Gemcitabine plus erlotinib followed by capecitabine versus capecitabine plus erlotinib followed by gemcitabine in advanced pancreatic cancer: final results of a randomised phase 3 trial of the 'Arbeitsgemeinschaft Internistische Onkologie' (AIO-PK0104).

OBJECTIVE: AIO-PK0104 investigated two treatment strategies in advanced pancreatic cancer (PC): a reference sequence of gemcitabine/erlotinib followed by 2nd-line capecitabine was compared with a reverse experimental sequence of capecitabine/erlotinib followed by gemcitabine. METHODS: 281 patients with PC were randomly assigned to 1st-line treatment with either gemcitabine plus erlotinib or capecitabine plus erlotinib. In case of treatment failure (eg, disease progression or toxicity), patients were allocated to 2nd-line treatment with the comparator cytostatic drug without erlotinib. The primary study endpoint was time to treatment failure (TTF) after 1st- and 2nd-line therapy (TTF2; non-inferiority design). KRAS exon 2 mutations were analysed in archival tumour tissue from 173 of the randomised patients. RESULTS: Of the 274 eligible patients, 43 had locally advanced and 231 had metastatic disease; 140 (51%) received 2nd-line chemotherapy. Median TTF2 was estimated with 4.2 months in both arms; median overall survival was 6.2 months with gemcitabine/erlotinib followed by capecitabine and 6.9 months with capecitabine/erlotinib followed by gemcitabine, respectively (HR 1.02, p=0.90). TTF for 1st-line therapy (TTF1) was significantly prolonged with gemcitabine/erlotinib compared to capecitabine/erlotinib (3.2 vs 2.2 months; HR 0.69, p=0.0034). Skin rash was associated with both TTF2 (rash grade 0/1/2-4:2.9/4.3/6.7 months, p<0.0001) and survival (3.4/7.0/9.6 months, p<0.0001). Each arm showed a safe and manageable toxicity profile during 1st- and 2nd-line therapy. A KRAS wild-type status (52/173 patients, 30%) was associated with an improved overall survival (HR 1.68, p=0.005). CONCLUSION: Both treatment strategies are feasible and demonstrated comparable efficacy; KRAS may serve as biomarker in patients with advanced PC treated with erlotinib.

Enhancing adherence to capecitabine chemotherapy by means of multidisciplinary pharmaceutical care.

PURPOSE: In this prospective multi-centre observational cohort study, we investigated the effect of an intensified multidisciplinary pharmaceutical care programme on the adherence of cancer patients treated with capecitabine, a prodrug of fluorouracil. PATIENTS AND METHODS: Twenty-four colorectal and 24 breast cancer patients participated in this study. Patients of the control group (n = 24) received standard care, patients of the intervention group (n = 24) received intensified pharmaceutical care consisting of written and spoken information. Adherence to capecitabine chemotherapy was measured using an electronic medication event monitoring system (MEMS™). RESULTS: Patients in the intervention group exhibited an enhanced but not significantly different mean overall adherence compared to the control group (97.9% vs 90.5%, p = 0.069). Mean daily adherence was significantly higher in the intervention group (96.8% vs 87.2%, p = 0.029). Variability of both adherence parameters was considerably reduced when pharmaceutical care was provided. At the end of the observation period of 126 days, the probability of still being treated with capecitabine was found to be 48% in the control group and 83% in the intervention group (p = 0.019, log-rank test). The relative risk for a deviating drug intake interval, i.e. <10 or >14 instead of 12 h, in the intervention group was found to be 0.51 (95% CI, 0.46-0.56) compared with the control group (p < 0.05, Chi-square test). CONCLUSIONS: The provision of intensified pharmaceutical care can enhance adherence to and prolong treatment with capecitabine. The results underline the importance of multidisciplinary care to assure the effectiveness of oral chemotherapy.

Stromal cell-derived factor 1alpha (SDF-1alpha) induces gene-expression of early growth response-1 (Egr-1) and VEGF in human arterial endothelial cells and enhances VEGF induced cell proliferation.

Stromal cell-derived factor-1 (SDF-1), mainly known as a chemotactic factor for haematopoietic progenitor cells, also provides angiogenetic potency. Since the intracellular signalling of SDF-1-induced neovascularization remains unclear, we studied in human umbilical arterial endothelial cells (HUAEC) the influence of SDF-1alpha on induction of the genes of early growth response-1 (Egr-1) and VEGF, as well as the activation of extracellular regulated kinases (ERK) 1/2, which are all known to be involved in endothelial cell proliferation. We found a time-dependent induction of Egr-1 and VEGF mRNA expression and phosphorylation of ERK1/2 by SDF-1alpha. Furthermore, we demonstrated that Egr-1 expression is dependent on ERK 1/2 activation. Finally, we tried to confirm the relevance of the induced gene expression by detecting the [3H]thymidine incorporation as a marker for cell proliferation in HUAEC after stimulation with SDF-1alpha alone or together with VEGF. This particular test showed, that SDF-1alpha alone has no effect, but is able to significantly enhance VEGF induced DNA synthesis. In summary, SDF-1alpha is involved in different steps of endothelial cell proliferation, but, since Egr-1 and VEGF offer different functions, it may also play a so far undefined role on other conditions of the endothelium.

