[Gastrointestinal oncology - therapy update 2008 / 2009]. / Gastrointestinale Onkologie - Therapieupdate 2008 / 2009.

As a consequence of recent studies the treatment of gastrointestinal cancers has become challenging and is undergoing constant changes on the basis of the results of new trials. The steering committee of the working group on gastrointestinal cancers of the Deutsche Gesellschaft für Verdauungs- und Stoffwechselkrankheiten has decided to summarise and present recent updates of the current treatment guidelines and recommendations for the most relevant gastrointestinal malignancies. In this review we have included recent findings from large trials on esophageal, gastric, pancreatic, cholangiocellular and liver cancers, as well as colorectal cancers, neuroendocrine tumours and lymphomas. This includes an update on the combination with novel targeted agents and the introduction of potential predictive biomarkers in the selection of the appropriate treatment strategy.

Chemotherapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials.

Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis was to analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trials published in English from 1985 to July 2006 were analysed as well as ASCO abstracts from 1999 to 2006. Response rate (RR=CR+PR), tumour control rate (TCR=CR+PR+SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and four trials comprising 112 trial arms and 2810 patients, thereof 634 responders and 1368 patients with tumour control were analysed. Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found. Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for GBC. Furthermore, superior RRs and TCRs of gemcitabine and platinum containing regimens were found with highest RRs and TCRs in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based standard has been defined.

Capecitabine for treatment of advanced hepatocellular carcinoma.

BACKGROUND/AIMS: Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis, as no effective palliative chemotherapy exists. Moreover, treatment of patients with hepatocellular carcinoma presents a major challenge, because associated cirrhosis limits the choice of chemotherapeutic agents. We evaluated the activity and toxicity of capecitabine in patients with advanced hepatocellular carcinomas. METHODOLOGY: The authors performed a retrospective analysis of all patients with HCC who were treated with capecitabine. The medical records of patients with HCC who were treated at our institution between October 2002 and July 2005 were reviewed. RESULTS: A total of eleven patients were treated with capecitabine. Eight patients had liver cirrhosis and Child-Pugh scores of A and B. Capecitabine was administered twice daily for 14 days at a total daily dose of 2000 mg/m2. Treatment was repeated every 21 days. Each patient received 2-16 treatment cycles. One partial response was observed (9%; 95% confidence interval (CI) 0.2-41.3%) and 3-month progression free survival rate was 27%. The median time to tumor progression and median overall survival were 2.2 months (95% CI 1.7-2.7 months) and 10.1 months (95% CI 3.0-17.2 months), respectively. The therapy was well tolerated, with hand-foot syndrome as the main toxicity. Grade 3 diarrhea occurred in one patient. Grade 3/4 hyperbilirubinemia was seen in five patients, but was mainly due to tumor progression. No other significant toxicities were observed. CONCLUSIONS: Capecitabine was found to be safe for treatment of patients with HCC, including those with compensated cirrhosis. However, the objective response rate was limited.

Hepatocellular carcinoma associated with hereditary hemochromatosis occurring in non-cirrhotic liver.

The occurrence of primary hepatocellular carcinoma (HCC) in patients with hereditary hemochromatosis (HH) is well known. Thereby, the development of liver cirrhosis seems to be a prerequisite. Whether or not a hepatic iron overload in the context of hereditary hemochromatosis is an independent risk factor for HCC remains unclear. To date there are only a few reports about HCC arising in non-cirrhotic livers in the presence of HH. We report the case of a 64-year-old man who presented to our outpatient clinic with HCC. Liver cirrhosis could be excluded. Detailed exploration of the patient's history revealed that he had been treated by venesection for about 10 years up to 15 years ago. Subsequent investigations showed an elevated serum ferritin and transferrin saturation. The diagnosis of HH was confirmed by genetic testing, with homozygosity for the Cys282Tyr mutation. The patient received palliative chemotherapy and finally died 15 months after initial diagnosis of HCC.

Pharmacokinetic and clinical phase II trial of imatinib in patients with impaired liver function and advanced hepatocellular carcinoma.

