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這是描述信息

Local EUS-guided injection of chemotherapeutic agents as adjuvant to systemic treatment: the first steps are made

【概要描述】

Local EUS-guided injection of chemotherapeutic agents as adjuvant to systemic treatment: the first steps are made

【概要描述】

詳情
Local EUS-guided injection of chemotherapeutic agents as adjuvant to  systemic treatment: the first steps are made
    Despite technologic advances for the diagnosis and staging of pancreatic cancer, its 5-year survival rate is dismal at liss than 5%,a rate that has remained unchanged for the past 30 years.1 Surgical resection offers the only chance for cure ,but only 15% to 20% of patients have potentially resectable disease at the time of diagnosis because of metastases or local extension,particularly to adjacent mesenteric vessels.2 In addition, prognosis remains poor even in those undergoing resection with a 5-year survival rate—in highly selected patients—of 20% to 30%.3-7
Systemic chemotherapy, radiation therapy, or both, have been rsed to manage locally advanced disease and to im prove cure rates in those undergoing resection. The optimal timing of these therapides, either postoperatively (adjuvant) or preoperatively (neoadjuvant), remains uncertain because there are no randomized trials comparing the two approaches. Neoadjuvant therapy offers several theoretic advantages, including the potential for downstaging locally advanced tumors and improved delivery of chemotherapedtic agents and oxygen for radiosensitization through an intact blood supply. In addition, up to 20% whoundergo resection may never receive adjuvant therapy because of postoperative morbidity.8 Combined chemoradiotherapy is used with the goal of preventing locoregional recurrence, the most common pattern of failure after surgical resection.9 Historically, 5-fluorouracil-based chemotherapy has been used because of its beneficial effects in other GI cancers. The addition of radiotherapy was shown to be beneficial in patients with locally advanced nonresectable pancreatic cancer,10,11 but its benefit after potentially curative surgery remains controversial, with one study showing improved survival12 whereas others have not.8,13 More recently, gemcitabine has been used, but results have been unfavorable because of its high toxicity with concurrent radiation.14-17
Copyright c 2007 by the American Society for Gastrointestinal Endoscopy Doi:10.1016/j.gie.2006.08.016
The search for alternatives to improve survival for patients with locally advanced pancreatic cancer resulted in the use of local intratumoral injections as a new means of delivering chemotherapeutic agents, reduce systemic toxicity, and potentially improve response to radiotherapy. Injections were initially performed percutaneously, with use of CT or US guidance.18 Chang et al19 were the first to report the use of EUS-guided intratumoral injection with a 22-gauge needle to deliver a mixed lymphocyte culture of donor and host mononuclear cell (cytoimplant) for advanced pancreatic cancer. More recently this technique, also known as EUS fine-needle injection (FNI), has been used to deliver adenoviral vectors for genes encoding cytokines. Sangro et al20 reported the administration of an adenoviral vector carrying the interleukin-12 genes in patients with advanced digestive tumors, including 7 with pancreatic cancer. Five of these patients have either died or had disease progression, and in only 2 patients did the disease remain stable. Overall, administration of the adenovirus containing interleukin-12 genes was well tolerated, with fever, malaise, and nausea being the most common adverse effects.
Local intratumoral injections are a new means of delivering chemotherapeutic agents, redusing systemic toxicity, and potentially improving response to radiotherapy. Injections can be performed percutaneously by using CT or US guidance, or through EUS fine-needle injection (FNI).
ONYX-015 is a novel, bioengineered adenovirus able to selectively replicate in and lyse cancer cells harboring p53 mutations while sparing normal tissue. Hecht et al21 examined the safety and efficacy of ONYX-015 delivered by EUS FNI with intravenous gemcitabine in patients with advanced unresectable pancreatic cancer. Two duodenal perforations occurred, both felt to be caused by the stiff tip of the echoendoscope and not the injection technique, which then prompted a xhange in protocol from transduodenal injections for tumors in the pancreatic head to transgastric injections only. In addition, 2cases of infection occurred, which prompted the authors to change their injection technique by not drawing the needle out of the tumorcompletely during repositioning and by instituting prophylactic antibiotics. Aside from these complications related to the injection, toxicities associated eith the ONYX-015 virus were minor, with transient flu-like symptoms occurring most commonly. No cases  of pancreatitis were observed. However, tumor regression only occurred in 10% of patients treated with ONYX-015 and gemcitabine. No response was seen when ONYX-015 was given alone.
