[Show abstract][Hide abstract] ABSTRACT: Background
Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study.
Patients and methods
102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0–2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks + 1-week rest followed by once 3-weeks + 1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA).
Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P = 0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P = 0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P = 0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRβ expression correlated with longer PFS.
The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.
European Journal of Cancer 12/2014; · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer.Methods:Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS).Results:Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities.Conclusion:The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.British Journal of Cancer advance online publication, 20 August 2013; doi:10.1038/bjc.2013.409 www.bjcancer.com.
British Journal of Cancer 08/2013; · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: The impact of erythropoiesis-stimulating agents in chemotherapy-induced anemia has been a constant topic of debate over recent years. We prospectively assessed the efficacy of epoetin beta (Epo-b) in improving hemoglobin (Hb) levels and outcome in patients within an open label, randomized clinical phase II trial with advanced or metastatic gastric/esophagogastric cancer. METHODS: Previously untreated patients were randomized to receive 3-weekly cycles of capecitabine (1000 mg/m(2) bid) for 14 days plus on day 1 either irinotecan 250 mg/m(2) or cisplatin 80 mg/m(2). Epo-b (30000 IU once weekly) was initiated in patients with Hb <11 g/dl and continued until Hb ≥12 g/dl was reached. If after 4 weeks the Hb increase was <0.5 g/dl, Epo-b was increased to 30000 IU, twice weekly. RESULTS: Of 118 patients enrolled, 32 received Epo-b treatment; of these, 65 % achieved an increase in Hb levels of at least 2 g/dl, with 74 % achieving the target Hb of ≥12 g/dl. Within the study population, patients receiving Epo-b showed better overall survival (median 14.5 vs. 8.0 months, P = 0.056) as well as a significantly improved disease control rate (78 vs. 55 %, P = 0.025). Patients in the irinotecan group profited significantly (P < 0.05) in terms of progression-free survival and overall survival under Epo-b treatment (median 6.5 vs 4.1 months and median 15.4 vs 8.4 months, respectively). CONCLUSIONS: Epo-b was effective in raising Hb levels in patients with advanced esophagogastric cancer. Patients receiving Epo-b had a significantly increased response to chemotherapy and a clear trend to improved survival.
International Journal of Clinical Oncology 03/2013; · 2.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 15-20% of all patients initially diagnosed with colorectal cancer develop metastatic disease and surgical resection remains the only potentially curative treatment available. Current 5-year survival following R0-resection of liver metastases is 28-39%, but recurrence eventually occurs in up to 70%. To date, adjuvant chemotherapy has not improved clinical outcomes significantly. The primary objective of the ongoing LICC trial (L-BLP25 In Colorectal Cancer) is to determine whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer patients following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from colorectal cancer. In a phase IIB trial, L-BLP25 has shown acceptable tolerability and a trend towards longer survival in patients with stage IIIB locoregional NSCLC.
This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 patients from 20 centers in 3 countries. Patients with stage IV colorectal adenocarcinoma limited to liver metastases are included. Following curative-intent complete resection of the primary tumor and of all synchronous/metachronous metastases, eligible patients are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with s.c. L-BLP25 930 μg once weekly for 8 weeks, followed by s.c. L-BLP25 930 μg maintenance doses at 6-week (years 1&2) and 12-week (year 3) intervals unless recurrence occurs. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint is the comparison of recurrence-free survival (RFS) time between groups. Secondary endpoints are overall survival (OS) time, safety, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. The primary endpoint will be assessed in Q3 2016. Follow-up will end Q3 2017. Interim analyses are not planned.
The design and implementation of such a vaccination study in colorectal cancer is feasible. The study will provide recurrence-free and overall survival rates of groups in an unbiased fashion.
EudraCT Number 2011-000218-20.
