.029). COX multivariate regression analysis showed that lymph node metastasis and TNM stage were both the independent prognostic factors. Rates of all grade adverse events were similar in the two treatment groups. CONCLUSIONS IMRT-C improved RFS, but did not significantly improve OS among patients with D2 lymph node dissection in gastric cancer. Using IMRT plus chemotherapy was feasible and well tolerated in patients with gastric cancer after D2 resection.

Correlation of Hedgehog Signal Activation with Chemoradiotherapy Sensitivity and Survival in Esophageal Squamous Cell Carcinomas

OBJECTIVE To investigate the significance of hedgehog signaling pathway in chemoradiotherapy sensitivity and its effect on the prognosis of esophageal squamous cell carcinoma. METHODS In the present study, we used the method of immunohistochemistry to examine the expression status of two hedgehog components, PTCH1 and glioma-associated oncogene GLI-1, in 100 pre-treated biopsy specimens of esophageal squamous cell carcinoma patients treated with definitive chemoradiotherapy. RESULTS We find that high levels of PTCH1 and GLI-1 were detected in 76.0 and 72.0% of esophageal squamous cell carcinoma, respectively. Significant associations of high PTCH1 and GLI-1 expression with large tumor size (both P = 0.01), locoregional progression (P= 0.001 and 0.003, respectively) and the lack of complete response to chemoradiotherapy (P= 0.008 and 0.01, respectively) were observed. Univariate analysis revealed that high PTCH1 and GLI-1 expression was associated with poor locoregional progression-free survival, distant progression-free survival and overall survival. Furthermore, esophageal squamous cell carcinoma patients with high PTCH1 and GLI-1 expression have the shorter survival time than the subgroups with negative and low PTCH1 and GLI-1 expression. In multivariate analysis, PTCH1 and GLI-1 expression status were both evaluated as independent prognostic factors for locoregional progression-free survival, distant progression-free survival and overall survival. CONCLUSIONS These findings suggest an important role for the activation of hedgehog signaling in esophageal squamous cell carcinoma progression and that PTCH1 and GLI-1 expression may be significantly associated with esophageal squamous cell carcinoma resistance to chemoradiotherapy.

High expression of long non-coding RNA AFAP1-AS1 predicts chemoradioresistance and poor prognosis in patients with esophageal squamous cell carcinoma treated with definitive chemoradiotherapy.

To evaluate the clinical significance of lncRNAs in the resistance to cisplatin‐based chemoradiotherapy in esophageal squamous cell carcinoma (ESCC). We focused on lncRNAs which were frequently reported in ESCC or were involved in chemoradiotherapy resistance. LncRNA expressions were examined in paired cisplatin‐resistant and parental ESCC cell lines. Dysregulated lncRNAs were further measured in 162 pretreatment biopsy specimens of ESCC who received definitive chemoradiotherapy (dCRT). Then the correlations between lncRNA expression and response to dCRT and prognosis were analyzed. Three lncRNAs (AFAP1‐AS1, UCA1, HOTAIR) were found to be deregulated in cisplatin‐resistant cells compared with their parent cells. AFAP1‐AS1 was significantly up‐regulated in tumor tissues compared with adjacent normal tissues (P = 0.006). Furthermore, overexpression of AFAP1‐AS1 was closely associated with lymph node metastasis (P < 0.001), distant metastasis (P = 0.016), advanced clinical stage (P = 0.002), and response to dCRT (P < 0.001). Kaplan–Meier survival analysis revealed that high expression of AFAP1‐AS1 was significantly associated with shorter progression free survival (PFS) (median, 15 months vs. 27 months, P < 0.001) and overall survival (OS) (median, 29 months vs. 42 months, P < 0.001). In the multivariate analysis, high expression of AFAP1‐AS1 was found to be an independent risk factor to predict poor PFS (HR, 1.626; P = 0.027) and OS (HR, 1.888; P = 0.004). Thus, high expression of AFAP1‐AS1 could serve as a potential biomarker to predict tumor response and survival. Determination of this lncRNA expression might be useful for selection ESCC patients for dCRT.

Efficacy Analysis of Simplified Intensity-modulated Radiotherapy with High or Conventional Dose and Concurrent Chemotherapy for Patients with Neck and Upper Thoracic Esophageal Carcinoma

For patients with neck and upper thoracic esophageal carcinoma, it is difficult to control lymph node metastases with conventional dose therapy. In this study, we assessed the feasibility of simplified intensity-modulated radiotherapy (sIMRT) and concurrent chemotherapy for 44 patients and boosted high-dose to metastatic lymph nodes.Three radiation treatment volumes were defined: PGTVnd, with which 68.1 Gy was delivered in high dose group (hsIMRT group), and 60 Gy in the conventional dose group (csIMRT group); PTV1, featuring 63.9 Gy in the hsIMRT group and 60Gy in the csIMRT group; PTV2, with 54 Gy given to both groups. The sIMRT plan included 5 equi-angular coplanar beams. All patients received the cisplatin and 5-FU regimen concurrently with radiotherapy. The treatment was completed within six weeks and one case with grade three acute bronchitis was observed in hsIMRT group. For esophageal lesions, 80% complete response (CR) and 20% partial response (PR) rates were found in the hsIMRT group, and 79.2% CR, with 20.8% PR, in the csIMRT group; for lymph node lesions, 75% CR and 25% PR rates were observed in the hsIMRT group, with 45.8% and 37.5% respectively in the csIMRT group (P <0.05). The differences in 1-, 2- and 3-year relapse-free survival rates were all statistically significant (P <0.05). The major toxicity observed in both groups was Grade I~II leucopenia. sIMRT can generate a desirable dose distribution in treatment of neck and upper thoracic esophageal carcinoma with a better short-term efficacy. Boosted high dosing to metastatic lymph nodes can increase the relapse-free survival rate.

