Feasibility of Endoscopic Ultrasound-Guided OncoGel (ReGel/Paclitaxel) Injection into the Pancreas in Pigs

Introduction

At the time of diagnosis, patients with pancreatic cancer often have locally advanced disease, either alone or associated with small liver metastases. These patients suffer from local complications, including pain and biliary or intestinal obstruction. Survival in this group of patients is poor, with a median life expectancy of 8 - 12 months for patients with locally advanced and unresectable disease and only 3 - 6 months for those with metastatic disease at presentation [1]. Historically, patients with locally advanced disease have been treated with chemotherapy and radiation to the pancreatic bed, but the prognosis of the patients remains poor.

Endoscopic ultrasound (EUS) has been used to guide the injection of cytotoxic material into pancreatic malignancies [2]. In one clinical trial, Chang et al. [3] administered local immunotherapy (cytoimplant) to patients with advanced pancreatic cancer under EUS-guidance: cultured activated T lymphocytes were safely injected directly into the pancreatic tumor by a single EUS-guided fine-needle injection.

Intratumoral chemotherapy may represent a new treatment option for locally unresectable cancer. This new approach to the local control of cancer has been made possible by the development of a stable agent that releases active chemotherapeutic drugs over a period of time. Thermosensitive, biodegradable hydrogels can be loaded with active agents in an aqueous phase at an elevated temperature (around 45 °C). When injected at 37 °C, the hydrogel will form a solid gel, which gradually releases the active therapeutic agents [4].

ReGel is a thermosensitive, biodegradable tri-block copolymer composed of poly(lactide-co-glycolide) (PLGA) and polyethylene glycol (PEG). OncoGel (ReGel/paclitaxel) is a formulation of the chemotherapeutic drug paclitaxel which can be injected intratumorally, developed by MacroMed Inc. (Salt Lake City, Utah, USA) for local treatment of solid tumors [5]. OncoGel utilizes MacroMed’s ReGel drug-delivery system. Paclitaxel is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization. Using this system, paclitaxel is released continuously into the adjacent tissue for up to 6 weeks.

The purpose of this study was to determine the feasibility and safety of EUS-guided injection of OncoGel into the pig pancreas.

References

• 1 Kozuch P, Petryk M, Evans A. et al . Therapy for regionally unresectable pancreatic cancer.  Surg Clin North Am. 2001;  81 691-697
• 2 Bhutani M S. Endoscopic ultrasound-guided antitumor therapy.  Endoscopy. 2003;  35 S54-S56
• 3 Chang K J, Nguyen P T, Thompson J A. et al . Phase I clinical trial of allogeneic mixed lymphocyte culture (cytoimplant) delivered by endoscopic ultrasound-guided fine-needle injection in patients with advanced pancreatic carcinoma.  Cancer. 2000;  88 1325-1335
• 4 Jeong B, Bae Y H, Lee D S. et al . Biodegradable block copolymers as injectable drug-delivery systems.  Nature. 1997;  388 860-862
• 5 Zentner G M, Rathi R, Shih C. et al . Biodegradable block copolymers for delivery of proteins and water-insoluble drugs.  J Control Release. 2001;  72 203-215
• 6 Takekuni K, Sakon M, Kishimoto S. et al . A patient with unresectable cancer of pancreas head, effectively treated by a local injection of the mixture of OK-432, fibrinogen and thrombin [in Japanese, English abstract].  Gan To Kagaku Ryoho. 1996;  23 1621-1623
• 7 Mulvihill S, Warren R, Venook A. et al . Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replication-selective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial.  Gene Ther. 2001;  8 308-315
• 8 Cohen E E, Rudin C M. ONYX-015. Onyx Pharmaceuticals.  Curr Opin Investig Drugs. 2001;  2 1770-1775
• 9 Makower D, Rozenblit A, Kaufman H. et al . Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies.  Clin Cancer Res. 2003;  9 693-702
• 10 Hecht J R, Bedford R, Abbruzzese J L. et al . A phase I/II trial of intratumoral endoscopic ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma.  Clin Cancer Res. 2003;  9 555-561