Communicative reprogramming non-curative hepatocellular carcinoma with low-dose metronomic chemotherapy, COX-2 inhibitor and PPAR-gamma agonist: a phase II trial.

Systemic therapy for advanced hepatocellular carcinoma (HCC) is still challenging. A biomodulatory therapy approach targeting the communicative infrastructure of HCC, including metronomic low-dose chemotherapy with capecitabine, pioglitazone and rofecoxib, has been evaluated in patients with non-curative HCC. Altogether 38 patients were evaluable in this one-arm, multicenter phase II trial. The primary endpoint, median progression-free survival was 2.7 months (95% CI: 1.6-3.79) for all evaluable patients and 8.4 months (95% CI: 0-18.13) for patients ≥ 6 weeks on protocol. Median overall survival (OS) was 6.7 months (95% CI: 4.08-9.31) and 9.4 months (95% CI: 4.82-13.97), respectively. Most common adverse events were edemas grade 3, which were commonly related to the advanced stage, with 66% of the patients suffering from liver cirrhosis. Exploratory data analyses showed significant impact of ECOG performance status grade 0 versus 1 and CLIP score 0/1 versus > 1 on OS, 9.8 months (95% CI: 4.24-15.35) versus 2.7 months (95% CI: 1.03-4.36; P = 0.002), and 9.8 months (95% CI: 3.23-16.37) versus 4.4 months (95% CI: 3.14-5.66; P = 0.009), respectively. Preceding tumor surgery had significant beneficial impact on survival, as well as maximal tumor diameter of < 5 cm. The correlation of C-reactive protein decrease with significantly improved OS underlines the close link between inflammation and tumor control. Biomodulatory therapy in advanced HCC may be a low toxic, efficacious treatment and principally demonstrates that such approaches should be followed further for treatment of advanced HCC.

Hypoxia induces the expression of transketolase-like 1 in human colorectal cancer.

BACKGROUND AND AIMS: Transketolase-like (TKTL) 1 is one of the key enzymes for anaerobic sugar degradation even in the presence of oxygen (aerobic glycolysis). Transketolase-dependent reactions supply malignant tumors with ribose and NADPH. Therefore, TKTL1 activity could be crucial for tumor proliferation and survival. The aim of the study was to evaluate the expression of TKTL1 in colorectal cancer (CRC) and its regulation under hypoxic conditions. METHODS: We studied TKTL1 mRNA and protein expression in CRC cell lines and human CRC biopsies by quantitative real-time PCR, Western blotting and immunohistochemistry. Regulation of TKTL1 under oxygen depletion was analyzed by cultivating cells either in a three-dimensional spheroid model or in a hypoxia incubator chamber. RESULTS: TKTL1 mRNA was heterogeneously expressed in monolayers of cells with high levels in HT-29 and SW480. TKTL1 protein was also clearly detectable in HT-29 and SW480. Hypoxia-inducible factor (HIF)-1α protein expression correlated with TKTL1 protein expression in SW480 spheroids over time. On the one hand, induction of hypoxia in T84 spheroids did not induce TKTL1; on the other hand, hypoxia by incubation at 1% O2 in a hypoxia incubator chamber clearly showed an upregulation of TKTL1. In 50% of CRC patients, TKTL1 protein expression was upregulated in tumor compared to non-tumor tissue. The immunohistochemical staining of TKTL1 in CRC patient samples resulted in 14 positive and 30 negative samples. CONCLUSIONS: TKTL1 expression correlated with HIF-1α protein expression and was induced upon hypoxic conditions which could facilitate energy supply to tumors under these circumstances.

Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP).

BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer.

BACKGROUND: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. METHODS: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. RESULTS: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. CONCLUSION: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.

KRAS mutation in metastatic pancreatic ductal adenocarcinoma: results of a multicenter phase II study evaluating efficacy of cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line therapy.

BACKGROUND: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy. METHODS: Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor. RESULTS: Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival. CONCLUSIONS: KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.

Cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric cancer: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: Cetuximab enhances the efficacy of chemotherapy in several cancer types. This trial assessed the activity of cetuximab and chemotherapy in advanced gastric cancer. METHODS: Patients with previously untreated, metastatic, gastric cancer received cetuximab 400 mg m(-2) at first infusion followed by weekly infusions of 250 mg m(-2) combined with FUFOX (oxaliplatin 50 mg m(-2), 5-FU 2000 mg m(-2), and DL-folinic acid 200 mg m(-2) d1, 8, 15 and 22 qd36). The primary endpoint was tumour response. RESULTS: Overall, 52 patients were enrolled. The most common grade 3/4 toxicities were diarrhoea (33%), and skin toxicity (24%). Efficacy was evaluable in 46 patients who showed a response rate of 65% (CI 95%: 50-79%) including four complete responses. Time to progression (TTP) was 7.6 months (CI 95%: 5.0-10.1 months) and overall survival (OS) was 9.5 months (CI 95%: 7.9-11.1 months). Epidermal growth factor receptor (EGFR) was detectable in 60% of tumours but showed no correlation with treatment outcome. A KRAS mutation was found in only 1 of 32 (3%) tumour samples analysed. CONCLUSION: Cetuximab plus FUFOX showed an interesting high response rate in metastatic gastric cancer. Cetuximab plus platinum-fluoropyrimidine chemotherapy is at present being investigated in a phase III randomised controlled trial.

[Reflux disease and Barrett's oesophagus - are there gender-specific differences?]. / Refluxerkrankung und Barrett-Osophagus - Gibt es geschlechtsspezifische Unterschiede?

Studies of the prevalence of gastroesophageal reflux disease (GERD) have reported that male gender is an independent risk factor especially for erosive reflux disease (ERD). Non erosive GERD (NERD) is more common in females. The rate of prevalence and severity of reflux symptoms increase in females with age, while among men it peaked between 50 and 70 years and thereafter declined. The gender effect may be caused by differences in parietal cell mass between males and females. Barrett's esophagus is a major complication of gastroesophageal reflux disease and is associated with 30-125 times increased risk of developing carcinoma. Most studies have found gender differences with females significantly less likely to have Barrett's esophagus with a 20-yr age shift between the parallel age specific prevalence curves, for males between the ages of 20 and 59 yr and for females between the ages of 20 and 79 yr. Male predominance for ERD as a precursor to Barrett's esophagus may be partly explain the greater male/female sex ratio for Barrett's esophagus. Female sex hormones may play a protective role. Knowledge of gender-specific differences of reflux disease and Barrett's esophagus may be helpful to improve surveillance and screening strategies, although distinct recommendations are lacking so far .

Cetuximab plus gemcitabine/oxaliplatin (GEMOXCET) in first-line metastatic pancreatic cancer: a multicentre phase II study.

Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.

Bleeding jejunal diverticulosis in a patient with myasthenia gravis.

A seventy-year-old male presented with severe myasthenia gravis and an episode of obscure bleeding. There was a history of gastric ulcer leading to Billroth II surgery twenty-five years ago. Upper endoscopy revealed no pathology. Colonoscopy showed a few solitary diverticula and traces of old blood in the terminal ileum. Capsule endoscopy pictured red smear in the upper jejunum. Diverticula were seen as well. Suspecting bleeding jejunal diverticulosis double balloon enteroscopy was performed. The complete jejunal ascending loop and about 100 cm of the jejunum through the descending jejunal loop could be inspected. Large diverticula with fecoliths were found in both loops. Bleeding had ceased. The patient was discharged to neurology for optimizing therapy for myasthenia gravis.

Irinotecan plus gemcitabine and 5-fluorouracil in advanced pancreatic cancer: a phase II study.

