Ying-Feng Peng

Multicenter Phase I/II Study of Docetaxel, Cisplatin and Fluorouracil Combination Chemotherapy in Patients with Advanced or Recurrent Squamous Cell Carcinoma of the Esophagus

Objective: Esophageal squamous cell carcinoma (ESCC) is refractory to current therapeutic regimens and more effective therapies are imperative. To this end, we conducted a multicenter phase I/II trial of docetaxel, cisplatin, and fluorouracil (DCF) combination chemotherapy for ESCC. Methods: The study subjects were 46 patients with advanced or recurrent ESCC. Treatment included docetaxel at 60, 70, and 75 mg/m2, cisplatin at 70 mg/m2 on day 1, and daily fluorouracil at 700 mg/m2 on days 1 through 5. The recommended dose of docetaxel was determined in phase I, while the response rate (RR) and progression-free survival rates were analyzed in phase II. Results: The recommended dose was determined to be 70 mg/m2 in phase I. In phase II, the RR was 72.5%. Interim analysis showed median and 1-year progression-free survival of 14 months and 55.6%, respectively. Grade 3/4 toxicities of leukopenia and neutropenia occurred in 72.5 and 90% of patients, respectively. No treatment-related death was recorded. Surgical resection was subsequently performed in 20 patients after chemotherapy, and curative resection was achieved in 19. Conclusion: DCF was tolerable and effective for advanced and recurrent ESCC. Such findings might encourage a change in the treatment strategy for ESCC.

Immunohistochemical Expression of Osteopontin in Gastric Cancer

Background/AimsOsteopontin (OPN) is significantly overexpressed in a variety of malignancies. However, little is known concerning the significance of OPN expression in human cancers. Thus, the aim of this study was to determine the relationship between the degree of OPN expression, the proliferative activity of cancer cells, and the clinicopathological findings for surgically resected gastric cancer.MethodologyWe evaluated the immunohistochemical expression of OPN in 85 specimens of cancer. Additionally, we investigated a cancer cell proliferative index using an anti-MIB-1 antibody and terminal deoxynucleotidyl transferase-mediated dUTP biotin nick end labeling staining. Levels of OPN expression in gastric cancers were classified into three groups. To compare the relationship between OPN expression and clinicopathological findings, the features of cancer lesions were classified using the TNM Classification of Malignant Tumors, 6th Edition.ResultsImmunohistochemical examination of OPN expression in gastric cancer revealed diffuse granular staining in the cytoplasm. High OPN expression was observed in 37 of 85 carcinomas. Strong OPN expression was significantly associated with a low apoptotic index, a high proliferative index, depth of invasion, lymphatic invasion, and venous invasion. Pathologically, intestinal type carcinoma showed strong expression of OPN.ConclusionsThese data suggested that OPN may play an important role in the invasiveness and the progressive nature of gastric cancer.

Impact of Intraperitoneal Chemotherapy after Gastrectomy with Positive Cytological Findings in Peritoneal Washings

Background: There is no standard treatment available for gastric cancer patients whose sole ‘non-curative factor’ is positivecytological findings in peritoneal washings (CFPW). The aim of this study was to examine the safety, pharmacokinetics and efficacy for free intraperitoneal cancer cells of intraperitoneal chemotherapy with paclitaxel after gastrectomy with en bloc D2 lymph node dissection in cases of gastric cancer with positive CFPW. Methods: Ten patients with gastric cancer who underwent gastrectomy and systemic lymphadenectomy with D2 dissection, without any other non-curative factors besides positive CFPW, were treated with early postoperative intraperitoneal paclitaxel. Intra-chemotherapeutic toxicity and operative complications were measured using NCI-CTC version 3.0. Intraperitoneal and plasma paclitaxel concentrations were measured using a high-performance liquid chromatographic assay. Results: Grade 3/4 toxic effects included anemia (20%) and neutropenia (10%) that required no treatment. Operative complications were, for example, superficial surgical site infections (10%) that were treated with antibiotics. No viable cancer cells were observed in the intra-abdominal fluid 24 h after intraperitoneal administration of paclitaxel. The intraperitoneal/plasma area under the drug concentration-time curve ratio was 2,003.3:1. Conclusion: Intraperitoneal chemotherapy with paclitaxel is a safe and effective treatment modality for free intraperitoneal cancer cells.

High expression of epithelial cellular adhesion molecule in peritoneal metastasis of gastric cancer

Intraperitoneally administrated epithelial cellular adhesion molecule (EpCAM) monoclonal antibody is a therapeutic agent in patients with malignant effusion in several types of carcinoma. However, the role of EpCAM in peritoneal metastasis (PM) lesions and primary lesions of gastric cancer (GC) is still unclear. Therefore, in this study, we investigated EpCAM expression in GC patients with PM. We investigated the expression of EpCAM in 35PM lesions and 104 biopsy samples as primary lesions. Immunohistochemical staining was performed using the Ventana Benchmark XT (Roche Diagnostics) system. EpCAM expression was evaluated by calculating the total immunostaining score, which is the product of the proportion score and the intensity score. Overexpression was defined as a total score greater than 4. All PM specimens showed overexpression of EpCAM, and GC cells in both the surface layer and the deep layer of the PM showed a high expression of EpCAM. Meanwhile, in the biopsy sample, the expression of EpCAM ranged from none to strong. The EpCAM score results for PM specimens and biopsy samples were 11.0 ± 2.0 and 6.9 ± 3.9, respectively. The difference between the scores was statistically significant (P < 0.05). The intraperitoneally administrated EpCAM antibody might have a anti-cancer effect in PM lesions of GC. Additionally, it can be assumed that only GC cells which express a high level of EpCAM might metastasize to the peritoneum.

