超声内镜引导下放射性~（125）I粒子组织间植入联合化疗治疗中晚期胰腺癌：前瞻性随机对照研究
|
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~(125)I粒子植入术,进行前瞻性随机对照研究,比较~(125)I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~(125)I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。~(125)I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~(125)I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)。~(125)I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~(125)I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%,~(125)I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)。~(125)I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~(125)I粒子治疗组为21周,化疗组为15周。
2.~(125)I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%,~(125)I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):~(125)I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):~(125)I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:~(125)I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~(125)I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~(125)I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。~(125)I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)。~(125)I粒子治疗组的肿瘤控制率为61.90%,GEM组为25%(P=0.03)。~(125)I粒子治疗组中位生存期为11个月,GEM组为6个月。~(125)I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~(125)I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~(125)I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~(125)I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。
Background
Pancreatic 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.
Results
The 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 assessment
The 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.
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~(125)I粒子植入术,进行前瞻性随机对照研究,比较~(125)I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~(125)I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。~(125)I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~(125)I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)。~(125)I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~(125)I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%,~(125)I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)。~(125)I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~(125)I粒子治疗组为21周,化疗组为15周。
2.~(125)I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%,~(125)I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):~(125)I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):~(125)I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:~(125)I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~(125)I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~(125)I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。~(125)I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)。~(125)I粒子治疗组的肿瘤控制率为61.90%,GEM组为25%(P=0.03)。~(125)I粒子治疗组中位生存期为11个月,GEM组为6个月。~(125)I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~(125)I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~(125)I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~(125)I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。
Background
Pancreatic 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.
Results
The 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 assessment
The 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.
引文
1. Cooperman AM. Pancreatic cancer : the bigger picture. Surg Clin North Am,2001 , 81 : 557-574.
2. Rosewicz S, Wiedenman B .Pancreatic carcinoma. Lancet, 1997 349:485-489
3. Evans DB, Abbruzzese JL, Rich TA .Cancer of the pancreas, Principles andPractice of Oncology. Cancer, 1997, pp 1054-1087
4. Howard S, Daniel G, Aimery G, et al. Consensus report of the internationalsociety of astro intestinal oncology on therapeutic progress in advanced pancreatic cancer,cancer. 2006, 107:676-685
5. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinicalbenefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:A randomized trial. J Clin Oncol. 1997, 15:2403-2413
6. CHUNG PIN LI, YEE CHAO, KWAN-HWA CHI, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study.Int. J. Radiation Oncology Biol. Phys. 2003, 57 (1) 98-104
7．王俊杰，黄毅，冉维强等。放射性粒子组织间种植治疗肿瘤近期疗效．中国微创外科杂志，2003，2(3)：148
8．张福君，吴沛宏，赵明等．CT导引下~(125)I粒子植入治疗胰腺癌．中华医学杂志，2006，86(4)：223—227
9. Sun S, Lu Q, Guo Q, et al. EUS-guided interstitial brachytherapy of the pancreas: a feasibility study. Gastrointest Endosc, 2005,62: 775-779.
10. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004.CA Cancer J Clin. 2004;54:8-29.
11. Van Cutsem E, Aerts R, Haustermans K, Topal B, Van Steenbergen W, Verslype C. Systemic treatment of pancreatic cancer. Eur J Gastroent Hepatol. 2004; 16:265-274
12. Willett CG,Safran H ,Abrams RA ,et al. Clinical research in pancreatic cancer : the Radiation Therapy Oncology Group trials. Int J Radiat OncolBiol Phys ,2003 ,56:31237.
13. Moore MJ . pancreatic cancer : what the oncologist can offer for palliation. Can J Gastroenterol ,2002 ,16 :1212124.
14．申文江，王绿化，夏延毅，主编．放射治疗学新技术进展[M]。北京：北京科学技术出版社，2003．155．
15. Peretz T, Nori D, Nilaris B, et al. Treatment of p rimaryunresectable carcinoma of the pancreaswith 12125 imp lantation. Int J Radiat Oncol Biol Phys, 1989,17: 9312935.
16. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399— 403
17. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.mce.org.uk/article.asp?a = 16790 (accessed March 2005).
