内镜超声引导下胰腺癌组织间放射治疗的初步研究
摘要
第一部分
内镜超声引导下:胰腺组织间放射治疗的可行性研究
目的
手术中腹腔镜下组织间放射治疗用于缓解局部进展期胰腺癌(locally advanced pancreatic cancer,LAPC)已被证明有一定疗效。本研究通过动物实验进行胰腺内镜超声引导下组织间放射治疗(EUS-guided interstitial brachytherapy,EUS-IBT),目的在于论证这种治疗方法的实用性和安全性。
方法
去除GIP内镜超声Hancke/Vilmann穿刺针(22-gauge,由德国Medi-Globe公司生产)的针尖,前端焊接2.5cm长18G针尖,针前端具有0.85mm腔道。将放射性粒子置于这种自制粒子植入针的前端针腔内,粒子放入后针前端用骨腊封闭针尖。将穿刺针安置于超声内镜腔道内,在EUS下观察要穿刺的部位,用彩色血流图排除进针路径有血管,选择合适的位点进针,在内镜超声影像持续的监视下推送穿刺针穿刺通过胃壁进入胰腺目标植入点。推进穿刺针针芯,放射性粒子被推出针道并植入到特定的组织内。此时拔出穿刺针,粒子被留植于胰腺组织内。在针内装入粒子,然后重复前面的过程,直到将24粒子全部根据计划植入到6只猪的胰腺内的特定位置。术后观察14天实验动物的表现后,处死动物,取出胰腺观察组织对EUS-IBT的反应。
PART 1Basic Feasibility Study EUS - guided interstitial brachytherapy of the pancreasBackgroundIntraoperative interstitial brachytherapy has been effective when utilized at laparotomy to improve local control in locally advanced pancreatic cancer. Our aim in this study was to investigate the feasibility and safety of EUS - guided brachytherapy of the pancreas in a porcine model.MethodsA modified 18 - gauge needle with radioactive seeds was inserted into the pancreas under EUS guidance. The radioactive seeds were implanted into the tissue by the needle. After 14 days of clinical observation, the animals were killed and the tissue response to brachytherapy was examined.Results All the seeds were implanted successfully and no migration occurred. Localized tissue necrosis and fibrosis was achieved in pancreas, without significant complication. One pig had mild hyperlipasemia. Biochemical parameters were normal in the remaining pigs.ConclusionsEUS - guided implantation of radioactive seed is a safe, simple and minimally invasive technique for interstitial brachytherapy.
PART 2Clinical Pilot Study:Endoscopic Ultrasound - Guided Interstitial Brachytherapy of Unresectable Pancreatic CancerBackground and Study AimsIntraoperative interstitial brachytherapy has been found to be effective when used during laparotomy to improve local control in patients with locally advanced pancreatic cancer. In this study, we report the results of using endoscopic ultrasound - ( EUS - ) guided interstitial brachytherapy in patients with advanced pancreatic cancer, with respect to tumor response, clinical response, safety, and complications.Patients and MethodsFifteen patients (eight men, seven women;median age 61 years) with unresectable pancreatic adenocarcinoma were enrolled into the study, eight patients with stage III disease and seven patients with stage IV disease. A mean number of 22 radioactive seeds per patient were implanted into the tumors by EUS -guided needle puncture. The mean total implanted activity was 19. 6 mCi, the minimum peripheral dose was 14 000 cGy, and the mean volume of implants was 52 cm3. Patients were followed - up by examination and by imaging tests every 2 3 months;clinical end points included the Karnofsky performance status and pain responses, tumor response ( assessed by computed tomography and/or EUS) , and survival.ResultsDuring a median follow - up period of 10.6 months, the objective tumor re-
sponse was classified as " partial" in 27 % of patients ( with a mean duration of partial response of 4.5 months) , " minimal" in 20 % patients, and indicative of " stable disease" in 33 % of patients. Clinical benefit was shown in 30 % of patients , mostly due to reduction in pain, but this lasted for a limited time. Local complications ( pancreatitis and pseudocyst formation) occurred in three patients;grade III hematologic toxicity occurred in five patients without serious clinical sequelae.ConclusionsEUS - guided intraoperative interstitial brachytherapy had a moderate local tumor effect and showed some clinical benefit in 30 % of the patients in this study. Combination of this form of treatment with external radiation and/or chemotherapy should be tested in future trials.