Intensified PCV-chemotherapy with optional stem cell support in recurrent malignant oligodendroglioma.

Six patients with recurrent or progressive anaplastic oligodendroglial tumors after surgical treatment and irradiation were treated with six/seven cycles of intensified PCV: Vincristine (1 mg/m(2)), CCNU (50 mg/m(2)) d.1,15 and procarbazine (75 mg/m(2)) d.2 to 29. If leukocytopenia (< 2.500/microl) or thrombocytopenia (< 75.000/microl) developed, 1 x 10(6) CD34(+) autologous stem cells/ kg body weight were reinfused three days after completion of subsequent cycles. Complete response was seen in 2/6 and partial response in 4/6 patients. Median follow up from time of recurrence was 35 months, progression free survival was 18 to > 39 months and overall survival 23 to > 39 months. We conclude that intensified PCV with stem cell support is feasable in recurrent/progressive anaplastic oligodendroglial tumors and appears to be sufficiently well tolerated to allow further study.

Inhibition of the vascular-endothelial growth factor-induced intracellular signaling and mitogenesis of human endothelial cells by epigallocatechin-3 gallate.

Galloyl group-containing catechins, such as epigallocatechin-3 gallate, inhibit receptor tyrosine kinase activity of several growth factor receptors. This study investigated the effects of epigallocatechin-3 gallate, as compared to epicatechin, on vascular endothelial growth factor-induced intracellular signaling and mitogenesis of human umbilical endothelial cells. Epigallocatechin-3 gallate concentration-dependently inhibited vascular endothelial growth factor-induced DNA synthesis, cell proliferation, autophosphorylation of vascular endothelial growth factor receptors-1 and -2, phosphorylation of extracellular signal-regulated kinases-1 and -2, and mRNA expression of the early growth response factor-1. In contrast, epicatechin was not effective. Thus, epigallocatechin-3 gallate may be an attractive candidate drug to inhibit tumour angiogenesis.

Early prediction of nonprogression in advanced non-small-cell lung cancer treated with erlotinib by using [(18)F]fluorodeoxyglucose and [(18)F]fluorothymidine positron emission tomography.

PURPOSE: Positron emission tomography (PET) with both 2'-deoxy-2'-[(18)F]fluoro-D-glucose (FDG) and 3'-[(18)F]fluoro-3'-deoxy-L-thymidine (FLT) was evaluated with respect to the accuracy of early prediction of nonprogression following erlotinib therapy, independent from epidermal growth factor receptor (EGFR) mutational status, in patients with previously untreated advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Thirty-four patients with untreated stage IV NSCLC were evaluated in this phase II trial. Changes in FDG and FLT uptake after 1 (early) and 6 (late) weeks of erlotinib treatment were compared with nonprogression measured by computed tomography after 6 weeks of treatment, progression-free survival (PFS), and overall survival (OS). RESULTS: Changes in FDG uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the receiver operating characteristic curve of 0.75 (P = .02). Furthermore, patients with an early metabolic FDG response (cutoff value: 30% reduction in the peak standardized uptake value) had significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.09 to 0.59; P = .002) and OS (HR, 0.36; 95% CI, 0.13 to 0.96; P = .04). Early FLT response also predicted significantly longer PFS (HR, 0.31; 95% CI, 0.10 to 0.95; P = .04) but not OS and was not predictive for nonprogression after 6 weeks of therapy. CONCLUSION: Early FDG-PET predicts PFS, OS, and nonprogression after 6 weeks of therapy with erlotinib in unselected, previously untreated patients with advanced NSCLC independent from EGFR mutational status.

Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera.

We report that TG101348, a selective small-molecule inhibitor of JAK2 with an in vitro IC50 of approximately 3 nM, shows therapeutic efficacy in a murine model of myeloproliferative disease induced by the JAK2V617F mutation. In treated animals, there was a statistically significant reduction in hematocrit and leukocyte count, a dose-dependent reduction/elimination of extramedullary hematopoiesis, and, at least in some instances, evidence for attenuation of myelofibrosis. There were no apparent toxicities and no effect on T cell number. In vivo responses were correlated with surrogate endpoints, including reduction/elimination of JAK2V617F disease burden assessed by quantitative genomic PCR, suppression of endogenous erythroid colony formation, and in vivo inhibition of JAK-STAT signal transduction as assessed by flow cytometric measurement of phosphorylated Stat5.

The use of suppression subtractive hybridization for the study of SDF-1alpha induced gene-expression in human endothelial cells.

Stromal cell-derived factor-1 (SDF-1), the only ligand of the CXCR4 receptor, is mainly known as a chemotactic factor for hematopoietic progenitor cells. However, studies of knock-out mice have shown malformation of different organ-systems suggesting that SDF-1 may have a role in angiogenesis and cardiac and cerebral development. However, the underlying mechanisms of its action are largely unknown. Therefore, we performed suppression subtractive hybridization (SSH) in order to identify genes that are differentially expressed after stimulation of human arterial endothelial cells (HUAEC) with SDF-1. Using SSH we found ten genes, with varied functions, whose mRNA expression is induced by SDF-1alpha in HUAEC. We show that SSH is a reliable method for identifying differentially expressed genes and that SDF-1alpha may have more functions than previously reported.