Safety of intraperitoneal administration of paclitaxel after gastrectomy with en-bloc D2 Lymph node dissection

The aim of this study was to examine the safety, pharmacokinetics, and cytological efficacy against free intraperitoneal cancer cells of intraperitoneal chemotherapy (IPC) with paclitaxel after gastrectomy with en‐bloc D2 lymph node dissection (GD2) in cases of gastric cancer with peritoneal carcinomatosis (PC) and/or positive cytological findings in peritoneal washings (CFPW).

A phase II trial of perioperative chemotherapy involving a single intraperitoneal administration of paclitaxel followed by sequential S-1 plus intravenous paclitaxel for serosa-positive gastric cancer.

We carried out a phase II trial to evaluate the feasibility, efficacy, and tolerability of perioperative chemotherapy including single intraperitoneal(IP) administration of paclitaxel(PTX) followed by intravenous(IV) administrations of PTX with S‐1 in a neoadjuvant setting for serosa‐positive gastric cancer.

Prospective randomized trial of short-term neoadjuvant chemotherapy for advanced gastric cancer

BACKGROUND We performed short-term neoadjuvant chemotherapy (s-NAC) to examine whether anticancer drugs can change the proliferative ability of cancer cells in gastric cancer patients. METHODS Chemotherapy was performed for 72 h before gastrectomy in 63 gastric cancer patients. Patients were classed into four groups: Group F, 16 cases who received a single administration of 5-fluorouracil (5-FU); Group C, 15 cases who received a single administration of cis-diamminedichloroplatinum (CDDP; cisplatin); Group FC, 16 cases who received both 5-FU+CDDP; and a Control group, 16 cases who did not receive chemotherapy. We reviewed neoadjuvant biopsy tissue and gastric cancer tissue delivered by operation in these cases. The TUNEL method and immunohistochemistry with an anti-MIB-1 antibody were used to evaluate cellular apoptosis and proliferative ability, respectively. The apoptotic index (AI) and an MIB-1 index (MI) were also calculated. RESULTS There were no differences in AI or MI in biopsy tissue between the groups. The AI of gastric cancer tissue in Group FC was significantly higher than in the other groups (P < 0.01). The MI of Group FC was significantly lower than in the other groups (P < 0.05). In addition, after s-NAC operation there was a significant inhibition of proliferative potency and an induction of apoptosis in Group FC. CONCLUSION Combination of CDDP and 5-FU reduced proliferative potency and increased cellular apoptosis in gastric cancer cells.

Abstract 4: Gene amplification of EGFR, HER2, HER3 and HER4 in esophageal squamous cell carcinoma

Overexpression of epidermal growth factor receptor (EGFR) and its family members HER2, HER3 and HER4 are found in a variety of human malignancies and their roles in cancer development and progression has been widely recognized for long time. Molecular drugs targeting EGFR family, such as small-molecule inhibitors and specific monoclonal antibodies, are now under intensive investigation in clinical setting. In esophageal squamous cell carcinoma (ESCC), EGFR and HER2 are frequently overexpressed and their poor prognostic impacts have been reported to date. However, there is no study evaluating gene amplification of EGFR, HER2, HER3 and HER4 simultaneously in ESCC in a large cohort. We examined gene amplification of EGFR, HER2, HER3 and HER4 using realtime PCR-based copy number assay on 196 surgical specimens of formalin-fixed, paraffin-embedded (FFPE) samples. Gene amplification of EGFR and HER2 (copy number > 4) was observed in 7 % and 11%, respectively. Although the copy numbers were relatively low, we found gene amplification of HER3 and HER4 to be observed in 8% and 7%, respectively. Gene amplification at least one or more genes was observed in 23 % (45/196) of ESCC samples. Overlapping gene amplification was identified in 8 % (15/196) of samples. In relation with clinical characteristics, gene amplification of HER2 and HER4 was significantly involved in shorter relapse-free survivals in stage III ESCC. In conclusion, gene amplification of EGFR family was frequently observed in ESCC and PCR-based copy number assay could be a powerful tool for detecting gene amplification using FFPE samples. Our results strongly encourage the development of EGFR family-targeted therapy for ESCC with gene amplification. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4. doi:1538-7445.AM2012-4

Phase I clinical trial of vaccination with URLC10-derived peptide for patients with advanced esophageal cancer

Background Up-regulated gene in lung cancer 10 (URLC10), confirmed to be lymphocyte antigen 6 complex locus K and defined as an oncoantigen, has been identified as a tumor-associated antigen by systematic analysis of expression levels of thousands of genes in lung cancer tissues and esophageal squamous cell carcinoma tissues, which were compared with those of normal human tissues by use of cDNA microarray analysis. Human leukocyte antigen (HLA)-A*2402-positive dendritic cells pulsed with URLC10-derived epitope peptide induced CD8+ cytotoxic T lymphocytes to exert specific cytotoxicity against the HLA-A*2402-positive URLC10-expressing esophageal carcinoma cell lines.