Phase I trial of the human immunodeficiency virus protease inhibitor Nelfinavir and chemoradiation for locally advanced pancreatic cancer
Phase I trial of the human immunodeficiency virus protease inhibitor Nelfinavir and chemoradiation for locally advanced pancreatic cancer
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DOI：
10.1200/jco.2007.15.2355
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发表时间：
2008-06-01
影响因子：
45.3
通讯作者：
McKenna, W. Gillies
中科院分区：
文献类型：
--
作者：
Brunner, Thomas B.;Geiger, Matthias;McKenna, W. Gillies
目的临床前HIV蛋白酶抑制剂通过激活PI 3-激酶/Akt通路对肿瘤放射增敏。我们确定的毒性nelfinavir chemoradiotherapy在边缘可切除和不可切除的pancreates.Patients和MethodsOral nelfinavir（2 X 1，250毫克）开始3天前，并继续在整个chemoradiotherapy 50.4戈伊（助推，59.4戈伊）在12例。检测了两种吉西他滨剂量水平（DL）（第1、8、22和29天200 mg/m2和300 mg/m2）。在同一天给予顺铂30 mg/m2。通过患者白细胞中的免疫印迹法监测奈非那韦对磷酸化Akt的下调。重新分期正电子发射断层扫描（PET）/计算机断层扫描（CT）和CA 19 -9水平，以评估响应，并响应肿瘤切除。ResultsAt每个DL，五个6例患者完成放化疗，和两个12例患者有不完整的放化疗，因为临床抑郁症（DL 1）和腹膜转移（DL 2）。4级毒性为胆道支架闭塞导致的转氨酶升高（DL 2）和腹膜转移导致的急性胆囊炎（DL 2）。支架闭塞导致3级肝酶和胆红素升高的剂量限制性毒性（DL 1时2例患者，DL 2时1例患者）。1例DL 2患者发生3级恶心和呕吐，1例DL 1患者发生体重减轻，拒绝支持性喂养。10例完全放化疗患者中有6例可能进行二次完全切除，其中1例肿瘤病理绝育。在完成放化疗的10例患者中，有5例观察到部分CT反应。PET评估的9例患者，反应是完整的5例患者和部分患者，稳定的疾病被观察到在2 patients.ConclusionThe nelfinavir和放化疗的组合显示出可接受的毒性和有前途的活动在胰腺癌患者。
PurposePreclinically, 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 MethodsOral 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.ResultsAt 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.ConclusionThe combination of nelfinavir and chemoradiotherapy showed acceptable toxicity and promising activity in patients with pancreatic cancer.