EUS or percutaneously guided intratumoral TNFerade biologic with 5-fluorouracil and radiotherapy for first-line treatment of locally advanced pancreatic cancer: a phase I/II study

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• 作者：J. Randolph Hecht ; MD^?/sup> ; ¹ ; James J. Farrell ; MD^?/sup> ; ² ; ; Neil Senzer ; MD³ ; John Nemunaitis ; MD³ ; Alexander Rosemurgy ; MD⁴ ; Theodore Chung ; MD ; PhD⁵ ; Nader Hanna ; MD⁶ ; Kenneth J. Chang ; MD⁷ ; Milind Javle ; MD⁸ ; Mitchell Posner ; MD⁹ ; Irving Waxman ; MD⁹ ; Anthony Reid ; MD¹⁰ ; Richard Erickson ; MD¹¹ ; Marcia Canto ; MD ; MHS¹² ; Amitabh Chak ; MD¹³ ; Gretta Blatner ; MS ; MPH¹⁴ ; Milan Kovacevic ; MD ; PhD¹⁴ ; Mark Thornton ; MD ; PhD ; MPH¹⁴
• 关键词：5-FU ; 5-fluorouracil ; ANC ; absolute neutrophil count ; CRT ; chemoradiation therapy ; DLT ; dose-limiting toxicity ; DVT ; deep vein thrombosis ; EUS-FNI ; EUS-guided fine-needle viral injection ; FNI ; fine-needle viral injection ; LAPC ; locally advanced pancreatic
• 刊名：Gastrointestinal Endoscopy
• 出版年：2012
• 出版时间：February 2012
• 年：2012
• 卷：75
• 期：2
• 页码：332-338
• 全文大小：633 K

文摘

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Background

TNFeradeBiologic (AdGVEGR.TNF.11D) is a replication-deficient adenoviral vector that expresses tumor necrosis factor-¦Á (TNF-¦Á) under the control of the Egr-1 promoter, which is inducible by chemotherapy and radiation.

Objective

This study was conducted to determine the maximal tolerated dose of TNFeradeBiologic with standard chemoradiotherapy and preliminary activity and safety of the combination in the treatment of locally advanced pancreatic cancer (LAPC).

Design

TNFeradeBiologic was injected into locally advanced pancreatic carcinomas by using EUS or percutaneous administration once a week for 5 weeks together with 50.4 Gy radiation and 5-fluorouracil (5-FU) 200 mg/m² daily over 5.5 weeks. Dose levels from 4 ¡Á 10⁹ to 1 ¡Á 10¹² particle units (PU) were studied.

Setting

Multicentered, academic institutions.

Patients

Fifty patients with LAPC were treated.

Interventions

Doses of TNFerade Biologic were administered to patients.

Main Outcome Measurements

Toleration of TNFerade Biologic was measured through toxicity and tumor response, by using the criteria of the Response Evaluation Criteria in Solid Tumors and the World Health Organization, and was reviewed by a central radiology facility. Overall survival and progression-free survival were also measured.

Results

Dose-limiting toxicities of pancreatitis and cholangitis were observed in 3 patients at the 1 ¡Á 10¹² PU dose, making 4 ¡Á 10¹¹ PU the maximum tolerated dose. One complete response, 3 partial responses, and 12 patients with stable disease were noted. Seven patients eventually went to surgery, 6 had clear margins, and 3 survived >24 months.

Limitations

This is a Phase1/2 non-randomized study.

Conclusions

Intratumoral delivery of TNFerade Biologic by EUS with fine-needle viral injection or percutaneously, combined with chemoradiation, shows promise in the treatment of LAPC. There appeared to be better clinical outcome at the maximal tolerated dose than at lower doses. The dose of 4 ¡Á10¹¹ PU TNFerade Biologic was generally well tolerated, with encouraging indications of activity, and will be tested in the randomized phase of this study. Delivery of TNFerade Biologic did not interfere with subsequent surgical resection.