18. Bums HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997; 15:2403-13.
1. Von Hoff DD ,Goodwin AL,Garcia L. Advance in the treatment of patient with pancreatic cancer: improvement in symptoms and survival time. The San Antonio Drug Development Team[J] .Br J Cancer ,1998,78 [ Suppl 3 ] :92131
2. Stephen CD. Gemcitabine :a new approach to treating pancreatic cancer [J] Oncol Nur Forum, 1998 ,25(1) :872931
3. Carmichael J . Clinical response benefitin patients with advanced pancreatic cancer. Role of gemcitabine [J ]. Digestion ,1997,58 (6): 5032-5071
4. Burns HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997;15:2403-13.
5. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.nice.org.uk/article.asp?a = 16790 (accessed March 2005).
6. Louvet, R. Labianca, PH,. Lledo, G,et al. Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial. JOURNAL OF CLINICAL ONCOLOGY,2005,23:3509-3516
7. Peretz T, Nori D, Nilaris B, et al. Treatment of p rimaryunresectable carcinoma of the pancreaswith 12125 imp lantation. Int J Radiat Oncol Biol Phys, 1989,17:9312935.
8.张福君，吴沛宏，赵明，等．CT导引下~(125)I粒子植入治疗胰腺癌，中华医学杂志,2006,86(4)：223-227
9. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399—403
1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004.CA Cancer J Clin. 2004;54:8-29.
2. Van Cutsem E, Aerts R, Haustermans K, Topal B, Van Steenbergen W, Verslype C. Systemic treatment of pancreatic cancer. Eur J Gastroent Hepatol. 2004; 16:265-274
3. Willett CG,Safran H ,Abrams RA ,et al. Clinical research in pancreatic cancer : the Radiation Therapy Oncology Group trials. Int J Radiat OncolBiol Phys ,2003 ,56:31237.
4. Moore MJ . pancreatic cancer : what the oncologist can offer for palliation. Can J Gastroenterol ,2002,16 :1212124.
5. MorrowM, Hilaris BS , Brennan MF , et al .Comparison of conventional surgicalresection ,radioactive implantation , and bypass procedures for exocrine carcinoma of the pancreas. Ann Surg, 1984,199:125.
6．王俊杰，白静，修典荣，等．放射性~(125)I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志2004；19：512．
7．张福君，吴沛宏，赵明，等.CT导引下~(125)I粒子植入治疗胰腺癌，中华医学杂志,2006,86(4)：223-227
8. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399— 403
9. PaoloM, Ralph D, Francesco C, et al. Interstitial brachytherapy forpa ncreatic cancer: report of seven cases treated with 125 I and a review of the literature . Int J Radiation Oncology Biol Phys, 1991,21:451 - 457.
10. Mohuiddin M, Rosato F , Barbot D , et al .Long2term results of combined modality treatment with 1251 implantation for carcinoma of the pancreas. Int J Radiat Oncol Biol Phys ,1992,23 :3032311.
11.Louvet, R. Labianca, PH,. Lledo, G,et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. Journal of Clinical Oncology,2005,23:3509-3516
1. Koprowski H, Herly M, Steplewski Z, et al. Specific in serum of patients with colon carcinoma. Science 1981 ;212 :53
2. Sperti C, Pasquali C, Guolo P, et al. Serum tumor markers and cystfluid analysis are useful for the diagnosis of pancreatic cystic tumors.Cancer 1996 ;78 :237
3. Kokhanenko Niu, Ignashov AM, Varga EV, et al. Role of the tumor markers CA19-9 and carcinoembryonic antigen (CEA) in diagnosis, treatment and prognosis of pancreatic cancer. Vopr Onkol 2001 ;47 :294
4．陈志南、刘民培。抗体分子与肿瘤。第1版．北京：人民军医出版社。2002；406
5. Sali F, Sch lo sser W, Falk enreck S et al. Prognostic value of CA 19- 9 serum course in pancreat ic cancer[J]. Hepato- Gastroenterology, 1998,45 : 253.
1．万崇华．生命质量测定与评价方法．昆明：云南大学出版社,1999，224-227。
2. World Health Orgnization. The First Ten Years of THE World Health Orgnization[M]. Geneva: World Health Orgnization ,1958
3. COX D R, FITZPATRICK R, FLETCHER A E, et al. Q uality - of- life ssessment: can we keep it simple ? J . R. Statist, Soc. A ,1992,155 :353.
