Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial.

PURPOSE: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial. MATERIALS AND METHODS: Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS. RESULTS: Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001). CONCLUSION: Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate.

Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes.

PURPOSE: Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression. EXPERIMENTAL DESIGN: HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay. RESULTS: The IC(50) to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated >2-fold and 23 miRNAs upregulated >2-fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC(50) to sorafenib. CONCLUSIONS: Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC.

Epigallocatechin-gallate modulates chemotherapy-induced apoptosis in human cholangiocarcinoma cells.

BACKGROUND: Green tea polyphenols are chemopreventive in several cancer models but their use as adjunctive therapeutic agents for cancer is unknown. AIMS: Cholangiocarcinomas respond poorly to chemotherapeutic agents and our aims were to assess the utility of green tea polyphenols as adjuncts to chemotherapy for cholangiocarcinoma. MATERIALS AND METHODS: We assessed the effect of purified green tea catechins on chemotherapy-induced apoptosis in KMCH, CC-LP-1 and Mz-ChA-1 human cholangiocarcinoma cells, and on chemosensitivity of Mz-ChA-1 cell xenografts in nude mice. RESULTS: Epigallocatechin-gallate (EGCG), but not the structurally related catechin epigallocatechin, sensitized cells to apoptosis induced by gemcitabine (GEM), mitomycin C or 5-fluorouracil in vitro. Mitochondrial membrane depolarization, cytosolic cytochrome c expression and apoptosis were increased in cells incubated with EGCG and GEM compared with either agent alone. Furthermore, EGCG decreased in vivo growth and increased the sensitivity to GEM of Mz-ChA-1 cell xenografts in nude mice. CONCLUSIONS: The green tea polyphenol EGCG sensitizes human cholangiocarcinoma cells to chemotherapy-induced apoptosis and warrants evaluation as an adjunct to chemotherapy for the treatment of human cholangiocarcinoma.

Paclitaxel and epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil for patients with stage IIIC breast cancer with ten or more involved axillary lymph nodes.

OBJECTIVE: The aim of this study was to evaluate the feasibility of a combination of epirubicin and paclitaxel followed by intravenous (iv) cyclophosphamide, methotrexate, and 5-fluorouracile (CMF) as adjuvant treatment of breast cancer patients with 10 or more metastatic axillary lymph nodes. METHODS: Forty-four patients entered this multicenter study and received 4 cycles of epirubicin (E 120 mg/m2 day 1, q3 weeks) and paclitaxel (T 135 mg/m2 day 1, q3 weeks), followed by 4 cycles of iv CMF (days 1 and 8, q4 weeks). Patients with positive hormonal receptors received sequentially tamoxifen associated with LH-RH analogue if premenopausal. The endpoints were the evaluation of the feasibility of this schedule and disease free survival (DFS). RESULTS: Median age of patients was 55; median number of positive axillary nodes was 14 (range, 10-47). Hormonal receptor status was positive in 57% of patients. The combination of epirubicin and paclitaxel was well tolerated; NCI grade 3/4 events were: leucopenia in 27% of patients, neutropenic fever in 5 patients, anemia in 7%, thrombocytopenia in 7%, nausea in 18%, vomiting in 14%, and neurotoxicity in 4%. CMF regimen caused a few cases of grade 3/4 hematologic toxicity. No cardiac toxicity was recorded. With a median follow-up of 59 months, 18 (41%) patients relapsed. Sites of relapse were mainly bone, skin/soft tissues, liver, and lung. Median DFS was 78 months, with a 5-year rate of 60%. CONCLUSIONS: The combination of paclitaxel at low dose and epirubicin followed by CMF is a feasible regimen, which seems to be effective in high-risk node positive breast cancer patients and requires further investigations.