OBJECTIVES: No effective chemotherapy for advanced hepatocellular carcinoma (HCC) exists. Expression of the platelet-derived growth factor receptor (PDGFR) has been demonstrated in HCC, which may derive from hepatic stem cells that express c-kit. The aim of this trial was to evaluate imatinib, a tyrosine kinase inhibitor of PDGFR and c-kit, in patients with advanced HCC and impaired liver function. PATIENTS AND METHODS: Patients were treated with 400-600 mg imatinib daily. Immunohistochemical staining was performed for PDGFR and c-kit. Response was assessed by CT scans every 8 weeks. For pharmacokinetics studies, 74 plasma samples were assessed. RESULTS: Of the 17 patients enrolled in the study, 15 were evaluable for response. Only 1 tumor was positive for PDGFR and none was positive for c-kit. Grade 3/4 neutropenia occurred in 2 patients (1 had neutropenic fever). There was no objective response, and 5 (33%) patients had stable disease. Median time to treatment failure was 1.8 months in the whole study cohort and 3.7 months in the patients with stable disease. Patients treated with 400 mg imatinib did not significantly differ in pharmacokinetics from patients with chronic myelogenous leukemia (CML). CONCLUSION: In this small group of patients with advanced, mostly PDGFR- and c-kit-negative HCC, imatinib showed no therapeutic effect. In contrast to CML patients, the pharmacokinetics of imatinib were not significantly affected by impaired liver function.

Treatment of HCC with pravastatin, octreotide, or gemcitabine--a critical evaluation.

BACKGROUND/AIMS: New perspectives in the treatment of advanced hepatocellular carcinomas have recently been inaugurated with the application of hydroxymethylglutaryl coenzyme A reductase inhibitors i.e. pravastatin, the somatostatin analogue octreotide, or the cytidine analogue gemcitabine. The present study aimed to evaluate these substances in patients with progressive tumor growth. METHODOLOGY: A total of 58 patients either received 3 x 200 microg/day octreotide for 2 months followed by 20mg octreotide LAR every 4 weeks (n=30) or 40-80 mg pravastatin (n=20) or 80-90 mg/m2 gemcitabine over 24 hours weekly in cycles of 4 weeks (n=8). Kaplan-Meier survival curves and the log-rank test were used for univariate comparison of sur vival. RESULTS: The median overall survival of patients receiving octreotide was 5 months, of patients receiving pravastatin 7.2 months and of patients receiving gemcitabine 3.5 months. The difference between the pravastatin and the gemcitabine groups was significant. No WHO grade 3 or 4 side effects were seen in either group of patients. CONCLUSIONS: These results do not confirm those of former studies. Neither pravastatin, nor octreotide, nor gemcitabine did prolong the patients' median overall survival as compared to control groups reported by other authors. New therapeutic strategies have to be found for patients with advanced hepatocellular carcinomas.

Monitoring of tumour glucose metabolism by PET in a phase I study evaluating hormonal therapy in advanced pancreatic cancer.

BACKGROUND: Positron emission tomography (PET) determines therapy-induced changes in tumour glucose utilization. Experimental data indicate that cholecystokinin (CCK) stimulates pancreatic cancer growth. In this study in patients with advanced pancreatic cancer, we evaluated the use of fluorodeoxyglucose (FDG) PET compared with magnetic resonance imaging (MRI) in monitoring hormonal therapy using a highly selective, non-peptide CCK receptor antagonist (SR 27897B). METHODS: Nineteen patients were enrolled on a 28-day course of SR 27897B. Initially, 4 patients received 20 mg of SR 27897B; 9 patients received 40 mg; and 6 patients 80 mg. Imaging studies, including FDG-PET and MRI, were performed at baseline and on days 14 and 28. RESULTS: No significant changes in FDG uptake by the primary tumours were observed. Rate of progression of disease was 11 (61%) of 18 evaluable patients by MRI. Median survival of all patients enrolled was 2.7 months. SR 27897B was fairly well tolerated at all doses tested. The most common side effects were gastrointestinal disorders such as diarrhoea, flatulence and nausea. CONCLUSION: SR 27897B, when used alone at the limited doses employed, led neither to an impairment of tumour glucose metabolism nor to a reduction of tumour size in advanced pancreatic cancer.

Recurrent pseudomembranous colitis as a cause of recurrent severe sepsis.

Clostridium difficile (C. difficile) colitis accounts for nearly 15-20 % of antibiotic-associated diarrhea. Manifestations include asymptomatic carriage, self-limited diarrhea, and pseudomembranous colitis, which is sometimes life-threatening. Despite effective therapy with metronidazole and vancomycin relapse rates are 15-33 %. Although colitis is seen in critically ill patients treated with combinations of broad-spectrum antibiotics, reports describing severe sepsis as a result of C. difficile infection are limited. We describe the case of recurrent severe sepsis due to recurrent local intestinal C. difficile infection as the only identifiable etiology. The mechanism of severe sepsis may be a derangement of the gastrointestinal barrier function. This could result in absorption of microbes or endotoxin or activation of inflammatory cascades in the submucosa of the intestine or liver. In general, for successful treatment of C. difficile infections other than anticlostridial antibiotics should be discontinued. However, in the present case bacterial translocation from the intestine is an attractive explanation for severe sepsis and therefore additional antibiotics had been administered.