[Show abstract][Hide abstract] ABSTRACT: Matrix metalloproteinase-9 (MMP-9) plays a central role in tumor invasion and development of metastases. Expression of MMP-9 had been shown in human hepatocellular carcinomas (HCCs). However, it remained unclear whether MMP-9 could influence development of HCC. In order to address this issue, we generated transgenic mice overexpressing MMP-9 in the liver. In order to avoid embryonic lethality a Cre-lox system was utilized for conditional overexpression of MMP-9 under control of an albumin enhancer and promoter. Induction of MMP-9 overexpression in transgenic mice was achieved by i.v. injection of an adenovirus coding for the Cre recombinase. Initiation of liver carcinogenesis was achieved by injection of diethylnitrosamine (DEN) followed by Phenobarbital administration in drinking water. Transgene expression was induced at the age of 6 wk. Four and six months later mice were sacrificed and examined macroscopically and microscopically in a blinded manner. Alb/Cre/MMP-9-transgenic mice showed liver specific overexpression of MMP-9-mRNA and protein after induction. At the age of 6 months livers of transgenic mice showed 15.7 ± 11.6 tumors (mean ± SD) in contrast to wildtype mice with only 7.9 ± 11.0 tumors (P < 0.03). By histopathology examination of the livers HCCs were identified in 42% of the transgenic mouse livers but only 8% in wildtype animals. In summary, we established a novel MMP-9 transgenic mouse model, and report on a significantly increased susceptibility of MMP-9 transgenic mice to chemically induced carcinogenesis. This is the first in vivo proof that MMP-9 overexpression promotes liver tumor development.
[Show abstract][Hide abstract] ABSTRACT: A genetic basis of hepatocellular carcinoma (HCC) has been well-established and major signaling pathways, such as p53, Wnt-signaling, transforming growth factor-β (TGF-β) and Ras pathways, have been identified to be essential to HCC development. Lately, the family of platelet-derived growth factors (PDGFs) has shifted to the center of interest. We have reported on spontaneously developing liver fibrosis in PDGF-B transgenic mice. Since HCC rarely occurs in healthy liver, but dramatically increases at the cirrhosis stage of which liver fibrosis is a preliminary stage, we investigated liver cancer development in chemically induced liver carcinogenesis in these mice. HCC induction was performed by treatment of the mice with diethylnitrosamine and phenobarbital. At an age of 6 months, the tumor development of these animals was analyzed. Not only the development of dysplastic lesions in PDGF-B transgenic mice was significantly increased but also their malignant transformation to HCC. Furthermore, we were able to establish a key role of PDGF-B signaling at diverse stages of liver cancer development. Here, we show that development of liver fibrosis is likely through upregulation of TGF-β receptors by PDGF-B. Additionally, overexpression of PDGF-B also leads to an increased expression of β-catenin as well as vascular endothelial growth factor and platelet endothelial cell adhesion molecule-1 (PECAM-1/CD31), all factors with established roles in carcinogenesis. We were able to extend the understanding of key genetic regulators in HCC development by PDGF-B and decode essential downstream signals.
International Journal of Cancer 03/2011; 128(6):1259-68. · 6.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Endoscopic Ultrasound (EUS) and the EUS guided fine-needle Aspiration (EUS-FNA) increasingly plays an important role in the diagnostic evaluation of lesions or lymph nodes in the mediastinum and upper gastrointestinal tract of unknown origin. The objective of this study was to assess safety and accuracy of EUS-FNA in two secondary and tertiary health care providers.
Prospectively, from Mai 2003 to June 2007, all patients underwent EUS with devices from Pentax (FG38UX, EC3830UT) with EUS-FNA (Cook or Mediglobe) at Johannes Gutenberg University and Catholic Hospital in Mainz. In all cases, cytology and extracted cells were histological examined by the same pathologists. In case of negative EUS results, patients were observed for at least 12 months after initial diagnosis later by reanalysis, CT-scan and follow-up clinical data to confirm the diagnosis.
In total, 776 patients with EUS and 167 EUS-FNA (21.5 %) could be evaluated. Median age was 62 years, 68 % of patients were male. Patients underwent EUS-FNA in the mediastinum (n = 54), pancreas (73), stomach (13), liver, adrenal glands and rectum (n = 6). The complication rate of EUS-FNA was very low with only 0.6 %, mainly consistent of one minor haemorrhage at the aspiration site. A clear histological diagnosis could not be achieved in 12.5 % (21/167). Statistical analyses of all EUS-FNA revealed a sensitivity of 77.8 % (95 %CI 67,2 - 86,3) and a specificity of 98.5 % (95 % CI 92,2 - 100), with a positive and negative predictive value of 98.4 % and of 78.1 %, respectively. The overall accuracy was 87 % (95 %CI 80,4 - 92,0).
EUS combined with FNA is a safe tool for first histological evaluation of unidentified lesions or lymph nodes in the mediastinum and upper gastrointestinal tract, indicative for gastrointestinal cancers.
[Show abstract][Hide abstract] ABSTRACT: LIM-domain-binding (Ldb) proteins have been demonstrated to be essential not only to key embryonic developmental processes but also to carcinogenesis. We have previously demonstrated Ldb1 to be of high biological and developmental relevance, as a targeted deletion of the Ldb1 gene in mice results in an embryonic lethal and pleiotropic phenotype.