4．洪明晃主编．科研设计测量评价．广州：中山大学出版社，1994：76
5．董宣，李天霖，王滨燕，等．生活质量评价——一种多维的健康评价方法．国外医学社会医学分册，1996，13(3)：118
6. Aaronson NK, Ahmedxai S. The European Organixation for Research and Treatment of Cencer QLQ - C30 : A Quality of life Instrument for use in International Conocal Trials in Oncology. Joureal of the National Cancer Institute, 1993 , 85(5) :365
7. 邱彩锋，赵继军．QLQ2C30的应用及计分方法．国外医学护理学分册,2005,24(11)：701-703
8．陈和年，方积乾，胡孟璇，等．生存质量研究．中华预防医学杂志，1993，27(3)：178
9. Aaronson NK, Cull A, Stein Kaasa, et al. The European Organixtion for Eesearch and Treatment of Cancer (EORTC) Modalar Approach to quality of life Aaaessment in oncology: An update. Int J ment Health, 1994,23 (2) :75
1. Peretz T, Nori D, Hilaris B, et al. Treatment of primary unresectable carcinoma of the pancreas with 1-125 implantation. Int J Radiation Oncology Biol Phys, 1989, 17: 931-935.
2. Lee W, Daly B, Morelli D, et al. Limited resection for lung cancer: improved local control with the implantation of Iodine-125 seeds. Int J Radiation Oncology Biol Phys, 2001, 51(s1): 354.
3. Lah JJ, Kuo JV, Chang KJ, et al. EUS-guided brachytherapy. Gastrointest Endosc, 2005,62: 805-808.
4. Sun S, Lu Q, Guo Q, et al. EUS-guided interstitial brachytherapy of the pancreas: a feasibility study. Gastrointest Endosc, 2005,62: 775-779.
5. Lebovics E, Mittelman A, Del Guercio LR, et al. Pancreaticobiliary fistula and obstructive jaundice complicating 1251 interstitial implants for pancreatic cancer: endoscopic diagnosis and management. Gastrointest Endosc, 1990,36: 610-611.
6．王俊杰，白静，修典荣，等。放射性125 I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志2004；19：512．
1.Blasko JC,Grimm PD,Sylsvester JE,et al.The role of external beam radiotherapy with I125/Pd103 brachytherapy for prostate carcinoma.Radiother Oncol 2000;57:273-278.
2.Lee W,Daly BD,DiPetrillo TA,et al.Limited resection for nonsmallcell lung cancer:observed local control with implantation of I125brachytherapy seeds.Ann Thorac Surg 2003;75:237-243
3.雷光焰,付改发,许建秦等。放射性125I粒子组织间永久植入治疗中晚期肺癌的研究。现代肿瘤医学 2005;13(1):77-78
4.王俊杰,白静,修典荣,等.放射性125I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志 2004;19:512.
5.周伟,洛小林,毛凯等。125I放射性粒子术中植入治疗晚期胰腺癌的疗效评价。中华放射肿瘤学杂志 2005;14(4):307-310
6.MorrowM,Hilaris BS,Brennan MF,et al.Comparison of conventional surgical resection,radioactive implantation,and bypass procedures for exocrine carcinoma of the pancreas.Ann Surg,1984;199:125.
7.Mohuiddin M,Rosato F,Barbot D,et al.Long2term results of combined modality treatment with125I implantation for carcinoma of the pancreas.Int J Radiat Oncol Biol Phys,1992;23:303-311.
8.王俊杰,白静,修典荣,等.放射性125I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志 2004;19:512.
9.Maier W,Henne K,Krebs A,et al.Endoscopic ultrasound-guided brachytherapy of head and neck tumors.A new procedure for controlled application.J Laryngol Otol 1999;113(1):41-48
10.Lah J J,Kuo JV,Chang KJ,et al.EUS-guided brachytherapy.Gastrointest Endosc 2005;62(5):805-808
11.Martinez-Monge R,Subtil JC,Lopez-Picazo JM.Transoesophageal endoscopic-ultrasonography-guided 125I permanent brachytherapy for unresectable mediastinal lymphadenopathy.Lancet Oncol.2006 Sep;7(9):781-3.
