Intensified chemotherapy and simultaneous treatment with heparin in outpatients with pancreatic cancer - the CONKO 004 pilot trial.

BACKGROUND: Advanced pancreatic cancer (APC), beside its high mortality, causes the highest rates of venous thromboembolic events (VTE). Enoxaparin, a low molecular weight heparin (LMWH), is effective in prevention and treatment of VTE. Some small studies indicated that this benefit might extend to patients with cancer and probably prolong survival due to independent mechanisms. We initiated this safety investigation to get feasibility information on intensified chemotherapy combined with LMWH in outpatients with APC treated in 1st line. METHODS: The trial was a prospective, open-label, single center investigation in outpatients with inoperable pancreatic cancer who were treated with intensified first-line chemotherapy along with concomitant application of subcutaneous LMWH. The combined chemotherapy consisted of gemcitabine 1 g/m2 (30 min), 5-FU 750 mg/m2 (24 h), folinic acid 200 mg/m2 (30 min), and Cisplatin 30 mg/m2 (90 min) on day 1 and 8; q3w for the first 12 weeks (GFFC) followed by gemcitabine alone in patients without cancer progression. The simultaneous application of prophylactic enoxaparin started on day 1 of chemotherapy with a fixed dose of 40 mg daily. Statistical analyses were performed using R 3.01 with software package CMPRSK and SPSS software v19.0. RESULTS: The investigation was stopped after recruitment of 19 patients. At this time 15 patients had completed the required 12 weeks of treatment. Based on 71 cycles of GFFC + enoxaparin (median 4/pt [range: 2-4]) and 108 cycles of single-agent gemcitabine + enoxaparin (median 4/pt [range: 0-18]) the cumulative frequency of NCI-CTC toxicities grade 3/4 was below 10%. One case (5%) of a symptomatic non-lethal thromboembolic event was observed while receiving LMWH treatment. No severe bleeding event as defined in the protocol has been observed. The median overall survival was 10.05 [95% CI: 8.67-18.14] months. CONCLUSIONS: The addition of enoxaparin to GFFC chemotherapy is feasible, safe and does not appear to affect the efficacy or the toxicity profile of the chemotherapy regimen in patients with advanced pancreatic adenocarcinoma. Based on these findings we have initiated the randomized CONKO-004 trial to examine whether enoxaparin reduces the incidence of thromboembolic events or increases overall outcome. TRIAL REGISTRATION: Clinical Trials NCT01945879.

POEMS syndrome treated with melphalan high-dose therapy and autologous blood stem cell transplantation: a single-institution experience.

The acronym POEMS syndrome stands for a rare multi-system disorder, comprised of polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes. Here, we present a single-center report of a series of five POEMS patients treated with melphalan high-dose therapy (HDT) with subsequent autologous blood stem cell transplantation (ABSCT). After a median follow-up of 52 months from time of diagnosis (range, 15-192) and a median follow-up of 18 months after ABSCT (range, 11-120), all patients were alive. Overall, no severe transplantation-associated complications such as engraftment syndrome or peri- or post-transplant death were noted. In two cases, HDT followed by ABSCT resulted in a complete hematologic response; in the additional three cases, partial responses (PR) were achieved including one very good hematologic PR. Only one patient with initial PR developed progressive disease nearly 2.5 years after transplantation. Consequently, a second HDT with ABSCT was successfully applied resulting in clinical improvement and hematologic PR. In line with previous single-center reports, melphalan HDT followed by ABSCT proved to be a first-line treatment option with tolerable side effects in severely affected POEMS patients with progressing symptoms.

Whole-organ perfusion of the pancreas using dynamic volume CT in patients with primary pancreas carcinoma: acquisition technique, post-processing and initial results.

