New and emerging combination therapies for esophageal cancer.

Esophageal cancer comprises two different histological forms - squamous cell carcinoma (SCC) and adenocarcinoma (AC). While the incidence of AC has increased steeply in Western countries during the last few years, the incidence of SCC is fairly stable. Both forms differ in pathogenesis and response to chemotherapy and radiation therapy. Plenty of studies have evaluated new chemotherapy combination regimens in the neoadjuvant, adjuvant, and palliative setting. In addition, new radiation and chemoradiation protocols have been investigated. Finally, molecular-targeted therapy has been included in several new randomized prospective trials. Therefore, this review presents new data on this topic and critically discusses promising approaches towards a more effective treatment in a disease with a grim prognosis.

Safety and efficacy of sunitinib in patients with unresectable pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PNETs) are becoming increasingly common, with the majority of patients presenting with either lymph node involvement or metastatic disease, thus requiring systemic therapy. Targeted therapy is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth rather than by simply interfering with rapidly dividing cells (eg, with traditional chemotherapy). In this review article, pharmacologic inhibition of multiple targets including vascular endothelial growth factor receptor (VEGF-R), platelet-derived growth factor receptor (PDGF-R), stem cell factor receptor (c-KIT-R), FML-like tyrosine kinase-3 receptor (FLT3-R), colony stimulating factor 1 receptor (CSF1-R), and glial cell-line derived neurotrophic factor receptor (RET-R) with sunitinib in patients with unresectable PNETs is discussed. Phase III data indicate that additional treatment with sunitinib can improve prognosis in these patients.

Molecular targeted therapy of hepatocellular carcinoma - results of the first clinical studies.

Hepatocellular carcinoma (HCC) is a common cancer with poor prognosis and worldwide rising incidence during the last years. Although orthotopic liver transplatation, surgical resection and local destruction (alcohol or acetic acid and thermal ablation) are the only curative approaches, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone curative treatment experience a high tumor recurrence rate. Non-resectable HCC is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data on molecular targeting therapy are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib and lapatinib were recently investigated. Furthermore, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), sunitinib, a multiple kinase inhibitor that blocks several receptor tyrosine kinases, and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Until now, the only agent that has to be proven to be effective in terms of survival outcome in two phase III placebo-controlled studies is sorafenib, which became the current standard for palliative treatment.

Molecular targeted therapy of biliary tract cancer--results of the first clinical studies.

Carcinoma of the biliary tree are rare tumors of the gastrointestinal tract with worldwide rising incidence for intrahepatic cholangiocarcinoma during the last years. Although complete surgical resection is the only curative approach, this can be accomplished in a minority of patients, since most of them present with advanced disease. In addition, those patients who have undergone complete surgical resection experience a high tumor recurrence rate. Non-resectable biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents and radiotherapy. It is therefore essential to search for new therapeutical approaches. After several years of preclinical research, the first clinical study data are now available for this tumor entity. Inhibitors of the epidermal growth factor receptor (EGFR) family, such as erlotinib, cetuximab, and lapatinib were recently investigated. Furthermore, bortezomib, an inhibitor of the proteasome, imatinib mesylate, an inhibitor of c-kit-R, bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), and sorafenib (BAY 43-9006), a multiple kinase inhibitor that blocks not only receptor tyrosine kinases but also serine/threonine kinases along the RAS/RAF/MEK/ERK pathway, were studied, as well. Although early evidence of antitumor activity was seen, the results are still preliminary and require further investigations.

TNF alpha inhibition as treatment modality for certain rheumatologic and gastrointestinal diseases.

With the development of biologicals that specifically target tumor necrosis factor (TNF)alpha, our therapeutic approach to inflammatory diseases has dramatically changed. There are currently three anti-TNFalpha drugs available: etanercept, infliximab, and adalimumab. Etanercept is a recombinant fusion protein that can be used alone or in combination with other medications for conditions such as rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, and ankylosing spondylitis. Infliximab, a chimeric humanized monoclonal antibody and adalimumab, a fully human monoclonal antibody are approved for the treatment of rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, and moderate to severe Crohn's disease. Infliximab is also approved for ulcerative colitis. Another anti-TNFalpha drug, certolizumab pegol, was declined approval as treatment option for active Crohn's disease due to a lack of sufficient efficacy. Phase III studies for the treatment of rheumatoid arthritis patients are still pending. It is the goal of this review article to summarize various therapeutic indications, underlying studies, safety, and use during pregnancy, as well as future directions for anti-TNF therapies.

Molecularly targeted therapy for gastrointestinal cancer.

Receptor and non-receptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating gastrointestinal cancer. Imatinib mesilate (STI-571, Gleevec(TM)), an inhibitior of bcr-abl TK, which was primarily designed to treat chronic myeloid leukemia is also an inhibitor of c-kit receptor TK, and is currently the drug of choice for the therapy of metastatic gastrointestinal stromal tumors (GISTs), which frequently express constitutively activated forms of the c-kit-receptor. The epidermal growth factor receptor (EGFR), which is involved in cell proliferation, metastasis and angiogenesis, is another important target. The two main classes of EGFR inhibitors are the TK inhibitors and monoclonal antibodies. Gefitinib (ZD1839, Iressa(TM)) has been on trial for esophageal and colorectal cancer (CRC) and erlotinib (OSI-774, Tarceva(TM)) on trial for esophageal, colorectal, hepatocellular, and biliary carcinoma. In addition, erlotinib has been evaluated in a Phase III study for the treatment of pancreatic cancer. Cetuximab (IMC-C225, Erbitux(TM)), a monoclonal EGFR antibody, has been FDA approved for the therapy of irinotecan resistant colorectal cancer and has been tested for pancreatic cancer. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) are critical regulators of tumor angiogenesis. Bevacizumab (Avastin(TM)), a monoclonal antibody against VEGF, was efficient in two randomized clinical trials investigating the treatment of metastatic colorectal cancer. It is also currently investigated for the therapy of pancreatic cancer in combination with gemcitabine. Other promising new drugs currently under preclinical and clinical evaluation, are VEGFR2 inhibitor PTK787/ZK 222584, thalidomide, farnesyl transferase inhibitor R115777 (tipifarnib, Zarnestra(TM)), matrix metalloproteinase inhibitors, proteasome inhibitor bortezomib (Velcade(TM)), mammalian target of rapamycin (mTOR) inhibitors, cyclooxygenase-2 (COX-2) inhibitors, platelet derived growth factor receptor (PDGF-R) inhibitors, protein kinase C (PKC) inhibitors, mitogen-activated protein kinase kinase (MEK) 1/2 inhibitors, Rous sarcoma virus transforming oncogene (SRC) kinase inhibitors, histondeacetylase (HDAC) inhibitors, small hypoxia-inducible factor (HIF) inhibitors, aurora kinase inhibitors, hedgehog inhibitors, and TGF-beta signalling inhibitors.

General principles of photodynamic therapy (PDT) and gastrointestinal applications.

The purpose of this review article is to describe the history of photodynamic therapy (PDT), its current medical applications, the mechanism of action, contraindications of the method, and different types of photosensitizers used. The second part of the article deals with applications for gastrointestinal diseases. The treatment of obstructing oesophageal cancer, early-stage oesophageal cancer, Barrett's esophagus, hilar cholangiocarcinoma, stomach-, colon- and pancreatic cancer are discussed. The final part focuses on future directions of PDT like certain innovative ideas, which are currently under investigation.