Current Clinical Pharmacology - Volume 10, Issue 4, 2015

The purpose of this article is to provide a critical review of the current systemic treatment and the emerging targeted therapeutic strategies in pancreatic adenocarcinoma. Cytotoxic chemotherapeutic drugs have been used for palliative treatment of pancreatic adenocarcinoma, as well as for neoadjuvant therapy to facilitate surgical resection, and as adjuvant therapy to prevent tumor recurrence. The recent findings of early metastasis of cancer cells in pancreatic adenocarcinoma provide support for systemic therapy even in the case of small and localized tumors. However, the clinical benefits of systemic chemotherapy are generally limited and it is typically associated with a multitude of toxicities. Cancer-specific therapies with improved efficacy and safety are urgently needed. Tremendous advances have been made in understanding the biology and genetic regulation of normal and neoplastic development of the pancreas. These have led to identification of molecular targets in pancreatic cancer cells, the tumor microenvironment, and the cancer stem cells. Tumor-specific modalities are emergent by exploitation of the aberrant signaling pathways and molecular alterations in pancreatic cancer with the goals of improving treatment response. Integrative approaches that combine various targeting strategies with molecular bioinformatics will hopefully lead to the development of personalized therapies that may produce a positive impact on the quality of life and survival for patients with this deadly disease.

Cancers of esophagus and stomach are common malignant diseases worldwide, and they are associated with serious morbidity and high mortality rates. When diagnosed at an early stage, gastro-esophageal cancers are potentially curable. Neo-adjuvant or adjuvant therapies using both chemotherapy and radiation therapy have been shown to reduce the risk of local recurrence and distant metastasis. For advanced or metastatic tumors, systemic chemotherapy offers symptomatic palliation and moderate benefits in survival. With recent advances in anti-cancer therapeutics, progress has been made to improve treatment response and life expectancy in patients with advanced gastro-esophageal cancers. Furthermore, the clinical use of molecularly targeted agents in combination with cytotoxic chemotherapeutics is being evaluated in a number of ongoing clinical trials. In this article, we review currently used standard systemic therapies including recently evolving targeted therapies for metastatic gastro-esophageal cancers, as well as the proven role and the regimens that are used as neoadjuvant and adjuvant treatment in localized gastro-esophageal cancers.

The survival rate of patients with colorectal cancer (CRC) is steadily increasing over the past decade. However, CRC continue to be one of the leading causes of cancer-related fatality in the United States. Current targeted strategies offer limited clinical benefits and the overall survival rate for CRC remains low. Improved understanding of the molecular changes associated with CRC that control growth factor signaling and evasion of cell death allow for the development of improved targeted therapy. This review aims to discuss some of the emerging therapies aimed to target CRC.

Medical therapy for hepatocellular carcinoma (HCC) is an area of active investigation because fewer than 25% of patients are candidates for curative resection or transplantation. Single agent doxorubicin, the former standard of care, generated a 10% tumor response but resulted in substantial toxicity. The resulting recommendation of the NCCN has been to administer cytotoxic chemotherapy only under clinical protocol. More recently, newer drugs with more specific targets have forced re-consideration of palliative chemotherapy in clinical practice. Bevacizumab is a promising therapy but data is limited to Phase 2 trials without impressive results. Sorafenib is the prototype multi-kinase inhibitor, which has demonstrated some but limited survival benefit in advanced HCC. This has subsequently become the standard of care. Epidermal growth factor receptor, the target of rapamycin (mTOR) pathway, transforming growth factor-β, and cyclin-dependent kinases have been recent targets of ongoing study for potential therapeutics. Overall, current therapeutics have been so promising that adjuvant therapy after curative treatment in under investigation to reduce recurrence.

Neuroendocrine tumors (NETs) are relatively uncommon. They typically arise in the gastrointestinal tract and lungs, and their incidence seems to be rising. Most patients have advanced disease at the time of diagnosis and many more will relapse after surgery. There is thus a great need for improvements in therapy for advanced neuroendocrine tumors. This article reviews the current therapy for both pancreatic NETs and non-pancreatic gastrointestinal NETs, and discusses recent advances in NET management with an emphasis on targeted therapy.

Imatinib therapy has revolutionized the treatment of patients with gastrointestinal stromal tumors (GISTs). Compared with older therapy, imatinib significantly improves outcomes in patients with metastatic disease and those with locally advanced tumors, raising progression-free and overall survival. Recent studies have evaluated variables such as timing of treatment, total dosing, and duration of therapy. Different genotypes are associated with a poorer response to imatinib therapy, whereas others may benefit from a higher starting dose. This review discusses recent data regarding optimal use of imatinib for treatment of GIST in both the adjuvant and metastatic settings, and addresses topics such as the impact of genotype on initial dose, dose escalation, optimal duration of treatment, and neoadjuvant therapy. Key ongoing clinical trials of imatinib in GIST are also discussed.

Hypertension is recognized as one of the leading risk factors for human morbidity and mortality. It is a major risk factor for myocardial infarction, congestive heart failure, stroke, and endstage renal disease. The difficulty in controlling hypertension is related, at least in part, to the complex pathogenesis of hypertension. In spite of the availability of variety of antihypertensive agents, the control of blood pressure in the general population is at best inadequate. It is being recognized that a balanced modulation of several targets can provide a superior therapeutic effect to side effect profile compared to the use of a selective ligand. Fixed combinations of drugs and multitargeted ligands provide answers to the problem of hypertension. This review provides a status report of current antihypertensive drug therapy with fixed combination of drugs and evolvement of multitargeted ligands for better management of the disease.