Neoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer.

Neoadjuvant chemotherapy with docetaxel, oxaliplatin, fluorouracil, and leucovorin (FLOT regimen) has shown promising results in terms of pathological response and survival rate in patients with locally advanced resectable gastric cancer (LAGC). However, tegafur gimeracil oteracil potassium capsule (S-1) plus oxaliplatin (SOX regimen) is the preferred chemotherapy regimen in Eastern countries. Here, we conduct an open label, two-arm, phase II randomized interventional clinical trial (Dragon III; ClinicalTrials.gov: NCT03636893) to evaluate the safety and efficacy of both regimens. Patients with LAGC are randomly assigned to receive either 4 cycles of the neoadjuvant FLOT regimen (40 patients) or 3 cycles of the SOX regimen (34 patients) before gastrectomy. The primary endpoint is the comparison of complete (TRG1a) or subtotal (TRG1b) tumor regression grading in the primary tumor. There are no significant differences in adverse effects or postoperative morbidity and mortality between the two groups. No significant differences in the proportion of tumor regression grading between the FLOT group and the SOX group are found. Complete or subtotal TRG is 20.0% in the FLOT group versus 32.4% in the SOX group. Therefore, our study does not find statistically significant differences between neoadjuvant FLOT and SOX regimens for the primary outcomes reported here in locally advanced gastric cancer.

The role of GLI2-ABCG2 signaling axis for 5Fu resistance in gastric cancer.

Gastric cancer is a leading cause of cancer-related mortality worldwide, and options to treat gastric cancer are limited. Fluorouracil (5Fu)-based chemotherapy is frequently used as a neoadjuvant or an adjuvant agent for gastric cancer therapy. Most patients with advanced gastric cancer eventually succumb to the disease despite the fact that some patients respond initially to chemotherapy. Thus, identifying molecular mechanisms responsible for chemotherapy resistance will help design novel strategies to treat gastric cancer. In this study, we discovered that residual cancer cells following 5Fu treatment have elevated expression of hedgehog (Hg) target genes GLI1 and GLI2, suggestive of Hh signaling activation. Hh signaling, a pathway essential for embryonic development, is an important regulator for putative cancer stem cells/residual cancer cells. We found that high GLI1/GLI2 expression is associated with some features of putative cancer stem cells, such as increased side population. We demonstrated that GLI2 knockdown sensitized gastric cancer cells to 5Fu treatment, decreased ABCG2 expression, and reduced side population. Elevated GLI2 expression is also associated with an increase in tumor sphere size, another marker for putative cancer stem cells. We believe that GLI2 regulates putative cancer stem cells through direct regulation of ABCG2. ABCG2 can rescue the GLI2 shRNA effects in 5Fu response, tumor sphere formation and side population changes, suggesting that ABCG2 is an important mediator for GLI2-associated 5Fu resistance. The relevance of our studies to gastric cancer patient care is reflected by our discovery that high GLI1/GLI2/ABCG2 expression is associated with a high incidence of cancer relapse in two cohorts of gastric cancer patients who underwent chemotherapy (containing 5Fu). Taken together, we have identified a molecular mechanism by which gastric cancer cells gain 5Fu resistance.

[Survival benefit of an herbal formula for invigorating spleen for elderly patients with gastric cancer].

BACKGROUND: Gastric cancer is one of the most common malignant tumors. Traditional Chinese medicine (TCM) has been widely used in treatment of gastric cancer, but still lacking large sample controlled trial to evaluate its efficacy. OBJECTIVE: To analyze the prognostic factors of 220 elderly patients with gastric cancer, and to further study the efficacy of an herbal formula for invigorating spleen and it modifications based on syndrome differentiation of TCM in treatment of gastric cancer in elderly patients and the influence on prognosis. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A total of 220 elderly patients aged 65 years or over with gastric cancer from Longhua Hospital of Shanghai University of Traditional Chinese Medicine, and Renji Hospital and Ruijin Hospital of Shanghai Jiao Tong University Medical College were prospectively enrolled. All patients were assigned to either traditional Chinese herbal medicine (TCHM) group (89 cases) or non-TCHM group (131 cases). Patients in the TCHM group were treated with an herbal formula for invigorating spleen plus chemotherapy, while patients in the non-TCHM group were only treated with chemotherapy. MAIN OUTCOME MEASURES: Univariate and Cox regression analyses were performed to determine all the potential prognostic factors. Kaplan-Meier curves were used to assess the differences in survival time between TCHM group and non-TCHM group after stratification for TNM stage, surgery or chemotherapy. RESULTS: The 220 eligible patients were histologically confirmed adenocarcinoma of the stomach from 2001 to 2007. Eighty-nine cases in the TCHM group received three or more months of TCHM treatment, and 131 cases in the non-TCHM group did not receive TCHM treatment. Cox regression analysis suggested that the TNM stage, radical resection, three or more treatment cycles of chemotherapy, and TCHM treatment were independent prognostic factors (P<0.01). The patients receiving TCHM treatment demonstrated better prognosis than the other prognostic factors in multivariate analysis; the odds ratio [Exp(beta)] of overall group was 0.322, and 95% confidence interval (CI) was from 0.212 to 0.489. Median overall survival of TCHM group was 41.129 months, and one-, three-, and five-year survival rates were 85.2%, 55.6% and 45.7% respectively. Median overall survival of non-TCHM group was 17.195 months, and one-, three-, and five-year survival rates were 63.9%, 26.9% and 21.9% respectively. In stratification analysis of stage for 96 patients who did not accepted radical resection or suffered from recurrence and metastasis (36 cases in the TCHM group, and 60 cases in the non-TCHM group), Cox regression analysis suggested that three or more treatment cycles of chemotherapy and TCHM treatment were independent prognostic factors for improving survival respectively (P<0.01). The hazard ratio [Exp(beta)] of TCHM in stratification for late stage was 0.421, and 95% confidence interval was from 0.255 to 0.693. Median overall survivals were 17.819 months for TCHM group and 8.548 months for non-TCHM group. In stratification analysis of surgery and chemotherapy for 102 patients with Ib-IV (M0) who accepted radical resection (R0 resection) and three or more treatment cycles of chemotherapy (33 cases in the TCHM group, and 69 cases in the non-TCHM group), the disease-free survival and overall survival did not reach the median at the time of analysis. In the TCHM group, one-, three-, and five-year disease-free survival rates were 97.0%, 59.9% and 50.4%, and one-, three-, and five-year survival rates were 100.0%, 74.1% and 61.4%, respectively. In the non-TCHM group, one-, three-, and five-year disease-free survival rates were 82.6%, 51.1% and 51.1%, and one-, three-, and five-year survival rates were 86.9%, 55.6% and 55.6%, respectively. CONCLUSION: The herbal formula for invigorating spleen has an important value for improving the prognosis of elderly patients with gastric cancer. This herbal formula show survival benefit for advanced gastric cancer in elderly patients. The influence of TCHM on disease-free survival and overall survival of postoperative gastric cancer in elderly patients need to be further evaluated.