【作者】 江月萍；

【导师】 金震东； 李兆申； 李淑德；

【作者基本信息】 第二军医大学 ， 内科学， 2008， 博士

【摘要】 研究背景胰腺癌因其解剖学特点,临床上很难早期发现,绝大多数患者确诊时已属晚期、丧失了手术切除的机会。据世界范围的综合资料显示,胰腺癌的5年生存率仅为5%,是预后最差的恶性肿瘤之一。在西方国家,胰腺癌在所有癌症发病率中占3%,而死亡原因居第五位。诊断胰腺癌时,接近1/2病人存在转移,其中位生存期不超过6个月,接近1/3病人诊断时已属于局部进展期,其中位生存期仅为6-9个月。只有不足15%病人能够手术切除。因此积极探索胰腺癌非手术切除的治疗方法具有重要的临床意义。对大多数手术不能切除的局部晚期胰腺癌,目前主要的治疗方法有各种体内、体外放疗和以吉西他宾为主的化疗。通过化疗可减轻症状,提高生活质量和延长生存期。自1997年始,在胰腺癌的治疗方面,吉西他宾（Gemcitabine,GEM）显示出了比5-Fu单药治疗更好的临床疗效,已成为胰腺癌的标准化疗药物。有报道,吉西他宾联合外放疗治疗胰腺癌其中位生存期明显延长。但是由于外照射治疗对胰腺周围组织的放射性损伤不易控制,限制了其应用。放射性粒子组织间照射是一种新兴的恶性肿瘤治疗手段,它主要是应用计算机立体定位治疗计划系统（treatment plan system,TPS）设计方案,在现代影像设备引导下将放射性粒子按肿瘤大小、形态植入肿瘤内或受肿瘤浸润侵犯的组织中,通过微型放射源发出持续、短距离的放射线,使肿瘤组织遭受最大程度的杀伤,而正常组织不被损伤或仅有微小损伤,最终达到治疗目的。已有术中或CT引导下放射性粒子组织间种植治疗胰腺癌报道,但大都没有进行随机对照实验。目的随着近年来内镜超声检查术（Endoscopic ultrasonography,EUS）技术的普及和发展,治疗性内镜超声检查术越来越受到重视,从而使通过EUS在实体肿瘤内植入放射性粒子成为可能。鉴于EUS引导下的穿刺技术具有定位准确、创伤小、穿刺距离短等优点,且前期研究已经证实了EUS引导下粒子植入术在动物试验中的安全性,因此本研究拟采用EUS引导下的放射性¹²⁵I粒子植入术,进行前瞻性随机对照研究,比较¹²⁵I粒子联合吉西他宾化疗和单纯吉西他宾化疗治疗中晚期胰腺癌的效果,评价其疗效和安全性,从而探讨该新技术用于胰腺癌治疗的可行性及临床价值。方法41例不能手术切除的中晚期胰腺癌患者随机分为二组,治疗组为放射性¹²⁵I粒子植入联合吉西他宾化疗,对照组行吉西他宾全身静脉化疗。其中联合组21例,单纯化疗组20例。所有病例于首次粒子植入或化疗后进入随访。疗效评估主要指标包括临床受益疗效（clinical benefit response,CBR）,客观肿瘤疗效（objective tumorresponse）,安全性和生活质量评估。次要指标包括肿瘤标志物疗效、无进展生存期（Progression-free survival,PFS）、中位生存期和1年生存率等。结果两组患者入组治疗的初始因素是均衡的。¹²⁵I粒子联合组平均化疗疗程为1.8次（范围1-6次）,总平均剂量为6g,对照组为2.4次（范围1-6次）,总平均剂量为8g;放射性¹²⁵I粒子平均种植次数1.7次（1-4次）,平均种植颗数26颗（10-50颗）,平均总活度为17.2mci（7.0-35.4 mci）。¹²⁵I粒子联合组平均随访时间为5.5月（2-16月）,对照组为5.2月（2-14月）。（一）疗效评价1.临床受益疗效:放射性¹²⁵I粒子联合吉西他宾治疗组的临床受益疗效为57.1%,单纯吉西他宾化疗组为25%,¹²⁵I粒子联合吉西他宾治疗组在临床受益疗效方面明显优于单纯吉西他宾化疗组（P=0.04）。¹²⁵I粒子治疗组疼痛缓解出现的平均时间为4天（n=12）,吉西他宾化疗对照组为4周（n=5）。临床受益疗效持续的中位时间¹²⁵I粒子治疗组为21周,化疗组为15周。2.¹²⁵I粒子治疗组达到完全缓解0例,部分缓解4例,疾病稳定9例,进展恶化8例,肿瘤治疗反应有效率为61.9%。GEM对照组达到完全缓解0例,部分缓解1例,疾病稳定4例,进展恶化15例,肿瘤治疗反应有效率为25%,¹²⁵I粒子治疗组在肿瘤控制率方面明显优于GEM化疗组（P=0.03）。3.无进展生存期（PFS）:¹²⁵I粒子治疗组PFS中位时间为4个月（95%CI,2.51±5.49）,GEM治疗组为3个月（95%CI,1.90±4.11）,两组PFS无统计学意义（P=0.16）。但达到CBR阳性改善的PFS时间较CBR阴性明显延长（P＜0.05）。4.生存期（OS）:¹²⁵I粒子组中位生存期为11个月(（95%CI,1.84±20.17）,其中7例死亡（33.71%）,最长1例生存期达到16个月,目前超过8个月生存期有5例（23.61%）。GEM组中位生存期为6个月（95%CI,3.39±8.61）,其中10例死亡（33.71%）,最长1例生存期达到14个月,目前超过8个月生存期有3例（15%）,两组生存期无统计学意义（P=0.65）。5:CA19-9:¹²⁵I粒子治疗组有4例CA19-9术后4月下降50%以上,化疗组有1例患者CA19-9术后4月下降50%以上。（二）安全性评价根据NCI-CTC制定的化疗毒性分级标准和RTOG制定的肿瘤放疗毒性分级标准,两组毒性分析经CMH检验,无统计学差异。毒性分级2级以上占4.8%。放射性¹²⁵I粒子所有患者均未出现胰瘘、放射性肠炎、消化道穿孔、急性胰腺炎、感染等并发症。半数病例术后24h出现低热伴血中性粒细胞升高。5例病人出现粒子移位丢失,发生率为24%,粒子移位部位为肝脏及肠腔。未出现肝功能异常及腹泻表现。结论超声内镜引导下的放射性¹²⁵I粒子组织间放疗联合吉西他宾化疗治疗不能手术切除的胰腺癌,在临床受益疗效（CBR）及客观肿瘤疗效（RR）方面较单纯吉西他宾化疗有明显优势。¹²⁵I粒子治疗组在疼痛、KPS体力评分及体重方面有明显改善,其临床受益率为57.11%,GEM组为25%（P=0.04）。¹²⁵I粒子治疗组的肿瘤控制率为61.90%,GEM组为25%（P=0.03）。¹²⁵I粒子治疗组中位生存期为11个月,GEM组为6个月。¹²⁵I粒子治疗组PFS中位时间为4个月,GEM组PFS为3个月。以上结果均表明粒子植入联合化疗在本研究中取得了满意的近期疗效。总结本研究采用EUS引导下的放射性¹²⁵I粒子植入术,联合吉西他宾化疗对中晚期胰腺癌治疗进行了前瞻性随机对照研究,认为超声内镜引导下¹²⁵I粒子组织间植入治疗局部晚期胰腺癌这一新型介入技术,副作用小,并发症少,是安全可行的。该技术联合吉西他宾化疗治疗不能手术切除的胰腺癌,在缓解疼痛,肿瘤控制率及提高生活质量方面较同期单一吉西他宾化疗取得了更为满意的近期疗效。特别是在改善疼痛程度方面尤为明显,疼痛改善起效快,维持时间长。肿瘤进展时间及生存期方面也有一定程度的改善。总之,晚期胰腺癌的姑息治疗是以缓解病情,提高生活质量和延长生存期为主要目的。本研究采用超声内镜引导下¹²⁵I粒子组织间植入联合化疗取得了很好的疗效。有望为中晚期胰腺癌患者提供一条新的治疗途径。更多还原