AIMS: The aim of the present study was to evaluate the 6-month survival rate of patients with inoperable or metastatic pancreatic cancer treated with irinotecan and gemcitabine plus 5-fluorouracil. Secondary efficacy end points included response rate, time to progression (TTP), overall survival (OS) and toxicity. PATIENTS AND METHODS: 30 patients with histologically proven pancreatic carcinoma and at least one bidimensionally measurable lesion were enrolled. Of the patients, 83% had metastatic and 17% locally advanced disease. One cycle, lasting 21 days, comprised treatment on days 1 and 8 consisting of 75 mg/m(2) irinotecan i.v. for 90 min, 1,000 mg/m(2) gemcitabine i.v. for 30 min and 2,000 mg/m(2) fluorouracil (5-FU) for 24 h. A total of six cycles was planned for each patient. RESULTS: 28 patients competed at least one treatment cycle and were therefore assessable for efficacy, and 75% of them achieved the primary end point of the study (survival after 6 months). One-year survival was 25%. Stabilization (partial response and stable disease) was observed in 35.7% (10/28) and partial remission in 7.1% (2/28). The objective response rate was 7.1% (2/28) after completion of the six cycles. Median TTP was 3.4 months (1.2-11.5), and median OS was 8.3 months (2.1-36.2). Regarding severe hematological toxicities, only neutropenia was observed (grade 3 20.7%, 6/29, and grade 4 3.5%, 1/29). In spite of anti-emetic supportive care, nausea affected most of the patients: 79.3% (23/29). Grade 3 vomiting was observed in 4 of the 29 patients (13.8%) and grade 4 in 1 patient (3.5%). Only 1 patient experienced diarrhea grade 3 (3.5%) and 1 patient (3.5%) suffered from a grade 3 peroneal nerve enervation. CONCLUSIONS: A combination of irinotecan, gemcitabine and 5-FU is feasible and shows considerable efficacy in patients with inoperable or metastatic pancreatic cancer. Due to its low toxicity, this combination might be an interesting cytotoxic regimen in addition to targeted therapies.

Self-expanding Polyflex plastic stents in esophageal disease: various indications, complications, and outcomes.

BACKGROUND: Esophageal stenting has become an important technique in the treatment of different clinical problems such as malignant or benign stenosis, anastomotic leaks after surgery, or fistulas. In this study we present our experience with the self-expanding Polyflex plastic stent in various indications, arising complications, and patient's outcomes. METHODS: Over a three-year period, 35 patients underwent self-expanding Polyflex plastic stent placement for esophageal stenosis (n = 23) with 22 malignant, and for perforations, fistulas, or anastomotic leaks after surgery (n = 12). The short-term efficacy and long-term outcomes were analyzed. RESULTS: In patients with stenosis, implantation was performed without any complications in 91% (21/23). In one patient perforation occurred while passing the stenosis; in another patient the stent dislocated during the insertion procedure. Dysphagia score improved from 3.0 to 1.0 after stenting. In all patients with perforations, fistulas, or anastomotic leaks (n = 12), stents were placed successfully without any complication. Complete sealing of the mucosal defect was proven by radiography in 92% (n = 11) and healing was seen in 42% (n = 5). If indicated, stent removal was performed without any complications. Stent migration (n = 13; 37%) was the most common long-term complication. CONCLUSIONS: The placement of self-expanding Polyflex plastic stents is a highly sufficient and cost-effective treatment for malignant and benign esophageal disorders. Because the long-term results were highly favorable, self-expanding plastic stent placement could be used as the initial treatment for various conditions.

[Palliative therapy in cholangio- and gallbladder carcinoma]. / Palliative Therapie von Gallengangs- und Gallenblasenkarzinomen.