The purpose of this study was to evaluate a whole-organ perfusion protocol of the pancreas in patients with primary pancreas carcinoma and to analyse perfusion differences between normal and diseased pancreatic tissue. Thirty patients with primary pancreatic malignancy were imaged on a 320-slice CT unit. Twenty-nine cancers were histologically proven. CT data acquisition was started manually after contrast-material injection (8 ml/s, 350 mg iodine/ml) and dynamic density measurements in the right ventricle. After image registration, perfusion was determined with the gradient-relationship technique and volume regions-of-interest were defined for perfusion measurements. Contrast time-density curves and perfusion maps were generated. Statistical analysis was performed using the Kolmogorov-Smirnov test for analysis of normal distribution and Kruskal-Wallis test (nonparametric ANOVA) with Bonferroni correction for multiple stacked comparisons. In all 30 patients the entire pancreas was imaged, and registration could be completed in all cases. Perfusion of pancreatic carcinomas was significantly lower than of normal pancreatic tissue (P < 0.001) and could be visualized on colored perfusion maps. The 320-slice CT allows complete dynamic visualization of the pancreas and enables calculation of whole-organ perfusion maps. Perfusion imaging carries the potential to improve detection of pancreatic cancers due to the perfusion differences.

Second-line therapy in refractory pancreatic cancer. results of a phase II study.

BACKGROUND: This phase II trial investigated the efficacy and safety of oxaliplatin (O), 5-fluorouracil (5-FU), and folinic acid (FA) (OFF) as second-line treatment for patients with metastatic pancreatic adenocarcinoma after failure of first-line gemcitabine treatment. PATIENTS AND METHODS: 37 patients with confirmed progressive disease on gemcitabine therapy were treated with OFF (O 85 mg/m(2) days 8, 22; FA 500 mg/m(2), followed by 5-FU 2,600 mg/m(2) days 1, 8, 15, 22) every 6 weeks. Patients were treated on an outpatient basis and remained on treatment until disease progression. RESULTS: All patients were assessable for toxicity and effectiveness. We observed moderate hematotoxicity, the most common non-hematologic toxicity was neurotoxicity. A total of 12 patients had grade 3 nonhematologic toxicities: nausea and vomiting (4 patients), reversible neurotoxicity (5 patients), and diarrhea (3 patients). No grade 4 toxicities were observed. Median time to progression was 12 (1-125) weeks. Survival in second line was 22 (4-326+) weeks. Overall disease control rate was 49% (complete remission = 3%; partial remission = 3%; stable disease > 12 weeks = 43%). CONCLUSIONS: This regimen is feasible and active with an acceptable toxicity profile; it can be safely administered in an outpatient setting. There is an urgent need for further investigation in phase III trials.

Rationale and design of PROSPECT-CONKO 004: a prospective, randomized trial of simultaneous pancreatic cancer treatment with enoxaparin and chemotherapy).

BACKGROUND: Advanced pancreatic cancer, in addition to its high mortality, is characterized by one of the highest rates of venous thromboembolic events (VTE) as compared to other types of cancer. Enoxaparin, a low molecular weight heparin (LMWH), has proven to be effective for the prevention and treatment of VTE in surgical and general medical patients. Results of some small studies suggest that this benefit might extend to patients with cancer, however, enoxaparin is not currently indicated for this use. This phase IIb study was designed to analyze the efficacy of enoxaparin in patients with locally advanced or metastatic pancreatic cancer undergoing systemic chemotherapy. METHODS: The aim of this prospective multicenter trial is to compare concomitant treatment with enoxaparin to no anticoagulation in 540 patients. Primary endpoint is the incidence of clinically relevant VTE (symptomatic deep venous thrombosis (DVT) of the leg and/or pelvic and/or pulmonary embolism (PE)) within the first 3 months. Secondary endpoints include the incidence of symptomatic and asymptomatic VTE after 6, 9 and 12 months as well as remission at 3, 6, 9 and 12 months, overall survival and bleeding. TRIAL REGISTRATION: isrctn.org identifier CCT-NAPN-16752, controlled-trials.com identifier: ISRCTN02140505. RESULTS: An interim analysis for safety performed after inclusion of 152 patients revealed no increased risk of bleeding (5 pts vs. 6 pts, Chi2: 0.763). CONCLUSION: PROSPECT is a pivotal study in elucidating the role of low molecular weight heparins in advanced pancreatic cancer. Its results will lead to a new understanding of the role of heparins in the prevention of venous thromboembolism and of their effect on survival, remission rates and toxicity of chemotherapeutic regimens.