12.Sun S,lu Q,Guo Q,et al.EUS-guided interstitial brachytherapy of the pancrease:a feasibility study.Gastrointestinal.Endoscopy,2005;62:775-779
13.Sun S,Xu H,Xin Jun,et al.EUS-guided Interstitial brachytherapy of irresectable pancreatic cancer-results of a pilot trial.Endoscopy,2006;38:398-402
14.金震东,李兆申,刘岩等.超声内镜引导下定向植入放射性~(125)I粒子治疗胰腺癌的临床研究。中华消化内镜杂志,2006;23(1):15-17
15.Chang KJ.EUS-guided fine needle injection(FNI) and anti-tumor therapy. Eendoscooy 2006;38(S1):588-593
16.金震东,李兆申主编。消化超声内镜学。科学出版社,2006:10,第一版。
1.Gress FG,Hawes RH,Savides TJ,et al.Role of EUS in the preoperative staging of pancreatic cancer:a large single-center experience.Gastrointest Endosc,1999,50:786-91.
2.Krinsky ML,Binmoeller KF.EUS-guided investigational therapy for pancreatic cancer.Gastroimest Endosc,2000,52:S35-8.
3.Legmann P,Vignaux O,Dousset B,Baraza AJ,et al.Pancreatic tumors:comparison of dual-phase helical CT and endoscopic sonography.A JR Am J Roentgenol,1998,170:1315-22.
4.Harewood GC.Wiersema MJ.Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses.Am J Gastroenterol,2002.97:1386-1391.
5.Michael JL,Maurits JW.Pancreatic neoplasms.Gastrointest Endoscopy Clin N Am,2005,5:117-142.
6.Sedlack R,Affi A,Vazquez-Sequeiros E,et al.Utility of EUS in theevaluation of cystic pancreatic lesions.Gastrointest Endosc,2002,56:543-547.
7.Gress FG.Barawi M,Kim D,et al.Preoperative localization of a neuroendocrine tumor of the pancreas with EUS-guided fine needle tattooing.Gastrointest Endosc,2002,55:594-597.
8.Levy MJ,Wiersema MJ.Endoscopic ultrasound in the diagnosis and staging of pancreatic cancer.Oncology(Huntington),2002,16:29-38.
9.Hemandez LV,Mishra G,Forsmark C,et al.Role of endoscopic ultrasound(EUS)and EUS-guided fine needle aspiration in the diagnosis and treatment of cystic lesions of the pancreas.Pancreas,2002,25:222-8.
10.Sedlack R,Affi A,Vazquez-Sequeiros E,et al.Utility of EUS in the evaluation of cystic pancreatic lesions.Gastrointest Endosc,2002,56:543-7.
11.金震东.超声内镜在胰腺疾病诊断与治疗中的应用.胰腺病学,2003,3:109-113.
12.Shyam V,Mohamad AE.The Role of Endoscopic Ultrasonography in the Evaluation of Pancreatico-Biliary Cancer.Gastrointest Endoscopy Clin N Am,2005,15:497-511.
1.Haycox A,Lombard M,Neoptolemos J,et al.Current practice and future perspectives in detection and diagnosis of pancreatic cancer.Aliment Pharmacol Ther,1998,12(10):937
2.上海市肿瘤研究所流行病学研究室.1995年上海市市区恶性肿瘤发病率.肿瘤,1998,18(3):封2
3.Van Hoe L,Baert AL.Pancreatic carcinoma:applications for helical computed tomography.Endoscopy,1997,29(6):539
4.Lin Y,Taurakoshi A,Wakai K,et al.Descriptive epidemiology of pancreatic cancer in Japan.J Epidemiol,1998,8(1):52
5.Talamini G,Bassi C,Falconi M,et al.Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer.Dig Dis Sci 1999;44:1303-11.
6.Coughlin SS,Calle EE,Patel AV,et al.Predictors of pancreatic cancer mortality among a large cohort of United States adults.Cancer Causes Control 2000;11:915-23.
7.Bansal P,Sonnenberg A.Pancreatitis is a risk factor for pancreatic cancer.Gastroenterology 1995;109:247-57.
