Ta-Chen Huang

Systematic review and network meta-analysis: neoadjuvant chemoradiotherapy for locoregional esophageal cancer

OBJECTIVE Neoadjuvant chemoradiotherapy improves survival in patients with locoregional esophageal cancer. This study compares the efficacy of two common regimens, paclitaxel plus platinum and platinum plus 5-fluorouracil, based on overall survival. METHODS We performed a systematic review and network meta-analysis of randomized trials comparing paclitaxel plus platinum-neoadjuvant chemoradiotherapy or and platinum plus 5-fluorouracil-neoadjuvant chemoradiotherapy with surgery alone. The outcome was the hazard ratios for death in the entire population and the two major histologic subgroups, squamous cell carcinoma and adenocarcinoma. RESULTS Ten clinical trials were included. Compared with surgery alone, the hazard ratios [95% credible interval (CrI)] in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.63 (0.50-0.80), 0.50 (0.36-0.71) and 0.74 (0.54-1.01) for paclitaxel plus platinum, and 0.79 (0.68-0.92), 0.82 (0.67-1.01) and 0.81 (0.63-1.05) for platinum plus 5-fluorouracil, respectively. When paclitaxel plus platinum was compared with platinum plus 5-fluorouracil, the hazard ratios (95% CrI) in the entire, squamous cell carcinoma, and adenocarcinoma population were 0.80 (0.60-1.06), 0.61 (0.41-0.91) and 0.91 (0.61-1.36), respectively. The probability of paclitaxel plus platinum being ranked the optimal treatment for the entire, squamous cell carcinoma, and adenocarcinoma population was 94.2, 99.1 and 67.6%, respectively. CONCLUSIONS Neoadjuvant chemoradiotherapy with paclitaxel plus platinum regimen seemed to be a better treatment than platinum plus 5-fluorouracil regimen for locoregional esophageal cancer, especially for squamous cell carcinoma.

Phase II study of weekly vinorelbine and 24-h infusion of high-dose 5-fluorouracil plus leucovorin as first-line treatment of advanced breast cancer

We prospectively investigated the efficacy and safety of combining weekly vinorelbine (VNB) with weekly 24-h infusion of high-dose 5-fluorouracil (5-FU) and leucovorin (LV) in the treatment of patients with advanced breast cancer (ABC). Vinorelbine 25 mg m−2 30-min intravenous infusion, and high-dose 5-FU 2600 mg m−2 plus LV 300 mg m−2 24-h intravenous infusion (HDFL regimen) were given on days 1 and 8 every 3 weeks. Between June 1999 and April 2003, 40 patients with histologically confirmed recurrent or metastatic breast cancer were enrolled with a median age of 49 years (range: 36–68). A total of 25 patients had recurrent ABC, and 15 patients had primary metastatic diseases. The overall response rate for the intent-to-treat group was 70.0% (95% CI: 54–84%) with eight complete responses and 20 partial responses. All 40 patients were evaluated for survival and toxicities. Among a total of 316 cycles of VNB–HDFL given (average: 7.9: range: 4–14 cycles per patient), the main toxicity was Gr3/4 leucopenia and Gr3/4 neutropenia in 57 (18.0%) and 120 (38.0%) cycles, respectively. Gr1/2 infection and Gr1/2 stomatitis were noted in five (1.6%) and 59 (18.7%) cycles, respectively. None of the patients developed Gr3/4 stomatitis or Gr3/4 infection. Gr2/3 and Gr1 hand–foot syndrome was noted in two (5.0%) and 23 (57.5%) patients, respectively. Gr1 sensory neuropathy developed in three patients. The median time to progression was 8.0 months (range: 3–25.5 months), and the median overall survival was 25.0 months with a follow-up of 5.5 to 45+ months. This VNB–HDFL regimen is a highly active yet well-tolerated first-line treatment for ABC.

Abstract 2616: Upregulation of program death ligand 1 expression after a single cycle of chemotherapy is associated with inferior survival in patients with local advanced esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy

