| Background Pancreatic carcinoma is one of the main cancer in China. It is difficult to detect in early stage for its anatomic properties.Most cases are in advanced stages and lost the opportunity of exairesis when they are defined diagnosed.Only less than 15% of the carcinomas could be resected by surgery.Because of the high resistance to chemo and radiation therapy, the overall survival rate for pancreatic cancer is extremely low. The prognosis of patients with pancreatic cancer is extremely poor,with overall 5-year survival rate of approximately 5%.Till now, treatment of pancreatic carcinoma remains a major challenge. The main therapy for locally advanced cancers involves kinds of radiotherapy in vivo and in vitro, and the chemotherapy(mainly base on Gemcitabine).But the efficiency are limited. Replication-de?cient oncolytic viruses are engineered to replicate only in tumor cells, which makes it an promissing therapeutic agent for cancer treatment. Those viruses kill tumor cells by a variety of mechanisms including direct cell lysis, cell–cell fusion, toxic proteins, and induction of antitumor immune responses. Commonly used oncolytic viruses include adenovirus, herpes simplex virus, and reovirus. H101 is an E1B-gene-deleted replication-selective adenovirus that preferentially replicates in malignant cells. In 2005, an adenovirus with E1B-55K gene deletion (H101) was approved in China as the world's first oncolytic virus for head and neck cancer in combination with chemotherapy. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response.To evaluate the efficacy and safety of intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating pancreatic carcinomas and to research new treatment approach,we constructed an orthotopic animal model of pancreatic carcinoma through cancer cell injection, which was validated by anatomy and histology. Then, we proceeded a comparative study of the efficiency and reliability between ethanol and oncolytic virus on treating pancreatic cancer based on this model. We found that this kind of virus is effective on inhibiting the pancreatic cancer, in spite of its lower effectiveness than ethanol. The immune response induced by these two agent at exterior and interior of the tumor were different. More lymphocytes infiltration were observed in oncolytic virus group. This difference may affect the immune escape of the cancer tremendously. This conjecture were proved partly by the follow clinical trial. Meanwhile, we studied the distribution of this virus after intratumoral injection. The H101 was absent in all the other organs besides the pancreas, which means that the selectivity of the H101 was tremendous. Based on these results, we studied the modality of the oncolytic virus treatment on pancreatic cancer in PART III. We found that the therapeutic effect of single track injection was similar to multipoint injection. What's more, intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine showed a more significant effect than intravenous virus and gemcitabine. These results may suggest the necessity of EUS-guided intratumoral injection in the therapy strategy of pancreatic cancer.Based on the results above, to evaluate the efficacy and tolerability of EUS-guided intratumoral injection of E1B gene-deleted adenovirus (H101) combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas, we carried the study of PART IV. Methods Forty-one patients with advanced adenocarcinoma of the pancreas enrolled in this study,who were allocated to two group randomly. Each one in virus group underwent two sessions of H101 intratumoral injection in combination with gemcitabine (i.v., 1000mg/m2, d3,10,17) at least. The control group undergone the chemotherapy of gemcitabine. The clinical indices, adverse effects and complications at one and four weeks after treatment were recorded respectively. The tumor size and the summation of the long diameter were calculated for efficacy assessment. The pain score and KPS were estimated before and one month after injection. Results All patients completed two cycles of treatment. Major adverse effects associated with H101 injection were fever and diarrhea. In virus group, among all the nineteen patients, 5 (26.3%) had partial response, 6 (31.6%) had progressive disease, 8 (42.1%) had stable disease, and none had complete response. The total effective power was 26.3%. While that were PR4.5%(1/22),PD45.5%(10/22),SD50.0%(11/22),CR0 in control group. The total effective power was 4.5% in control group which was significantly different to that in virus group. The CA199 level of virus group was decreased deeper than control group(P=0.032). While CEA was similar(P=0.513). The pain score in virus group were decreased after 2 sessions with a significant statistical difference (3.1±1.7 vs 3.9±1.6, P=0.004). Meanwhile KPS had significant increase (68.4±12.1 vs 61.1±9.9, P=0.003). There were significant different between two groups on improvement rate of pain, aggratation of jaundice and improvement of KPS(P=0.000,0.017,0.003). The survival time and median survival time of virus group were 2.5 to 10 months and 9 months, respectively. Nine patients are still alive. While there were 3 to 10 months and 6 months in control group. The survival rate were significantly different(P=0.004). Conclusion EUS-guided E1B gene-deleted adenovirus intratumral injection in unresectable pancreatic carcinomas is efficient, feasible and well tolerable in combination with intravenous gemcitabine, which can improve the living quality and cut down the pain score of patients.Our study showed the efficiency and reliability of intratumoral injection of oncolytic adenovirus combined with intravenous gemcitabine in treating unresectable pancreatic carcinomas based on the results from animal experiment and clinic trail. The oncolytic virus was predominant in pain release and other symptom reduction. The virus may play a more important role in pancreatic cancer therapy in future.
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