Osamu Shiraishi

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.

Gene amplification of EGFR, HER2, FGFR2 and MET in esophageal squamous cell carcinoma

Molecular targeted therapy is expected to be a promising therapeutic approach for the treatment of esophageal squamous cell carcinoma (ESCC); however, the gene amplification status of molecular targeted genes in ESCC remains largely unclear. The gene amplification of EGFR, HER2, FGFR2 and MET was examined using a real-time PCR-based copy number assay of 245 ESCC surgical specimens of formalin-fixed, paraffin-embedded samples. Fluorescence in situ hybridization (FISH) and comparative genomic hybridization analyses verified the results of the copy number assay. EGFR mutation was detected using the Scorpions-ARMS method. The EGFR status and drug sensitivity to an EGFR tyrosine kinase inhibitor was then evaluated in vitro. Gene amplification of EGFR and HER2 was observed in 7% (16/244) and 11% (27/245) of the ESCC specimens. A multivariate analysis revealed that HER2 amplification was a significant predictor of a poor prognosis in patients with stage III post-operative ESCC. The L861Q type of EGFR mutation with hypersensitivity to EGFR tyrosine kinase inhibitor was found in one of the eight ESCC cell lines and one del745 type of EGFR mutation was identified in 107 clinical samples. In addition, we demonstrated for the first time that FGFR2 amplification was observed in 4% (8/196) of the ESCC specimens. MET amplification was observed in 1% (2/196). In conclusion, the frequent gene amplification of EGFR, HER2 and FGFR2 and the presence of active EGFR mutations were observed in ESCC specimens. Our results strongly encourage the development of molecular targeted therapy for ESCC.

Randomized study of clinical effect of enteral nutrition support during neoadjuvant chemotherapy on chemotherapy-related toxicity in patients with esophageal cancer.

BACKGROUND & AIMS Enteral nutrition (EN) is provided for patients with cancer. However, Little is known about the clinical efficacy of EN support during chemotherapy in patients with cancer. METHODS Ninety-one patients who received neoadjuvant chemotherapy (5-fluorouracil, cisplatin and adriamycin) for esophageal cancer were enrolled to receive either EN (n = 47) or PN (n = 44) at random. The primary endpoint was the incidence of chemotherapy-related toxicities during chemotherapy. RESULTS Total and dietary intake calories during chemotherapy were equal in the two groups. There were no significant differences in serum albumin level and body weight change after chemotherapy between the two groups. There was no significant difference in tumor response to chemotherapy between the two groups (EN: 51%, PN: 55%, p = 0.886). Leukopenia and neutropenia of grade 3 or 4, defined according to the Common Toxicities Criteria of the National Cancer Institute, were significantly less frequent in the EN group than PN group (leukopenia: 17% vs 41%, p = 0.011, neutropenia: 36% vs 66%, p = 0.005). Lymphopenia and thrombocytopenia tended to be less frequent in the EN group, albeit insignificantly. CONCLUSIONS Compared with PN support, EN support during neoadjuvant chemotherapy reduced the incidence of chemotherapy-related hematological toxicities in patients with esophageal cancers.

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.

Multicenter randomized phase II study of cisplatin and fluorouracil plus docetaxel (DCF) compared with cisplatin and fluorouracil plus Adriamycin (ACF) as preoperative chemotherapy for resectable esophageal squamous cell carcinoma (OGSG1003)

BACKGROUND This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC. PATIENTS AND METHODS Patients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat. RESULTS Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P = 0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33-0.83, P = 0.0057) and 78.6% versus 65.4% (P = 0.08), respectively. CONCLUSION Compared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC. CLINICAL TRIAL REGISTRATION University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616).Background This phase II trial evaluated the efficacy of cisplatin and fluorouracil (CF)-based combination neoadjuvant chemotherapy on the outcome of patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). We compared the recurrence-free survival (RFS) associated with CF plus Adriamycin (ACF) with that associated with CF plus docetaxel (DCF) to select an alternative regimen in a new phase III trial investigating the optimal neoadjuvant treatment of patients with ESCC. Patients and methods Patients with resectable advanced ESCC were randomly assigned to either ACF (Adriamycin 35 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 7 days) every 4 weeks or DCF (docetaxel 70 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 5 days) every 3 weeks. Surgery was scheduled after completion of two cycles of chemotherapy. The primary end point was RFS, analyzed by the intention-to-treat. Results Between October 2011 and October 2013, 162 patients at 10 institutions were enrolled in the study, all of whom were eligible and randomly assigned to the two groups (81 to the ACF group and 81 to the DCF group). The R0 resection rates for the ACF and DCF groups were equivalent (95.9% versus 96.2%, P = 0.93). The 2-year RFS and overall survival rates for DCF versus ACF were 64.1% versus 42.9% (hazard ratio 0.53, 95% confidence interval 0.33-0.83, P = 0.0057) and 78.6% versus 65.4% (P = 0.08), respectively. Conclusion Compared with ACF, DCF chemotherapy was associated with prolonged RFS for patients with resectable advanced ESCC. Thus, DCF chemotherapy has potential as a standard neoadjuvant therapy for resectable ESCC. Clinical Trial Registration University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN000004555/000004616).