Introduction Previous studies have demonstrated that the expression of program death-ligand 1 (PD-L1), a ligand of an immune checkpoint, on cancer cells or on immune cells may have prognostic significance in multiple cancer types including esophageal squamous cell carcinoma (ESCC). We evaluated the expression of PD-L1 and its dynamic changes following one cycle of chemotherapy before standard preoperative chemoradiotherapy (CRT) in a cohort of locally advanced ESCC patients. Patients and Methods A cohort of 66 patients of locally advanced ESCC have been enrolled to a phase II clinical trial of a single-cycle chemotherapy (a combination of weekly paclitaxel, cisplatin and 24 hour infusional 5-fluorouracil, 2 week on plus one week off, followed by paclitaxel/cisplatin (TP) -based preoperative CRT and radical surgery. Paired tumor tissues from endoscopic biopsy before and after the single-cycle chemotherapy were available in 21 patients. Immunohistochemical stain for PD-L1 expression was performed using the Clone SP142 antibody (Spring Bioscience, Pleasanton, CA, USA). The expression of PD-L1 was scored as previously reported. Tumor cells were scored according to percentage of positively-stained cells: TC3≥50%, TC2≥5% and Results In 21 baseline ESCC tissues, 7 of 19 (37%) exhibited positive PD-L1 expression on tumor cells, and 10 of 21 (48%) exhibited positive expression on immune cells. In 21 ESCC tissues obtained a median of 18 days after initiating chemotherapy, 9 of 18 (50%) and 15 of 21 (71%) demonstrated positive PD-L1 expression on tumor cells and immune cells, respectively. The expression of PD-L1 was significantly increased in post-chemotherapy ESCC tissues compared with baseline tissues (p=0.010); and the increased PD-L1 expression between paired tissues was significant on immune cells (p=0.0056) but did not reach statistical significance on tumor cells (p=0.11). The positive PD-L1 expression in baseline ESCC tissues was correlated with better survival (HR: 0.37, p=0.023). Besides, patients with more increase of PD-L1 expression after chemotherapy had significantly worse survival than those with less (median survival: 19.4 vs 71.20 months, HR: 4.07, p=0.0089). Conclusion PD-L1 expression of ESCC can be up-regulated by chemotherapy. The up-regulation of PD-L1 is associated with poor outcome for locally advanced ESCC patients. (The study was supported by the grant NTUH 104-M2891 and the grant MOST 105-2314-B-002-186-MY3) Citation Format: Ta-Chen Huang, Cher-Wei Liang, Chia-Chi Lin, Ya-Jhen Chen, Kuan-Ling Lin, Ann-Lii Cheng, Chin-Hung Hsu. Upregulation of program death ligand 1 expression after a single cycle of chemotherapy is associated with inferior survival in patients with local advanced esophageal squamous cell carcinoma treated with preoperative chemoradiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2616. doi:10.1158/1538-7445.AM2017-2616

The recurrence patterns and post-recurrence survivals in patients with locally advanced esophageal squamous cell carcinoma (ESCC) treated with preoperative paclitaxel/cisplatin-based chemoradiotherapy.

80 Background: More than half of patients (pts) with locally advanced ESCC would have disease recurrence after curative preoperative chemoradiation (CRT) followed by surgery. Whether recurrence pattern correlates with the post-recurrence survival remains uncertain. Methods: We included 131 pts with locally advanced ESCC (clinical T3N0-1M0 or T1-3N1M0 or M1a according to AJCC 6thedition) who were enrolled in 3 phase II clinical trials of preoperative CRT followed by surgery and had successfully completed CRT and surgery. These pts received preoperative twice weekly paclitaxel/cisplatin-based CRT with radiotherapy 40Gy given in 20 fractions followed by esophagectomy. When pts had first disease recurrence, we divided them into three groups according to their recurrence patterns: loco-regional recurrence (LRR), distant metastasis only (DM), and both LRR and DM (LRR+DM). Survival outcomes were compared using the Kaplan-Meier curves. Results: With a median follow-up of 34.8 months, 75 pts (57.3%) had disease re...

Abstract 4980: Upregulation of PD-L1 expression by cisplatin in esophageal squamous cell carcinoma cells is independent of interferon/JAK/STAT pathway

Introduction Blockade of immune check points, especially the program cell death 1 (PD-1) and its major ligand PD-L1 signaling, has become an important mode of therapy against cancers. The upregulation of PD-L1 expression in cancer cells is an important mechanism contributing to immune evasion of cancers. The PD-L1 upregulation in cancer cells could be mediated by intrinsic genetic or signaling alterations, or could be induced in response to specific cytokines, in particular interferon (IFN)-gamma, produced by tumor-infiltrating immune cells. Whether chemotherapy per se has direct impact on PD-L1 expression in cancer cells is currently unclear. Materials and Methods Four esophageal squamous cell carcinoma (ESCC) cell lines, TE5, KYSE70, KYSE270, KYSE510, were included. The expression of PD-L1 in ESCC cells, treated with various concentrations of cisplatin, were evaluated by flow cytometry, Western blotting, and qRT-PCR. To study the potential signaling pathways involved in the PD-L1 upregulation induced by cisplatin, we evaluated the nuclear expression of p-STAT1 and IRF1 (for IFN/JAK/STAT pathway), and p65 and p50 (for NF-kB pathway). Finally, we used BAY-11-7082, an irreversible inhibitor of IKKα, to validate the significance of NF- kB pathway in mediating the PD-L1 upregulation induced by cisplatin. Results Cisplatin at the doses of 5∼ 10 μM increased the proportions of PD-L1-expressing cells detected by flow cytometry in all tested ESCC cells. The folds of increase were 19.29±2.27, 10.13±8.42, 23.19±10.12, 6.20±0.81 for TE5, KYSE70, KYSE270, and KYSE510 treated with 10 μM of cisplatin, respectively. The kinetics of this cisplatin- induced PD-L1 expression, evaluated in TE5 cells, was: after exposure to cisplatin for 24 hours, the PD-L1 expression peaked at 48 hours, and remained elevated at 144 hours after drug exposure. In multiple ESCC cells, exposure to cisplatin did not increase the expression of p-STAT1 and IRF1, suggesting that IFN/JAK/STAT pathway did not involve in the PD-L1 upregulation induced by cisplatin. In co-culture experiments with cisplatin-treated TE5 cells or with condition medium from cisplatin-treated TE5 cells, we confirmed that the PD-L1 upregulation in ESCC cells was not through paracrine manners. In TE5 cells, cisplatin treatment induced nuclear translocation of p65, suggesting that NF-kB pathway was activated. The cotreatment of BAY11-7082 could partially abrogate the PD-L1 upregulation induced by cisplatin in TE5 cells. Conclusion PD-L1 expression in ESCC cancer cells can be up-regulated by cisplatin. Our data indicated that this activation is not mediated through the IFN/JAK/STAT pathway, but may involve in activation of NF-κB signaling. (The study was supported by the grant NTUH 104-M2891 and the grant MOST 104-2314-B-002-111) Citation Format: Ta-Chen Huang, Kuan-Ling Lin, Ann-Lii Cheng, Chih-Hung Hsu. Upregulation of PD-L1 expression by cisplatin in esophageal squamous cell carcinoma cells is independent of interferon/JAK/STAT pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4980.