内镜超声引导下:胰腺组织间放射治疗的可行性研究
目的
手术中腹腔镜下组织间放射治疗用于缓解局部进展期胰腺癌(locally advanced pancreatic cancer,LAPC)已被证明有一定疗效。本研究通过动物实验进行胰腺内镜超声引导下组织间放射治疗(EUS-guided interstitial brachytherapy,EUS-IBT),目的在于论证这种治疗方法的实用性和安全性。
方法
去除GIP内镜超声Hancke/Vilmann穿刺针(22-gauge,由德国Medi-Globe公司生产)的针尖,前端焊接2.5cm长18G针尖,针前端具有0.85mm腔道。将放射性粒子置于这种自制粒子植入针的前端针腔内,粒子放入后针前端用骨腊封闭针尖。将穿刺针安置于超声内镜腔道内,在EUS下观察要穿刺的部位,用彩色血流图排除进针路径有血管,选择合适的位点进针,在内镜超声影像持续的监视下推送穿刺针穿刺通过胃壁进入胰腺目标植入点。推进穿刺针针芯,放射性粒子被推出针道并植入到特定的组织内。此时拔出穿刺针,粒子被留植于胰腺组织内。在针内装入粒子,然后重复前面的过程,直到将24粒子全部根据计划植入到6只猪的胰腺内的特定位置。术后观察14天实验动物的表现后,处死动物,取出胰腺观察组织对EUS-IBT的反应。
PART 1Basic Feasibility Study EUS - guided interstitial brachytherapy of the pancreasBackgroundIntraoperative interstitial brachytherapy has been effective when utilized at laparotomy to improve local control in locally advanced pancreatic cancer. Our aim in this study was to investigate the feasibility and safety of EUS - guided brachytherapy of the pancreas in a porcine model.MethodsA modified 18 - gauge needle with radioactive seeds was inserted into the pancreas under EUS guidance. The radioactive seeds were implanted into the tissue by the needle. After 14 days of clinical observation, the animals were killed and the tissue response to brachytherapy was examined.Results All the seeds were implanted successfully and no migration occurred. Localized tissue necrosis and fibrosis was achieved in pancreas, without significant complication. One pig had mild hyperlipasemia. Biochemical parameters were normal in the remaining pigs.ConclusionsEUS - guided implantation of radioactive seed is a safe, simple and minimally invasive technique for interstitial brachytherapy.
PART 2Clinical Pilot Study:Endoscopic Ultrasound - Guided Interstitial Brachytherapy of Unresectable Pancreatic CancerBackground and Study AimsIntraoperative interstitial brachytherapy has been found to be effective when used during laparotomy to improve local control in patients with locally advanced pancreatic cancer. In this study, we report the results of using endoscopic ultrasound - ( EUS - ) guided interstitial brachytherapy in patients with advanced pancreatic cancer, with respect to tumor response, clinical response, safety, and complications.Patients and MethodsFifteen patients (eight men, seven women;median age 61 years) with unresectable pancreatic adenocarcinoma were enrolled into the study, eight patients with stage III disease and seven patients with stage IV disease. A mean number of 22 radioactive seeds per patient were implanted into the tumors by EUS -guided needle puncture. The mean total implanted activity was 19. 6 mCi, the minimum peripheral dose was 14 000 cGy, and the mean volume of implants was 52 cm3. Patients were followed - up by examination and by imaging tests every 2 3 months;clinical end points included the Karnofsky performance status and pain responses, tumor response ( assessed by computed tomography and/or EUS) , and survival.ResultsDuring a median follow - up period of 10.6 months, the objective tumor re-
sponse was classified as " partial" in 27 % of patients ( with a mean duration of partial response of 4.5 months) , " minimal" in 20 % patients, and indicative of " stable disease" in 33 % of patients. Clinical benefit was shown in 30 % of patients , mostly due to reduction in pain, but this lasted for a limited time. Local complications ( pancreatitis and pseudocyst formation) occurred in three patients;grade III hematologic toxicity occurred in five patients without serious clinical sequelae.ConclusionsEUS - guided intraoperative interstitial brachytherapy had a moderate local tumor effect and showed some clinical benefit in 30 % of the patients in this study. Combination of this form of treatment with external radiation and/or chemotherapy should be tested in future trials.
