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PostSubject: pancreatic cancer treatment chemotherapy   Mon Aug 29, 2011 9:59 pm

pancreatic cancer treatment chemotherapy


Chemotherapy for Pancreatic Cancer

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomeraseinhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies.

Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volumespeciality centres.

Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.
Introduction

Pancreatic ductal adenocarcinoma remains one of the deadliest cancers world-wide. It claims over 6500 lives per year in the U.K., over 40 000 in Europe,[1,2] nearly 19 000 in Japan[3] and almost 30 000 annually in the United States.[4-7] The incidence of pancreatic cancer is continuing to rise in most westernised countries,[1,7] especially in women where, in most European countries, the prevalence is now equal to that of men.[1,7] Although recent figures from the Surveillance, Epidemiology and End Result (SEER) programme in the USA have shown a decrease in the total incidence of pancreatic cancer, it remains a major cause of cancer-related mortality, with universally poor survival rates (http://seer.cancer.gov/reportcard/). Pancreatic cancer is aggressive and presents with disseminated or locally advanced disease due to its relatively asymptomatic nature during its early course.[1-9] The median survival for all stages of pancreatic cancer is less than 3-5 months from diagnosis, with a 5-year survival of 0.4-3%.[1,7,9]

Surgery is the only treatment that offers the prospect of cure, although at present this is more hope than reality. The resection rate is 4% or less in general surgical units, but is at least 10-15% in specialist pancreatic cancer units.[10-13] Post-operative mortality has also been dramatically reduced in specialist high-volume centres from over 20% to less than 6%.[8] After successful surgery the prognosis is still relatively poor (median and 5-year survivals of around 13-15 months and 15- 20%, respectively,[14-18] but is far superior in specialist centres.[8,13,19] With this increasing success there has also been greater attention focused towards adjuvant and neo-adjuvant chemotherapy. This article examines the current thinking and evidence for the use of chemotherapy and how it compares to other forms of treatment for pancreatic cancer.

Although pancreatic cancer has been classed as a tumour that is largely resistant to chemotherapy, 5-fluorouracil (5-FU) and 5-FU-based combination regimens have been shown to be superior to observation alone or no treatment arms in adjuvant trials,[20,21] and to best supportive care in palliative therapy trials[22,23] ( Table 1 ). An important breakthrough was the demonstration that gemcitabine was able to improve the major symptoms of pancreatic cancer (weight loss and tumour-associated pain) as well as achieving a modest survival benefit compared to bolus 5-FU.[24] Nevertheless gemcitabine and other traditional cytotoxic agents rarely extend median survival much beyond 6 months, so there is an imperative for further progress. Extensive translational and clinical research is underway to improve the effectiveness of existing classes of drug and identify new agents based on traditional modes of action or from novel biological pathways.
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