Phase I trial of the human immunodeficiency virus protease inhibitor nelfinavir and chemoradiation for locally advanced pancreatic cancer.

PURPOSE: Preclinically, HIV protease inhibitors radiosensitize tumors with activated PI3-kinase/Akt pathway. We determined the toxicity of nelfinavir chemoradiotherapy in borderline resectable and unresectable pancreatic cancer. PATIENTS AND METHODS: Oral nelfinavir (2 x 1,250 mg) was started 3 days before and continued throughout chemoradiotherapy to 50.4 Gy (boost, 59.4 Gy) in 12 patients. Two gemcitabine dose levels (DL) were tested (200 mg/m(2) and 300 mg/m(2) on days 1, 8, 22, and 29). Cisplatin was administered on the same days at 30 mg/m(2). Phospho-Akt downregulation by nelfinavir was monitored by immunoblotting in patient leukocytes. Restaging positron emission tomography (PET)/computed tomography (CT) and CA19-9 levels served to assess response, and responding tumors were resected. RESULTS: At each DL, five of six patients completed chemoradiotherapy, and two of 12 patients had incomplete chemoradiotherapy because of clinical depression (DL1) and peritoneal metastasis (DL2). Grade 4 toxicities were a transaminase elevation (DL2) as a result of biliary stent occlusion and acute cholecystitis as a result of peritoneal metastasis (DL2). Stent occlusions led to dose-limiting toxicities of grade 3 liver enzyme and bilirubin elevations (two patients at DL1, one patient at DL2). Grade 3 nausea and vomiting occurred in a DL2 patient, and weight loss occurred in a DL1 patient who refused supportive feeding. Secondary complete resection was possible in six of 10 patients with complete chemoradiotherapy, including one tumor with pathologic sterilization. Partial CT responses were observed in five of 10 patients who completed chemoradiotherapy. Of nine patients assessable by PET,responses were complete in five patients and partial patients, and stable disease was observed in two patients. CONCLUSION: The combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer

Law, public debates and professionals' attitudes: a comparative study on the use of advance directives in England, France and Germany

Advance directives to refuse treatment (ADs) are legally binding in many Western European countries. Yet, in practice ADs are only rarely used. This chapter explores the influence of different socio-cultural and legal contexts on the implementation of ADs in three European countries: England, Germany and France. More precisely, this chapter focuses on physicians’ perspectives on the law and the reasons given by them for failing to implement it. It will show how physicians’ sense of duty to respect ADs depends on: (1) the definition of the legal status of ADs in a country; (2) the way the law addresses physicians’ concerns regarding the use of ADs (e.g. uncertainty about validity, respect for patient preferences); and (3) the way ADs are discussed in the public (or not). The findings presented are based on literature review and qualitative interviews