【Abstract】 BackgroundPancreatic carcinoma 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.The prognosis of patients with pancreatic cancer is extremely poor, with overall 5-year survival rate of approximately 5%.In west,the incidence of pancreatic cancer is 3%,pancreatic cancer has become the fifth cause of death.Nearly one half of the patients have metastasis when the diagnosis was defined,with the median duration of less than 6 month.About one-third cases are locally advanced cancer with the median range of 6 to 9 month.Only less than 15%cancers could be resected by surgery.Therefore, exploring the novel conservative method of treating pancreatic carcinoma is worth momentous clinical significance.At present,the main therapy for most cases of locally advanced cancers involves kinds of radiotherapy in vivo and in vitro,and the chemotherapy(Gemcitabine is widely used).Chemotherapy could relieve the symptoms, promote the quality of life and improve the survival.Since 1997,chemotherapy with the drug gemcitabine showed better curative effect than 5-Fu and has been a standard treatment option for patients with advanced pancreatic cancer that cannot be removed by surgery.It was reported that chemotherapy of gemcitabine with radiotherapy could significantly improve the median duration of the patients.However,the radiation damage of external radiation to the surrounding tissues of pancreas was hard to control,which limited its application.Objectives With the development of endoscopic ultrasonography(EUS),remedial EUS has become more and more important and make EUS-guided implantation of radioactive particle possible.Since EUS guided punctuation possesses many advantages, such as accurate localization,less trauma,short punctuation distance,and the safety has been confirmed in previous animal trials,we select EUS-guided Iodine-125 seed implantation combined with chemotherapy of gemcitabine,comparing simple chemotherapy of gemcitabine,and assessed the curative effect and safety in treating the unresectable pancreatic carcinoma in order to approach the feasibility and clinical worth of EUS-guided Iodine- 125 seed implantation.Methods:Forty-one patients with unresectable pancreatic carcinoma were randomly divided into two groups,one group(Group A) included 21 cases which were accepted EUS-guided Iodine-125 seed implantation combined with chemotherapy of gemcitabine, the rest 20 cases(Group B) were treated with chemotherapy of gemcitabine.All patients were involved in follow up after the first therapy.The principal indexes of assessing the curative effect included clinical benefit response(CBR),objective tumor response,safety and the evaluation of quality of life.The changes of tumor markers,progression-free survival(PFS),median duration and 5-year survival rate were secondary indexes.ResultsThe general conditions of the patients of both two groups were comparable.For Group A,the times implanted ranged from 1 to 6 times,with a median implant times of 1.8 times.The total implanted volume of Group A is 6g.For Group B,the times implanted ranged from 1 to 6 times,with a median implant times of 2.4 times.The total implanted volume of Group B is 8g.A median of 26 seeds(range,10-50) was implanted per patient, with an average activity per seed of 17.2 mCi(7.0-35.4mci) and a median implanted times of 1.7 times(range,1-4 