Postchemoradiotherapy Pathologic Stage Classified by the American Joint Committee on the Cancer Staging System Predicts Prognosis of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma

Introduction: To determine whether the postchemoradiotherapy (post-CRT) pathologic stage predicts the outcomes of patients with locally advanced esophageal squamous cell carcinoma (ESCC) undergoing preoperative CRT followed by surgery. Methods: From three phase II trials of preoperative CRT for locally advanced ESCC, 140 patients were included. Preoperative CRT comprised twice weekly paclitaxel and cisplatin-based regimens and 40-Gy radiotherapy in 20 fractions. The post-CRT pathologic stage was classified according to the American Joint Committee on Cancer, 7th edition staging system. The prognostic effects of clinicopathologic factors were analyzed using Cox regression. Results: With a median follow-up of 61.9 months, the median progression-free survival (PFS) and overall survival (OS) of the entire cohort were 24.5 and 30.9 months, respectively. The post-CRT pathologic stage was 0 in 34.5%, I in 12.9%, II in 29.3%, III in 13.6%, and ypT0N1-2 in 6.4% of the patients. The median PFS was 47.2, 25.9, 16.0, 9.4, and 15.1 months, and the median OS was 57.4, 34.1, 26.2, 14.1, and 17.6 months for patients with post-CRT pathologic stage 0, I, II, III, and ypT0N1-2, respectively. In multivariate analysis, performance status (p < 0.001), tumor location (p = 0.016), and extranodal extension (p = 0.024) were independent prognostic factors for PFS, whereas performance status (p < 0.001) and post-CRT pathologic stage (p = 0.027) were independent prognostic factors for OS. Conclusions: The post-CRT pathologic stage classified by American Joint Committee on Cancer, 7th edition staging system predicted the survival of locally advanced ESCC patients who underwent preoperative paclitaxel and cisplatin-based CRT followed by esophagectomy.

Abstract 3761: Tissue processing time affects the expression of phosphoproteins after breast cancer resection

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Background: Many phosphoproteins are among the targeted pathways of cancer signal transduction and are therefore candidates for cancer biomarkers. However, the collection procedures of biospecimens might affect the expression of the phosphoproteins significantly because the time interval between surgical removal of tissues and fixation, i.e. warm ischemia time, are variable. This study aimed to evaluate the stability of phosphoprotein expression under the differential tissue processing time. Materials and Methods: Specimens were obtained from patients who received mastectomy at National Taiwan University Hospital. Each specimen was cut into 5 pieces, stored at 4oC for 10 minutes, 2, 4, 6, and 24 hours before further processing. At each assigned time point, a small section of the specimen was fixed immediately in 10% buffered formalin, then paraffin embedded for immunohistochemical stains (IHC) of phospho-Akt (p-Akt) and phospho-Erk (p-Erk). The remaining specimens were snap frozen in liquid nitrogen, followed by homogenization in RIPA buffer. Western blot analysis was performed for phospho-Akt (p-Akt), total Akt, phospho-Erk (p-Erk), total Erk, phospho-STAT3 (p-STAT3), and total STAT3 staining. Results: Western blot analysis showed that the expression of p-Erk declined significantly as early as 2 hours. The expression of p-Akt was relatively stable and decreased slightly after 24 hours. The expression of p-STAT3 gave variable results. The expression of total Akt, Erk, and STAT3 remain unchanged at each assigned time point. The immunohistochemical expression of p-ERK declined in a time-dependent manner whereas no obvious p-Akt decrease was detected. Conclusions: Our results indicate that the expression of some phosphoproteins by IHC may be affected by warm ischemia time. Caution should be given to the interpretation of the results of these biomarkers. (The study was supported by the grant NSC 98-3112-B-002-038) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3761.