引文
1. Takacsi - Nagy Z, Varga J, Poller I, Fodor J, Polgar C, Petranyi A, et al. S uccessful treatment of a T1 cancer of the pancreatic head with high dose rate brachytherapy and external radiotherapy. Hepatogastroenterology. 2002 May - Jun;49(45) :844-846.
2. Bodner WR, Hilaris BS, Mastoras DA. Radiation therapy in pancreatic cancer;current practice and future trends. J Clin Gastroenterol. 2000 Apr;30(3) :230-233.
3. Sakurai H, Mitsuhashi N, Harashima K, Muramatsu H, Ishikawa H, Kitamoto Y, et al. CT - fluoroscopy guided interstitial brachytherapy with image- based treatment planning for unresectable locally recurrent rectal carcinoma. Brachytherapy. 2004;3(4) :222 -230.
4. Hannoun -Levi JM, Houvenaeghel G, Ellis S, Teissier E, Alzieu C, Lalle- ment M, et al. Partial breast irradiation as second conservative treatment for local breast cancer recurrence. Int J Radiat Oncol Biol Phys. 2004 Dec 1;60(5) :1385-1392.
5. Merrick GS, Butler WM, Wallner KE, Galbreath RW, Adamovich E. Related Articles, Permanent interstitial brachytherapy for clinically organ - confined high - grade prostate cancer with a pretreatment PSA < 20 ng/mL. Am J Clin Oncol. 2004 Dec;27(6) :611 -615.
6. Viola A, Major T, Julow J. The importance of postoperative CT image fusion verification of stereotactic interstitial irradiation for brain tumors. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60( 1) :322 - 328.
7. Takacsi -Nagy Z, Polgar C, Oberna F, Somogyi A, Major T, Remenar E, et al. Interstitial High - Dose - Rate Brachytherapy in the Treatment of Base of Tongue Carcinoma. Strahlenther Onkol. 2004 Dec;180(12) :768 -775.
8. Soetikno RM, Chang K. Endoscopic ultrasound - guided diagnosis and therapy in pancreatic disease. Gastrointest Endosc Clin N Am 1998 Jan;8(1);237-247
9. Chang KJ, Nguyen PT, Thompson JA. 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 Mar 15;88(6) :1325 -1335
10. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM, 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 Feb;9(2) :555 -561.
11. Chan HH, Nishioka NS, Mino M, Lauwers GY, Puricelli WP, Colher KN, Brugge WR. EUS - guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc. 2004 Jan;59(1) :95-99.
12. Goldberg SN, Mallery S, Gazelle GS, Brugge WR. EUS -guided radiofre- quency ablation in the pancreas: results in a porcine model. Gastrointest Endosc. 1999 Sep;50(3) :392 -401.
13. Bhutani MS. Endoscopic ultrasonography - - new developments and interesting trends. Endoscopy. 2004 Nov;36(11) :950-6.
14. Sun S, Qingjie L, Qiyong G, Mengchun W, Bo Q, Hong X. EUS -guided interstitial brachytherapy of the pancreas;a feasibility study. Gastrointest Endosc. 2005 Nov;62(5) :775 -9.
15. Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg. 2002 Sep;236(3) :355 -66;discussion 366 -8.
16. Bodner WR, Hilaris BS. Brachytherapy and pancreatic cancer. Semin Surg Oncol. 1997 May-Jun;13(3):204-207.
17. Peretz T, Nori D, Hilaris B, Manolatos S, Linares L, Harrison L, et al. Treatment of primary unresectable carcinoma of the pancreas with 1-125 implantation. Int J Radiat Oncol Biol Phys. 1989 Nov;17(5) :931 -5.