Value of carbohydrate antigen 19-9 in predicting response and therapy control in patients with metastatic pancreatic cancer undergoing first-line therapy.

BACKGROUND: Serum carbohydrate antigen 19-9 (CA 19-9) has been shown to be a sensitive and specific serum marker for pancreatic cancer. Little has been published about correlations between baseline CA 19-9 level or changes to CA 19-9 level and median overall survival (mOS). Its impact on monitoring treatment efficacy remains under discussion, however. METHODS: CA 19-9 serum level was measured in 181 consecutive patients with advanced pancreatic cancer (APC) being treated with gemcitabine-based first-line chemotherapy. We separated the patients into several groups depending on baseline CA 19-9 levels and the CA 19-9 response after 6-8 weeks of treatment. Evaluations were made using SPSS 19.9. RESULTS: Median baseline CA 19-9 level was 1,493 U/ml (range 40-1,043,301). Patients with baseline CA 19-9 ≤1,000 U/ml had a mOS of 14.9 months (95% CI: 11.36:18.44), whereas patients with CA 19-9>1,000 U/ml had a mOS of 7.4 months [(95% CI: 5.93:8.87) p < 0.001, HR 2.12]. With regard to the change in CA 19-9 after 6-8 weeks of treatment: patients with increased CA 19-9 levels had a mOS of 8.1 months, those with stabilized CA 19-9 levels 11.6 months, and those with decreased CA 19-9 levels 11.1 months (p < 0.019). CONCLUSION: CA 19-9 levels can separate patients with differing mortality risks at baseline. Patients with stabilization or high response of CA 19-9 after 6-8 weeks of treatment had no significant differences in survival rates, whereas patients with increased CA 19-9 had significantly lower survival rates, indicating an early treatment failure.

Transforming growth factor beta in pancreatic cancer.

Pancreatic cancer has high incidence and mortality rates, and effective treatment remains a clinical challenge. As deregulation of the cytokine transforming growth factor beta (TGF-ß) contributes to the progression of pancreatic carcinoma, the TGF-ß pathway has been targeted using various strategies, including small molecule inhibitors of TGF-ßRI, TGF-ß-specific neutralizing antibodies and antisense compounds. As increased TGF-ß2 levels in serum or tumor tissue of patients with pancreatic cancer correlated with poor prognosis, inhibition of TGF-ß2 synthesis via the antisense oligonucleotide trabedersen (AP 12009) is a promising approach.

Adjuvant therapy of pancreatic cancer.

Pancreatic adenocarcinoma is one of the most aggressive tumors, with a high potential for early dissemination and a relatively poor sensitivity to radiation therapy and cytotoxic agents. Complete resection of the tumor is currently the only curative option but only 10-15% of patients present with localized, potentially resectable disease at the time of diagnosis. Median overall survival for all resected patients (R0 and R1) averages between 11 and 23 months, 5-year overall survival ranges from 10 to 25% (R0) and 0 to 5% (R1), leading to a case-fatality index of 95%. Despite the latest trend toward adjuvant chemotherapy with gemcitabine due to the results from the Charité Onkologie-001 trial, there is no broad consensus regarding the adjuvant regimen that should be applied. Early data from the European Study Group for Pancreatic Cancer-3(v2) trial revealed no difference in terms of overall survival between 5-fluorouracil/folinic acid and gemcitabine after resection of pancreatic cancer.

Gemcitabine in the treatment of metastatic pancreatic cancer.