Clinical study of concurrent chemoradiotherapy or radiotherapy alone for esophageal cancer patients with positive lymph node metastasis

AIMS AND BACKGROUND Esophageal cancer patients with pathologic lymph node involvement generally have a poor prognosis. Many randomized controlled trials have not achieved consistent results similar to those of the RTOG8501 trial, and the long-term survival rate has not increased. The present study aimed to compare the efficacy and toxic side effects of concurrent chemoradiotherapy and radiotherapy alone to treat N1 esophageal carcinoma. METHODS AND STUDY DESIGN A total of 130 N1 esophageal carcinoma patients were enrolled and randomly divided into two groups: concurrent chemoradiotherapy group (n = 65) and radiotherapy group (n = 65). Both groups received three-dimensional conformal radiotherapy with a total dose of 64-66 Gy. Meanwhile, to the concurrent chemoradiotherapy group, an additional chemotherapy protocol (nedaplatin, 20 mg/m²/d, 5-FU, 500 mg/m²/d for four days) was given from day 1, and such treatment was repeated until day 29. From day 21 after radiotherapy, two cycles of a consolidated chemotherapy protocol were given at an interval of 28 days. RESULTS The survival rates at one, two, and three years were 72.3%, 55.3%, and 40% in the concurrent chemoradiotherapy group, respectively, and 75.3%, 38.5%, and 18.5% in the radiotheray group (P = 0.007), respectively. The survival rates of the patients in the concurrent chemoradiotherapy group who completed one to two cycles and three to four cycles at one, two, and three years were 70%, 53.3%, and 30%, and 74.2%, 57.1%, 48.6% (P = 0.128), respectively. Three-year distant metastasis rates were 10.7% in the concurrent chemoradiotherapy group and 16.9% in the radiotherapy group. Acute toxicity in the concurrent chemoradiotherapy group was higher than in the radiotherapy group. Late toxic side effects were similar in the two groups. CONCLUSIONS Compared with radiotherapy alone, concurrent chemoradiotherapy in the treatment of esophageal carcinoma with local lymph node enlargement can improve the three-year survival rate. Moreover, completion of three to four cycles of chemotherapy may have better efficacy than one to two cycles.

Neutrophil-to-lymphocyte ratio as a prognostic biomarker for patients with locally advanced esophageal squamous cell carcinoma treated with definitive chemoradiotherapy

The present study evaluated the clinical and prognostic value of neutrophil-to-lymphocyte ratio (NLR) in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (dCRT). A total of 517 patients with ESCC were enrolled and analysed retrospectively. The NLR was calculated at three time points: baseline, post-treatment, and at the time of tumor progression. Elevated NLR was defined as a ratio ≥5. High NLR at baseline was present in 204 (39%) patients and was significantly correlated with larger tumour size, advanced TNM stage, worse ECOG performance status, and dCRT response (p < 0.05). At a median follow-up of 17 months, patients with higher NLR at baseline had poorer progression-free survival (PFS) and overall survival (OS). On multivariate analysis, elevated NLR at baseline was independently associated with PFS and OS (HR = 1.529, p < 0.001 for PFS; HR = 1.856, p < 0.001 for OS). In addition, patients with high pre- and post-treatment NLR demonstrated worse clinical outcomes than other groups. Our results suggest that NLR is an independent prognostic indicator for patients with ESCC undergoing dCRT and changes in NLR level with treatment may indicate therapeutic benefit.

Combination of long noncoding RNA MALAT1 and carcinoembryonic antigen for the diagnosis of malignant pleural effusion caused by lung cancer

Purpose Long noncoding RNAs (lncRNAs) are present in body fluids, but their potential as tumor biomarkers has never been investigated in malignant pleural effusion (MPE) caused by lung cancer. The aim of this study was to assess the clinical significance of lncRNAs in pleural effusion, which could potentially serve as diagnostic and predictive markers for lung cancer-associated MPE (LC-MPE). Patients and methods RNAs from pleural effusion were extracted in 217 cases of LC-MPE and 132 cases of benign pleural effusion (BPE). Thirty-one lung cancer-associated lncRNAs were measured using quantitative real-time polymerase chain reaction (qRT-PCR). The level of carcinoembryonic antigen (CEA) was also determined. The receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) were established to evaluate the sensitivity and specificity of the identified lncRNAs and other biomarkers. The correlations between baseline pleural effusion lncRNAs expression and response to chemotherapy were also analyzed. Results Three lncRNAs (MALAT1, H19, and CUDR) were found to have potential as diagnostic markers in LC-MPE. The AUCs for MALAT1, H19, CUDR, and CEA were 0.891, 0.783, 0.824, and 0.826, respectively. Using a logistic model, the combination of MALAT1 and CEA (AUC, 0.924) provided higher sensitivity and accuracy in predicting LC-MPE than CEA (AUC, 0.826) alone. Moreover, baseline MALAT1 expression in pleural fluid was inversely correlated with chemotherapy response in patients with LC-MPE. Conclusion Pleural effusion lncRNAs were effective in differentiating LC-MPE from BPE. The combination of MALAT1 and CEA was more effective for LC-MPE diagnosis.