18. Order SE, Siegel JA, Principato R, Zeiger LE, Johnson E, Lang P, et al. Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer;a phase I study. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5) :1117 -26.
2. Bodner WR, Hilaris BS, Mastoras DA. Radiation therapy in pancreatic cancer;current practice and future trends. J Clin Gastroenterol. 2000 Apr;30(3) :230-233.
3. Sakurai H, Mitsuhashi N, Harashima K, Muramatsu H, Ishikawa H, Kitamoto Y, et al. CT - fluoroscopy guided interstitial brachytherapy with image- based treatment planning for unresectable locally recurrent rectal carcinoma. Brachytherapy. 2004;3(4) :222 -230.
4. Hannoun -Levi JM, Houvenaeghel G, Ellis S, Teissier E, Alzieu C, Lalle- ment M, et al. Partial breast irradiation as second conservative treatment for local breast cancer recurrence. Int J Radiat Oncol Biol Phys. 2004 Dec 1;60(5) :1385-1392.
5. Merrick GS, Butler WM, Wallner KE, Galbreath RW, Adamovich E. Related Articles, Permanent interstitial brachytherapy for clinically organ - confined high - grade prostate cancer with a pretreatment PSA < 20 ng/mL. Am J Clin Oncol. 2004 Dec;27(6) :611 -615.
6. Viola A, Major T, Julow J. The importance of postoperative CT image fusion verification of stereotactic interstitial irradiation for brain tumors. Int J Radiat Oncol Biol Phys. 2004 Sep 1;60( 1) :322 - 328.
7. Takacsi -Nagy Z, Polgar C, Oberna F, Somogyi A, Major T, Remenar E, et al. Interstitial High - Dose - Rate Brachytherapy in the Treatment of Base of Tongue Carcinoma. Strahlenther Onkol. 2004 Dec;180(12) :768 -775.
8. Soetikno RM, Chang K. Endoscopic ultrasound - guided diagnosis and therapy in pancreatic disease. Gastrointest Endosc Clin N Am 1998 Jan;8(1);237-247
9. Chang KJ, Nguyen PT, Thompson JA. 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 Mar 15;88(6) :1325 -1335
10. Hecht JR, Bedford R, Abbruzzese JL, Lahoti S, Reid TR, Soetikno RM, 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 Feb;9(2) :555 -561.
11. Chan HH, Nishioka NS, Mino M, Lauwers GY, Puricelli WP, Colher KN, Brugge WR. EUS - guided photodynamic therapy of the pancreas: a pilot study. Gastrointest Endosc. 2004 Jan;59(1) :95-99.
12. Goldberg SN, Mallery S, Gazelle GS, Brugge WR. EUS -guided radiofre- quency ablation in the pancreas: results in a porcine model. Gastrointest Endosc. 1999 Sep;50(3) :392 -401.
13. Bhutani MS. Endoscopic ultrasonography - - new developments and interesting trends. Endoscopy. 2004 Nov;36(11) :950-6.
14. Sun S, Qingjie L, Qiyong G, Mengchun W, Bo Q, Hong X. EUS -guided interstitial brachytherapy of the pancreas;a feasibility study. Gastrointest Endosc. 2005 Nov;62(5) :775 -9.
15. Yeo CJ, Cameron JL, Lillemoe KD, Sohn TA, Campbell KA, Sauter PK, et al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg. 2002 Sep;236(3) :355 -66;discussion 366 -8.
16. Bodner WR, Hilaris BS. Brachytherapy and pancreatic cancer. Semin Surg Oncol. 1997 May-Jun;13(3):204-207.
17. Peretz T, Nori D, Hilaris B, Manolatos S, Linares L, Harrison L, et al. Treatment of primary unresectable carcinoma of the pancreas with 1-125 implantation. Int J Radiat Oncol Biol Phys. 1989 Nov;17(5) :931 -5.
18. Order SE, Siegel JA, Principato R, Zeiger LE, Johnson E, Lang P, et al. Selective tumor irradiation by infusional brachytherapy in nonresectable pancreatic cancer;a phase I study. Int J Radiat Oncol Biol Phys. 1996 Dec 1;36(5) :1117 -26.