We have now established a liver-specific Ldb1 knock out to investigate the role of Ldb1 in carcinogenesis, in particular in hepatocellular carcinoma (HCC) development, in vivo.
These mice demonstrated a significantly enhanced growth of liver cancer by means of tumor size and number, advocating for an essential role of Ldb1 in HCC development. In addition, proliferation and resistance against apoptosis were increased. In order to identify the functional disturbances due to a lack of Ldb1, we performed a 15k mouse gene microarray expression analysis. We found the Myc oncogene to be regulated in the microarray analysis and were able to further confirm this regulation by demonstrating an over-expression of its downstream target Cyclin D1. Furthermore, we were able to demonstrate a down-regulation of the tumor suppressor p21. Finally, the liver stem cell marker EpCAM was also identified to be over expressed in Ldb1(-/-) knock out mice.
We have established a significant role of Ldb1 in cancer development. Furthermore, we provided evidence for a myc/cyclin D1, p21, and EpCAM-dependent signalling to be key downstream regulators of this novel concept in HCC development.
Journal of Hepatology 12/2010; 53(6):1078-84. · 9.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out.
Patients received weekly cetuximab (400 mg/m(2) on day 1, subsequently 250 mg/m(2)) plus irinotecan (80 mg/m(2)) and a 24-hour continuous infusion of folinic acid (200 mg/m(2)) and 5-FU (1500 mg/m(2)) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD).
The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months [95% confidence interval (CI) 7.1-15.6] and 16.5 months (95% CI 11.7-30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression.
Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.
Annals of Oncology 11/2010; 22(6):1358-66. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the pathomechanisms of autoimmune diseases in various organs remain unresolved, an accumulation of autoimmune diseases in individual patients has been observed. An overlap of autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) or primary sclerosing cirrhosis has been well documented. However, the overlap of autoimmune diseases other than PBC or PSC has not yet been investigated in a large cohort.
The goal of our analysis was to investigate the incidence of concurrent autoimmune diseases in patients with AIH.
We analyzed our cohort of 278 patients with AIH for concurrent autoimmune diseases.
A total of 111 patients (40%) were diagnosed with additional autoimmune diseases. Besides overlap syndromes for PBC and PSC, autoimmune thyroiditis was the most common concurrent disease (28 patients, 10%). Other concurrent autoimmune diseases comprised vitiligo (5 patients), rheumatoid arthritis (5 patients), Sjogren syndrome (4 patients), ulcerative colitis (4 patients), conjunctivitis (4 patients), celiac disease (3 patients), systemic lupus erythematodes (2 patients), type I diabetes (2 patients), multiple sclerosis (2 patients), polymyalgia rheumatica (2 patients), and urticaria (2 patients). One patient each was diagnosed with Crohn's disease, autoimmune gastritis, collagenous colitis, hypophysitis, and sarcoidosis. Investigating 100 patients with polyglandular syndrome and autoimmune thyroid disease for the occurrence of autoantibodies associated with AIH, we identified AIH-associated antibodies only in 1 patient.
Concurrent autoimmune diseases are common in patients with AIH and mirror the full range of known autoimmune diseases. Therefore, an extended diagnostic screening for accumulating autoimmune diseases, especially autoimmune thyroiditis, seems reasonable in patients with AIH.
Journal of clinical gastroenterology 03/2010; 44(3):208-13. · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1).
This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg(-1) every 14 days), followed by maintenance therapy with 10 mg kg(-1) infused every 14 days.
A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab.
No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.
British Journal of Cancer 02/2010; 102(3):506-12. · 5.08 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The combination of irinotecan with 5-fluorouracil demonstrates efficacy with tolerable safety in the first-line treatment of metastatic gastroesophageal cancer (mGC). This randomized phase II trial compared for the first time capecitabine with irinotecan or cisplatin in this setting.
Patients were randomly assigned to receive 3-week cycles of capecitabine 1000 mg/m(2), twice daily for 14 days, with on day 1 either irinotecan 250 mg/m(2) (XI) or cisplatin 80 mg/m(2) (XP). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and safety.