Fulminate intracardiac thrombosis associated with Budd-Chiari-syndrome and inferior vena cava thrombosis.

The most common cause of edema of the legs and dyspnea is congestive heart failure. Further differential diagnosis such as renal or hepatic failure have to be considered. We report the case of a previous healthy 65-year-old woman who developed dyspnea and massive edema of the legs followed by acute hepatic and renal failure. Imaging studies showed a thrombosis of the inferior vena cava (IVC) caused by a tumor between the right kidney and the IVC. Histological examination revealed a leiomyosarcoma of the IVC. Hepatic failure due to venous outflow obstruction (Budd-Chiari syndrome, BCS) was diagnosed. Coagulation profile showed a complex disorder due to acute hepatic failure. Factor V Leiden and prothrombin gene mutation G20210A could be excluded. The thrombosis extended from the femoral veins up to the right atrium. After 11 days of anticoagulation with heparin platelet counts decreased by more than 50%. Suspecting a heparin-induced thrombocytopenia the patient was placed on recombinant hirudin (lepirudin) for anticoagulation. Hepatic venogram showed a thrombosis of the hepatic vein orifices but not of the hepatic veins. The tumor and the thrombi were removed surgically. When the cardiopulmonary bypass was terminated new intracardiac thrombi occurred. Despite immediate surgical intervention the patient finally died due to right ventricular failure caused by the fulminate intracardiac thrombosis. In conclusion, thrombosis of the IVC may mimic congestive heart failure and may cause BCS. Neoplasms and coagulation disorders may cause thrombosis of the IVC.

[Prevention of oxaliplatin-induced neuropathy by carbamazepine. A pilot study]. / Prophylaxe der Oxaliplatin-induzierten Neuropathie mit Carbamazepin(1). Eine Pilotstudie.

INTRODUCTION: Oxaliplatin has been proven antitumoral activity in numerous clinical trials. Peripheral sensory neuropathy with predominantly hyperpathic symptoms induced by cold is the most severe and dose-limiting toxicity resulting from oxaliplatin therapy. We demonstrated that oxaliplatin alters sodium channel kinetics on sensory neurons. This effect could be antagonized in vitro by the sodium channel blocker carbamazepine. Therefore a pilot study was initiated to investigate if carbamazepine prevents oxaliplatin-induced neuropathy in patients with colorectal cancer. PATIENTS AND METHODS: Ten patients (six males, four females, mean age 56 +/- 12 years) refractory to 5-fluorouracil were treated with oxaliplatin, 5-fluorouracil, and folinic acid. The patients additionally received carbamazepine. Doses were adapted to a serum level of 3 - 6 mg/l. Patients were questioned about side-effects weekly and treatment-related toxicities were documented using the modified WHO scale. Results were compared with 30 historic controls treated with the same chemotherapy without carbamazepine. RESULTS: The cumulative oxaliplatin dose was higher in the carbamazepine group (median 722 mg/m(2) and 510 mg/m(2), respectively, p = 0.020). Carbamazepine levels were 4.5 +/- 1.5 mg/l. In contrast to the control group no neuropathy higher than grade 1 occurred in the carbamazepine group. Rate of carbamazepine-induced side effects was low. CONCLUSIONS: These observations demonstrate that oxaliplatin-induced sensory neuropathy more than grade 1 may be prevented by carbamazepine. Prevention of oxaliplatin-induced neurotoxicity by carbamazepine would possibly enable chemotherapy with considerable higher doses of oxapliplatin and thus enhance activity. A multicenter trial will elucidate if more serious distal neurotoxicities, which occur after application of higher cumulative doses of oxaliplatin, can also be prevented by carbamazepine.

Multimicrobial sepsis including Clostridium perfringens after chemoembolization of a single liver metastasis from common bile duct cancer.

A 65-year-old woman underwent resection of a distal common bile duct carcinoma (Whipple's procedure). Twelve months later a single hepatic metastasis was detected and a chemoembolization was performed. Immediately after chemoembolization the patient developed a multimicrobial sepsis including Clostridium perfringens. CT scans depicted pathognomonic signs of gas-containing abscess in the necrotic liver metastasis. She was subsequently treated with broad-spectrum antibiotics, abscess drainage and hyperbaric oxygen therapy. We conclude that antibiotic prophylaxis is recommendable for chemoembolization of liver metastasis in patients with risk factors like intestinal biliary reflux (bilioenteric anastomosis or papillotomy and biliary stenting) and bile duct cancer, otherwise severe sepsis including clostridium bacteremia may occur.