times).The median follow-up of Group A and Group B was 5.5 months(range:2-16 months) and 5.2 months(range:2-14 months),respectively.1.Curative effects(1) Clinical benefit response(CBR):CBR of Group A and Group B were 57.10% and 25%respectively,and there were significant difference between two groups(P=0.04). Patients of Group A experienced relief an average of 4d(n=12),while the patients of Group B experienced relief an average of 4w(n=5).The median CBR was 21w and 15w for Group A and B,respectively.(2) For Group A,0 cases of completely response,4 cases of partial response,9 cases of stable disease,8 cases of progressive disease,The objective tumor response rate were 61.9%and 25%for Group A and B.The objective tumor response of Group A was obviously better than Group B(P=0.028).(3) Progression-free survival(PFS):Median PFS of Group A was 4m(95% CI,2.51±5.49),while median PFS of Group B was 3m(95%CI,1.89±4.11).There were no significant difference between two groups(P=0.160).But the PFS of the patients with positive CBR was longer than the PFS of those with negative CBR(P＜0.05).(4) Overall survival(OS):The median OS of Group A was 11m(95%CI, 1.835±20.17),including 7 cases died(33.71%),the maximum OS was 16m,the OS of 5 cases(23.60%) have exceed 8m so far.The median OS of Group B was 6m(95% CI,3.39±8.61),including 10 cases died(33.71%),the maximum OS was 14m,the OS of 3 cases(15.00%) have exceed 8m so far.The OS of two groups were no significant difference(P=0.65).(5) CA19-9:The value of CA19-9 of 4 patients of Group A decreased over 50%, while the value of CA19-9 of merely 1 patient of Group A decreased over 50%.2.Safety assessmentThe number of toxic and adverse effects that occurred in the 41 study patients, classified according to the the National Cancer Institute Common Toxicity Criteria (NCI-CTC) and the criteria of Radiation Therapy Oncology Group(RTOG).The toxicity was analyzed by CMH method,and there was no significant difference between two groups.Toxicity exceeded Grade 2 was about 4.8%.All involved patients with iodine-125 seed implantation did not complicated with pancreatic fistula,radiation enterocolitis, perforation of alimentary tract,acute pancreatitis and infection,etc.Fifty percent of patients of Group A appeared low-grade fever with increasing of neutrophil,5 cases(24%, 5/21) had the shifting and loss of the iodine-125 seed.The iodine- 125 seed immigrated to liver and enteric cavity,but without abnormal hepatic function and the diarrhea.Conclusions EUS-gnided Iodine-125 seed implantation was a novel technique for treating the locally advanced stage of pancreatic carcinoma,with obviously more advantages on CBR and RR.The patients of Group A showed great improvement of pain relieving,KPS physical score and body weight.The CBR of Group A was 57.11%,while the CBR of Group B was 25%(P=0.04).The objective tumor response rate were 61.90% and 25%for Group A and B(P=0.03).The median duration and Median PMS of Group A were 11m and 4m respectively,while those of Group B were 6m and 3m.Above results suggested that EUS-guided iodine-125 implantation combined with chemotherapy of gemcitabine showed better effects.更多还原