Of 118 patients recruited, 112 were eligible for safety analysis and 103 for efficacy analysis. In the XI and XP treatment arms, there were no marked differences in ORR, 37.7% versus 42.0%, and median PFS, 4.2 versus 4.8 months, although median OS was longer, 10.2 versus 7.9 months, respectively. Grade 3/4 toxicity was higher in the XP regimen for thrombocytes (18.2% versus 1.8%), nausea (23.6% versus12.3%) and vomiting (16.4% versus 1.8%) and in the XI arm for diarrhea (22.8% versus 7.3%).
The comparable activity and safety of the XI and XP regimens establish XI as a relevant platinum-free first-line treatment choice for patients with mGC.
Annals of Oncology 08/2009; 21(1):71-7. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Autoimmune hepatitis (AIH) is a necroinflammatory liver disease of unknown etiology that occurs in children and adults of all ages. Characteristics are its autoimmune features, hyperglobulinemia (IgG), and the presence of circulating autoantibodies, as well as a response to immunosuppressant drugs. Current treatment consists of prednisone and azathioprine and in most patients this disease has become very treatable. Over the past 2 years, a couple of new insights into the genetic aspects, clinical course and treatment of AIH have been reported, which will be the focus of this review. In particular, we concentrate on genome-wide microsatellite analysis, a novel mouse model of AIH, the evaluation of a large AIH cohort for overlap syndromes, suggested novel criteria for the diagnosis of AIH, and the latest studies on treatment of AIH with budenoside and mycophenolate mofetil.
World Journal of Gastroenterology 04/2009; 15(9):1035-41. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate and confirm the low incidence of hepatocellular carcinoma (HCC) in patients with autoimmune hepatitis (AIH). At present only very few cases of HCC in patients with AIH and definite exclusion of chronic viral hepatitis have been published, suggesting that HCC due to AIH is rare.
In order to further investigate the incidence of HCC in patients with AIH, we reviewed our large cohort of 278 patients with AIH.
Eighty-nine patients (32%) were diagnosed with liver cirrhosis, a preneoplastic condition for HCC. We studied a total of 431 patient years of cirrhosis in these patients, an average 4.8 years per patient. During this period none of the patients of our own study cohort developed HCC. However, three patients with HCC due to AIH associated liver cirrhosis were referred to our department for further treatment of HCC. In all three patients chronic viral hepatitis was excluded.
We conclude that HCC may under rare circumstances develop due to chronic AIH dependent liver cirrhosis. Compared to other causes of liver cirrhosis such as chronic viral hepatitis, alcohol, or hemochromatosis, the incidence of HCC is significantly lower. Pathophysiological differences between AIH and chronic viral hepatitis responsible for differences in the incidence of HCC are yet to be further characterized and may lead to new therapeutic concepts in prevention and treatment of liver cancer.
World Journal of Gastroenterology 03/2009; 15(5):578-82. · 2.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The multikinase inhibitor sorafenib provides survival benefit for patients with advanced hepatocellular carcinoma (HCC) and liver cirrhosis (LCI) Child-Pugh A. We report our experiences with sorafenib in advanced HCC, particularly in patients with LCI Child-Pugh B/C, where only limited data are available in regard to safety and efficacy of sorafenib.
Thirty-four patients with advanced HCC were treated with sorafenib regardless of liver function and prior anticancer therapy. Adverse events (AEs) were graded using Common Toxicity Criteria version 3.0, tumor response was assessed according to Response Evaluation Criteria in Solid Tumors.
Fifteen patients presented without LCI or with LCI Child- Pugh A, 15/4 patients had LCI Child-Pugh B/C. Barcelona Clinic Liver Cancer stage was B/C/D in 4/22/8 patients. During treatment period (median 2.2 mo), therapy was discontinued in 61.8% of patients due to tumor progression (32.3%), death (17.6%), AEs (8.8%), or noncompliance (2.9%). Most common grade 3/4 AEs included liver dysfunction (23.5%), diarrhea (14.7%), increased lipase (8.8%), fatigue (8.8%), and hand-foot skin reaction (5.9%). Worsening liver dysfunction/failure was more frequent (P=0.036) in patients with LCI Child-Pugh B/C compared with patients with maintained liver function (no LCI/LCI Child-Pugh A). Median overall survival was 7.2 months for patients with maintained liver function versus 3.3/3.4 months for patients with LCI Child-Pugh B/C.
These data do not support the use of sorafenib in patients with LCI Child-Pugh C, and patients with LCI Child-Pugh B should be treated with caution until larger trials provide more safety data and a clinically relevant survival benefit under sorafenib therapy.
Journal of clinical gastroenterology 03/2009; 43(5):489-95. · 2.21 Impact Factor