Non-resectable cholangiocarcinoma and gallbladder carcinoma have a poor prognosis. In addition to the general aspects of "best supportive care", biliary drainage is an important part of the palliative treatment of patients with malignant biliary stenosis. Photodynamic therapy has led to an improved median survival in hilar cholangiocarcinoma in two controlled studies. The survival benefit of external radiation or intraluminal brachytherapy has not yet been convincingly demonstrated. Whether or not systemic chemotherapy should be applied is still under debate. A single study including advanced biliary and pancreatic cancer patients has demonstrated a survival benefit for the combined group. In recent years, new chemotherapy protocols have been applied, some with promising results. Intra-arterial chemotherapy and chemotherapeutically coated stents have not been evaluated well enough to be recommended outside clinical studies. Ablative therapies have been used in a limited number of patients only. Further studies are necessary to clarify whether these treatment modalities are effective.

Barrett's esophagus: a discrepancy between macroscopic and histological diagnosis.

BACKGROUND AND STUDY AIMS: The diagnosis of Barrett's esophagus at present requires endoscopic and histological confirmation of specialized intestinal metaplasia. This study prospectively analyzed the endoscopic and histological prevalence of Barrett's esophagus and the risk factors for the presence of Barrett's esophagus among patients being treated in an endoscopy unit. PATIENTS AND METHODS: A total of 474 unselected patients (58% men; mean age 52 y) were included in the study. Two biopsy specimens each were taken from below and above the squamocolumnar junction and from the antrum and gastric body. Four-quadrant biopsies were taken every 1-2 cm to confirm a macroscopic suspicion of Barrett's esophagus. RESULTS: Barrett's esophagus was suspected at endoscopy in 109 patients (23%). Of the 109 patients with endoscopically suspected Barrett's esophagus, only 46 (42%) had the finding confirmed histologically. The sensitivity and specificity for the endoscopic diagnosis of Barrett's esophagus were 62% and 84%, respectively. A multivariate logistic regression analysis identified age (P = 0.0001; odds ratio per life-year 1.087; 95% CI, 1.046-1.139), male sex (P = 0.0020; OR 6.346; 95% CI, 2.094-22.314), and the number of biopsies (P = 0.0025; OR 1.661; 95% CI, 1.247-2.392) as factors associated with evidence of intestinal metaplasia on biopsy. CONCLUSION: The striking discrepancy between the endoscopic findings and the histological diagnosis may be due to the focal distribution of intestinal metaplasia. This emphasizes the importance of an adequate biopsy protocol. In addition, better methods of detecting focal islands of intestinal metaplasia that are not visible at conventional endoscopy are needed.

[Endoscopic mucosal resection for early esophageal cancer with esophageal varices]. / Endoskopische Mukosaresektion eines Osophagusfrühkarzinoms bei Leberzirrhose und Osophagusvarizen.

Squamous cell carcinomas account for more than 80 % of esophageal malignancies in Germany. Alcohol and tobacco smoke are two of the most important risk factors. In superficial esophageal squamous cell carcinoma, endoscopic mucosal resection (EMR) is a very useful and effective treatment modality. However, in patients with submucosal esophageal cancer, radical esophageal resection is regarded as the gold standard for treatment at present. We report the case of a 71-year-old female patient with alcohol-induced liver cirrhosis with esophageal varices and a - therefore inoperable - early esophageal squamous cell carcinoma. Photodynamic therapy (PDT) using 5-aminolevulinic acid (5-ALA) seemed not to be an effective treatment modality due to its limited penetration depth (< 2 mm) and the liver toxicity of 5-ALA. PDT using Photofrin(R) with a higher penetration depth seemed to be associated with a high risk of bleeding due to the esophageal varices. Furthermore, this sensitizer is associated with a high rate of strictures and a long-lasting skin sensitivity. In contrast, arguments against an endoscopic mucosal resection (EMR) were endosonographically suspected submucosal tumor growth and a high risk of bleeding. Nevertheless, with respect to the lack alternatives we decided to perform an EMR after ligation of esophageal varices. The tumor could be resected in sano without major bleeding complication. Histology demonstrated a carcinoma in situ without submucosal invasion. After 3 months a second EMR was necessary due to recurrence. Meanwhile after a follow-up period of 18 months only low grade intraepithelial neoplasia without macroscopically suspicious lesions was observed.