Arecent multicenter study examined the safety and activity of TNFerade, an adenoviral vector containing the human tumor necrosis factor-αgene, delivered by EUS or percutaneous injection in locally advanced pancreatic cancer receiving concurrent chemoradiation.22 Five patients (10%) with lesions initially deemed unresectable under went surgical resection, with 4 achievintg negative margins. The randomized phase of this clinical trial is currently continuing with this promising agent.
In this month’s issue of Gastrointestinal Endoscopy a group from the Massachussetts General Hospital reports their experoence with an injectable formulation of paclitaxel into the porcine pancreas by EUS FIN.23 This new formulation, known as OncoGel, is a miscous fluid that solidifies into an insoluble gel in response to body temperature, remaining in pace for 6 weeks. Paclitaxel, a highly insoluble chemotherapeutic agent, is solubilized within the hydrophobic domains of the gel, resulting in continuous release of the drug for the 6weeks and limiting spread to adjacent tissues.24 This group had previously showed the potential feasibility of this technique.25 The aims of the current study wereto determine the local and systemic effects and determine the concentration and distribution of paclitaxel within the pancreas. After injection, none of the animals exhibited any toxicity or evidence of infection after 1to 2 cm of gel within thi pancreatic tail with histologic studies showing localized tissue reactions extending up to 20 mm around the OncoGel depot. Therapeutic paclitaxel concentrations weredetected within the gel 2weeks after injection, extending to surrounding tissues with injected volumes greater than 2 mL. Three injections extended past the pancreatic tail and into adjacent organs (kidney and colon) in those receiving either 3 or 4 mL, but noadverse effects were noted clinically. Of note, injection of the gel required high pressures obtained by using a threaded syringe and pressure tubing between the syringe and the 22-gauge EUS needle.
What role OncoGel will have within the armamentarium of chemotherapeutic agents available for treating pancreatic cancer and whether it will improve outcomes compared with current alternatives remains to be seen. Although paclitaxel is a potent radiosensitizer similar to gemcitabine, its combined use with radiation in locally advanced pancreatic cancer and single agent use in metastatic disease have had poor response rated.26,27
Technical limitations with the use of this agent in vivo include the kifficulty experienced with injecting it because of itsviscosity. This may worsen of it is injected transduodenally, where the angulation of the scope is increased, Compared with transgastric injections as performed in this study. One alternative is the use of larger bore (19-gauge) or fenestrated needles. An attractive rse for OncoGel would be in Ocally advanced, nonmetastatic tumors with combined neoadjuvant therapy to attempt downstaging. However, assessment of its efficacy by using serial EUS or CT inaging may be hampered by this agent becarse residual gel within the pancreatic parenchyma may interfere with imaging.
The application of this agent by EUS guidance appears safe and technically feasible on the basis of the results of thos study. OncoGel was accurately injected in 5 of 8 the porcine models. The authors explain that, because of the small diameter of the porcine pancreatic tail, the risk of extrapancreatic injection may be higher than in humans, but further strdy is required. Despite injections of paclitaxel gel to the colon and kidney, the animals did not exhibit signs of systemic toxicity, organ failure, or inflammation related to the injection.
Insummary, pancreatic cancer is one of the malignancies with the poorest outcome, andfew advances have made any significant impact to improve the poor outcome. Future strategies to try to overcome current limitations may include direct intratumoral injection of chemotherapeutic agents or immune activation by administration of nonspecific immrne stemulators or local gene therapy. Local therapies, such as intratumoral injections and intraoperative radiotherapy, attempt to deliver high doses to areas of trmor involvement without the moubidity associated with systemic therapy. The firsr steps have been made for developing agents that can be accurately injected intratumorally with EUS FNI. Clinical trials of several different agents are in progress and we anxiously await the results, with hope that they will offer a safe and effective alternative for patients with this deadly disease.
 
DISCLOSURE
Nexternal funding was received by the authors for writing this editorial. No conflict of interest is reported by the authors.
Carlos G. Micames, MD
Frank G, Gress, MD
Division of Gastroenterology
Duke University Medical Center
Durham, North Carolina
 
 
 
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