Gemcitabine (2 ,2 -difluorodeoxycytidine) is a deoxycytidine-analog antimetabolite with broad activity against a variety of solid tumors and lymphoid malignancies. It was approved as standard of care in patients with pancreatic cancer one decade ago, based primarily on improvement in clinical benefit response such as pain reduction, improvement in Karnofsky performance status and increase in body weight. This article gives an overview of the pharmacodynamics and pharmacokinetics of gemcitabine, highlights the clinical activity of gemcitabine and summarizes the treatment options in metastatic pancreatic cancer with focus on gemcitabine-based chemotherapy. The emerging role of combinations of gemcitabine with novel targeted agents, including small-molecule inhibitors and other investigational drugs, is also discussed.

Continuous endothelial cell activation increases angiogenesis: evidence for the direct role of endothelium linking angiogenesis and inflammation.

There is increasing evidence that chronic inflammation is tightly linked to diseases associated with endothelial dysfunction, including the induction of aberrant angiogenesis. While leukocytes have been described as mediators of inflammation-associated angiogenesis, the effects of direct chronic endothelial activation have not been addressed in this context. Using an uncleavable mutant of the transmembrane form of tumor necrosis factor-alpha (TNF-alpha), we have established models of stable TNF-alpha expression in endothelial cells in vitro and in transgenic mice in vivo. In the in vitro model, continuous endothelial activation leads to increased leukocyte cellular adhesion molecule expression and intracellular reactive oxygen species, hallmarks of a proinflammatory and dysfunctional endothelium. In addition, stable expression of TNF-alpha in endothelial cells increased angiogenic sprout formation in the presence but also in the absence of angiogenic growth factors. The partial neutralization of this effect by TNF-alpha antibodies and the inability of conditioned media from stable TNF-alpha-expressing endothelial cells to induce angiogenic activities in control endothelial cells suggest that this effect does not require expression of additional autocrine factors, but is an autonomous effect of the transmembrane TNF on the endothelial cells. Furthermore, using the Matrigel plug assay in vivo, increased angiogenesis was observed in endothelial TNF-alpha-expressing transgenic versus control mice. In conclusion, chronic inflammatory changes mediated by TNF-alpha can induce angiogenesis in vitro and in vivo, suggesting endothelial cell activation as a direct link between inflammation and angiogenesis.

Inhibition of solid tumor growth by gene transfer of VEGF receptor-1 mutants.

Vascular endothelial growth factor (VEGF) and the high-affinity VEGF receptor Flk-1/KDR (VEGFR-2) are key regulators of tumor angiogenesis. Strategies to block VEGF/VEGFR-2 signaling were successfully used to inhibit experimental tumor growth and indicated that VEGFR-2 is the main signaling VEGF receptor in proliferating tumor endothelium. Here, we investigated the role of the VEGF receptor-1 (VEGFR-1/Flt-1) in the vascularization of 2 different experimental tumors in vivo. VEGFR-1 mutants were generated that lack the intracellular tyrosine kinase domain. Retrovirus-mediated gene transfer of the VEGFR-1 mutants led to a strong reduction of tumor growth and angiogenesis in xenografted C6 glioma and in syngeneic BFS-1 fibrosarcoma. Histological analysis of the inhibited fibrosarcoma revealed reduced vascular density, decreased tumor cell proliferation as well as increased tumor cell apoptosis and the formation of necrosis. The retroviral gene transfer of the full length VEGFR-1 also caused a significant reduction of tumor growth in both models. The inhibitory effects of the VEGFR-1 mutants and the full length VEGFR-1 in BFS-1 fibrosarcoma were mediated through host tumor endothelial cells because the BFS-1 fibrosarcoma cells were not infected by the retrovirus. The formation of heterodimers between VEGFR-2 and full length or truncated VEGFR-1 was observed in vitro and might contribute to the growth inhibitory effect by modulating distinct signal transduction pathways. The results of our study underline the central role of the VEGF/VEGFR-1 signaling system in tumor angiogenesis and demonstrate that VEGFR-1 can serve as a target for anti-angiogenic gene therapy.