A newly modified esophagogastrostomy with a reliable angle of His by placing a gastric tube in the lower mediastinum in laparoscopy-assisted proximal gastrectomy

BackgroundAn optimal reconstruction method for proximal gastrectomy (PG) remains elusive. Esophagogastrostomy (EG) is technically simple but suffers from the disadvantage of gastroesophageal reflux. Jejunal interposition (JI) has a low rate of gastroesophageal reflux, but the procedure is more complicated, and delayed gastric emptying is a problem.MethodsWe created a modified EG and have used the modified technique for PG since 2006. The procedure involves shaping the remnant stomach into a gastric conduit. The EG is performed high on the anterior wall, and the conduit is kept straight by applying a circular stapler inserted from the anterior wall of the antrum. The tip of the gastric conduit is then inserted into the lower mediastinum, creating a sharp angle of His. In this retrospective cohort study, the clinical and physiological outcomes were compared between 25 patients who underwent this procedure and 21 patients who underwent JI from 2001 to 2005.ResultsLaparoscopic procedures were performed more frequently, and residual food and bile reflux were less common in the EG group than in the JI group. No significant differences in remnant gastritis or reflux esophagitis were observed between the two groups. However, the late complication of intestinal obstruction occurred only in the JI group.ConclusionsThe modified EG technique has advantages over the JI technique because of its simplicity and low incidence of residual food and bile reflux. The next step would be to explore this technique further by a prospective multi-institutional study to confirm the reproducibility of its benefits. Miniabstract: The modified EG technique has advantages over the JI technique because of its simplicity, high rate of laparoscopy use, and low incidence of gastroesophageal reflux.

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).

Relationship between Immunological Parameters and the Severity of Neutropenia and Effect of Enteral Nutrition on Immune Status during Neoadjuvant Chemotherapy on Patients with Advanced Esophageal Cancer

Objectives: Chemotherapy may cause various toxicities as well as impair immunological function. However, little is known about the relationship between toxicities and immunological parameters or the effect of enteral nutrition (EN) on immunological status during chemotherapy. Methods: 91 patients who received neoadjuvant chemotherapy (NACT) for esophageal cancer were randomly assigned to receive either EN or parenteral nutrition (PN). Immunological parameters, including total lymphocyte count (TLC), type 1 and type 2 CD4-positive T cells (Th1/Th2) balance, human leukocyte antigen (HLA)-DR expression on monocytes, natural killer cell activity, and phytohemagglutinin-stimulated lymphocyte proliferation were measured at baseline and day 14 of the first chemotherapy cycle. Results: In the PN group, patients with grade 3–4 neutropenia showed significantly lower TLC, HLA-DR expression, and Th1/Th2 balance at day 14 compared to those with grade 0–2 neutropenia. Among pretherapeutic factors, Th1/Th2 balance was the only factor significantly associated with the severity of neutropenia. Concerning the comparison of immunological parameters between the EN and PN groups, HLA-DR expression at day 14 was significantly higher in the EN group. Conclusions: Baseline Th1/Th2 balance predicted the severity of neutropenia, and EN significantly reduced the decline of monocyte HLA-DR expression in patients with esophageal cancer receiving NACT.

Significance of HBV DNA in the Hepatic Parenchyma from Patients with Non-B, Non-C Hepatocellular Carcinoma

IntroductionThe etiologic and prognostic factors for non-B, non-C hepatocellular carcinoma (HCC), which is defined by its seronegativity for both hepatitis B surface antigen and hepatitis C virus (HCV) antibody, remain unclear.MethodsNonneoplastic liver tissue from 46 patients with non-B, non-C HCC were examined for hepatitis B virus (HBV) DNA and HCV RNA using in situ hybridization. Recurrence-free survival rates were compared between patients showing high or low HBV DNA expression. Other potential prognostic factors were examined as well.ResultsHBV DNA was detected in nonneoplastic liver specimens from 35 patents (76.1%), whereas HCV RNA was not detected in any case. In patents with high HBV DNA group expression, recurrence-free survival rates at 1 and 5 years after onset were 68.8% and 13.8%, respectively; those with low expression had higher rates of 89.2% and 59.2%, respectively. Multivariate analysis identified high tumor stage (P = 0.042) and high HBV DNA expression (p = 0.014) as independent negative prognostic factors.ConclusionsIn many patients with non-B, non-C HCC, HBV DNA in the liver appears to be involved in the carcinogenesis, with intense HBV DNA expression predicting poor outcome for patients with these cancers.