The chemotherapeutic oxaliplatin alters voltage-gated Na(+) channel kinetics on rat sensory neurons.

The chemotherapeutic oxaliplatin causes a sensory-motor neuropathy with predominantly hyperpathic symptoms. The mechanism underlying this hyperexcitability was investigated using rat sensory nerve preparations, dorsal root ganglia and hippocampal neurons. Oxaliplatin resulted in an increase of the amplitude and duration of compound action potentials. It lengthened the refractory period of peripheral nerves suggesting an interaction with voltage-gated Na(+) channels. Application of oxaliplatin to dorsal root ganglion neurons resulted in an increase of the Na(+) current, a block of the maximal amplitude and a shift of the voltage-response relationship towards more negative membrane potentials. The effect was detectable on 13 of 18 tested cells. This observation, together with the absence of any effect on Na(+) currents of hippocampal neurons, suggests that the interaction of oxaliplatin is restricted to one or more channel subtypes. The effect of oxaliplatin could be antagonised by the Na(+) channel blocker carbamazepine which could be used to reduce side effects of oxaliplatin therapy in patients.

[A 42-year-old patient with the hemolytic-uremic syndrome under gemcitabine therapy for an adenocarcinoma of the liver. The hemolytic-uremic syndrome and gemcitabine]. / 42-jähriger Patient mit hämolytisch-urämischem Syndrom unter Gemcitabin-Therapie eines Adenokarzinoms der Leber. Hämolytisch-urämisches Syndrom und Gemcitabin.

We report on the case of a 42-year-old man suffering from an irresectable adenocarcinoma of the liver. The patient was treated with 5-fluorouracil for 6 months when the disease progressed and second line therapy with gemcitabine was started. After 4 months diastolic blood pressure increased and edema of the legs as well as vomiting occurred. Laboratory tests revealed anemia and thrombopenia accompanied by an elevation of plasma D-dimer, lactatdehydrogenase, creatinine, and urea levels in the serum. In addition, a pronounced proteinuria as well as renal hematuria were detected and subsequently a hemolytic uremic syndrome was diagnosed. After treatment with high-dose glucocorticoids, anticoagulants and transfusions of packed RBC the course of disease improved. Since Gemcitabine is now widely used for treatment of solid organ cancer (e.g. pancreatic adenocarcinoma, biliary tract cancer, lung cancer etc.), it is necessary to be aware of Gemcitabine-induced hemolytic uremic syndrome as a rare but potentially fatal side effect.

Endohyperthermia--experimental evaluation of a new therapeutic approach for treatment of biliary carcinoma.

BACKGROUND AND STUDY AIMS: To improve the prognosis of patients with unresectable, locally advanced bile duct carcinoma, new treatment strategies need to be evaluated. Hyperthermia has been successfully applied as part of multimodal therapy in esophageal and rectal carcinoma. We performed in-vitro and in-vivo experiments with a new intraluminal hyperthermia system in the biliary tract. METHODS: A radiofrequency system (13.56 MHz, Endoradiotherm XERT-200A; Olympus Optical Co., Tokyo, Japan) was used with a special intraluminal microelectrode (diameter 4.5 mm, length 40 mm) covered by a silicone balloon with cooling water and a large counter electrode for focusing the electromagnetic field around the electrode. The heating capacity of the endohyperthermia unit was examined in vitro in a muscle-equivalent phantom (agar 4 %), in isolated livers of pigs and cows, as well as in vivo in anesthetized sheep. Continuous thermometry was done with thermosensors at the applicator surface, and with multichannel thermocouple probes in the environment of the applicator. RESULTS: Endohyperthermia induced a homogeneous heating of the phantom and the isolated liver bile duct preparation to a temperature > or = 40 degrees C in an area at least 10 mm in depth. After placement of the applicator into the common bile duct of anesthetized sheep, endohyperthermia led to a consistent and repeatable heating of the surrounding tissue to 40.5 +/- 0.5 degrees C at 1 cm distance, and 39.9 +/- 0.7 degrees C at 2 cm distance. Blood pressure, heart rate, and systemic temperature did not change in vivo. Histological examination of the bile duct showed superficial mucosal necrosis (depth 100-200 microm), microvascular damage with petechiae, congestion and edema of the bile duct wall and adventitia after hyperthermia treatment in vivo. CONCLUSIONS: The intraluminal endohyperthermia system produces consistent and repeatable heating of the surrounding tissue. Since effective thermal power can reach a depth of up to 2 cm, tumors may also be heated adequately.