These data show that apatinib treatment significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy.

Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.

XP showed significant noninferiority for PFS versus FP in the first-line treatment of AGC. XP can be considered an effective alternative to FP.

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Key words: pancreatic cancer; NF-B; angiogenesis; metastasis; apoptosisMetastatic pancreatic adenocarcinoma is a deadly disease, the aggressive nature of which is related to several abnormalities in growth factors and their receptors that affect the downstream signal transduction pathways involved in the control of growth and differentiation. 1,2 Other contributing molecular changes in pancreatic adenocarcinoma include activation of oncogenes and inactivation of tumor suppressor genes. 3,4 These perturbations confer a tremendous survival and growth advantage to pancreatic cancer cells. Understanding the biology and pathogenesis of pancreatic cancer is crucial to reversing the metastatic biology of this disease. As with other solid tumors, the growth and metastasis of pancreatic adenocarcinoma are dependent on angiogenesis. 5 Of the numerous angiogenic factors discovered so far, vascular endothelial growth factor (VEGF) 6 -8 and, most recently, interleukin-8 (IL-8) 9,10 have been identified as key mediators of pancreatic tumor angiogenesis.VEGF has been shown to induce the proliferation of endothelial cells, increase vascular permeability and induce the production of plasminogen activators by these cells. 11,12 IL-8, a chemoattractant cytokine, has been shown to attract and activate neutrophils in inflammatory regions and be angiogenic. 13,14 The mechanism of regulation of constitutive expression of these genes in malignant pancreatic cancer cells is not clear, however. Recent studies demonstrated that the pleiotropic transcription factor nuclear factor-B (NF-B) regulates the expression of multiple genes, including IL-8 and VEGF, in several types of cells. 10,14 -17 NF-B has been shown to be constitutively activated in pancreatic cancer cells; 18,19 NF-B activity can also be elevated by several stress factors in human pancreatic cancer cells, such as hypoxia, acidosis, nitric oxide and proinflammatory cytokines. 20 Accumulating evidence from in vitro and in vivo studies suggests an important role for NF-B in the regulation of apoptosis, cell adhesion and oncogenesis. [21][22][23] However, the critical role of constitutive NF-B activity in pancreatic cancer angiogenesis has not been investigated.NF-B is an inducible dimeric transcription factor belonging to the Rel/NF-B family of transcription factors whose prototype in most nonlymphoid cells is a heterodimer composed of the RelA (p65) and NF-B1 (p50) subunits. 24 -26 NF-B activation involves its release from a cytoplasm inhibitor of NF-B (IB); it subsequently translocates to the nucleus, where it binds to cognate sequences in the promoter region of multiple genes. Regulation of gene expression by NF-B is controlled mainly by the inhibitory IB proteins, which include IB␣. 24,26 Upon stimulation, IB␣ is rapidly phosphorylated and degraded via the ubiquitin-proteasome pathway, permitting activation and nuclear importation of NF-B. Researchers engineered dominant-negative mutant forms of IB␣ (IB␣M) that could not be phosphorylated and degraded and thus constitutively...

BackgroundThe V325 study showed that docetaxel, cisplatin, and fluorouracil (DCF) prolonged overall survival (OS) of patients with advanced gastric cancer, but with a high incidence of dose-limiting toxicities. We investigated the efficacy and safety of a modified DCF (mDCF) regimen for Chinese patients with advanced gastric cancer.MethodsUntreated advanced gastric cancer patients randomly received docetaxel and cisplatin at 60 mg/m2 (day 1) followed by fluorouracil at 600 mg/m2/day (days 1–5; mDCF regimen) or cisplatin at 75 mg/m2 (day 1) followed by fluorouracil at 600 mg/m2/day (days 1–5; CF) every 3 weeks. The primary end point was progression-free survival (PFS). The secondary end points were OS, overall response rate (ORR), time-to-treatment failure (TTF), and safety.ResultsIn total, 243 patients were randomized to treatment (mDCF regimen 121; CF 122). Compared with CF, the mDCF regimen significantly improved PFS and OS: the median PFS was 7.2 and 4.9 months, respectively [hazard ratio (HR) 0.58, log-rank P = 0.0008], and the median OS was 10.2 and 8.5 months, respectively (HR = 0.71, P = 0.0319). Additionally, the mDCF regimen improved the parameters used as secondary objectives: the ORR was 48.7 % with the mDCF regimen versus 33.9 % with CF (P = 0.0244); the median TTF was 3.4 months with the mDCF regimen and 2.4 months with CF (HR = 0.67, P = 0.0027). Grade 3 and grade 4 treatment-related adverse events occurred in 77.3 % of patients who received the mDCF regimen versus 46.1 % of patients who received CF (P < 0.001).ConclusionsThe mDCF regimen, compared with CF, significantly prolonged PFS and OS and enhanced ORR of Chinese patients with advanced gastric cancer. The mDCF regimen achieved efficacy comparable to that of DCF but with fewer toxicities, which is appropriate for the Chinese population.Electronic supplementary materialThe online version of this article (doi:10.1007/s10120-015-0457-4) contains supplementary material, which is available to authorized users.

BackgroundReliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients.Patients and methodsWe conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan–Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival.ResultsPresence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64–0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53–0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival.ConclusionPresence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.Electronic supplementary materialThe online version of this article (10.1186/s13045-017-0521-0) contains supplementary material, which is available to authorized users.