8.Lo"wenfels AB,Maisonneuve P,DiMagno EP,et al.Hereditary pancreatitis and the risk of pancreatic cancer.J Natl Cancer Inst 1997;89:442-6.
9.Howes N,Wong T,Greenhalf W,et al.Pancreatic cancer risk in hereditary pancreatitis in Europe.Digestion 2000;61:300.
10.Tersmette AC,Petersen GM,Offerhaus GJ,et al.Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.Clin Cancer Res 2001;7:738-44.
11.Silverman DT,Schiffman M,Everhart J,et al.Diabetes mellitus,other medical conditions and familial history of cancer as risk factors for pancreatic cancer.Br J Cancer 1999;80:1830-7.
12. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002;62:3789-93.
13. Hahn SA, Greenhalf W, Ellis I, et al. BRCA2 germ line mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003;95:214-21.
14. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000; 119:1447-53.
15. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer—anupdated review. Gastroenterology 1993; 104:1535-49.
16. Phelan CM, Lancaster JM, Tonin P, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996; 13:120-2.
17. Offerhaus GJ, Giardiello FM, Krush AJ, et al. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992;102:1980-2.
18. Whelan AJ, Bartsch D, Goodfellow PJ. A familial syndrome of pancreatic carcinoma and melanoma with a mutation in the CDKN2 tumor suppressor gene. N Engl J Med 1995;333:975-7.
19. Solcia E, Capella C, Kloppel G, eds. Tumours of the pancreas. Washington DC: Armed Forces Institute of Pathology, 1997:262.
20. Moossa AR, Levin B. The diagnosis of 'early' pancreatic cancer: the University of Chicago experience. Am Cancer Soc 1981;47:1688—97.
21. Gambil EF. Pancreatitis associated with pancreatic carcinoma: study of 26 cases. Mayo Clin Proc 1971;46:174.
22. Karlson BM, Ekbom A, Lindgren PG, et al. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. Radiology 1999;213:107-11.
23. McCarthy MJ, Evans J, Sagar G, et al. Prediction of resectability of pancreatic malignancy by computed tomography. Br J Surg 1998;85:320-5.
24. Griffanti-Bartoli. Malignant tumours in the head of the pancreas and periampullary region. Anti Cancer Res 1994; 14:657-66.
25. Vitellas KM, Keogan MT, Spritzer CE, et al. MR cholangiopancreatography of bile and pancreatic duct abnormalities with emphasis on single-shot fast spin-echo technique. Radiographics 2000;20:1108-12.
26. Palazzo L, Roseau G, Gayet B, et al. Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma.Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy 1993;25:143-50.
27.Midwinter MJ,Beveridge CJ,Wilsdon JB,et al.Correlation between spiral computed tomography,endoscopic ultrasonography and findings atoperation in pancreatic and ampullary tumours.Br J Surg 1999;86:189-93.
28.Mertz HR,Sechopoulos P,Delbeke D,et al.EUS,PET and CT scanning for evaluation of pancreatic adenocarcinoma.Gastrointest Endosc 2000;52:367-71.
29.Diehl SJ,Lehmann KJ,Sadick M,et al.Pancreatic cancer:value of dual-phase helical CT in assessing resectability.Radiology,1998,206(2):373
30.Bottger TC,Boddin J,Duber C,et al.Diagnosing and staging of pancreatic carcinoma-what is necessary?Oncology,1998,55(2):122
31.袁世珍,徐克强。1988年亚太地区胃肠病学会议简介。国外医学内科学分册,1999,26(5):185
32.Caletti G,Ferrari A.Endoscopic ultrasonography.Endoscopy,1996,28(2):156
33.袁世珍.胰腺癌的研究进展.实用老年医学,1999,13(1):6
34.Brandt KR,Charbonneau JW,Stephens DH,et al.CT and US guided biopsy of the pancreas.Radiology 1993;187:99-104.
35.Lees WR.Imaging diagnosis of pancreatic cancer.Curr Pract Surg 1994;6:143-6.
36.陆星华.胰腺癌研究现状与展望。胰腺病学。2003,6(3):63
37.Polati E,Finco G,Gottin L,et al.Prospective randomised double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer.Br J Surg 1998;85:199-201.
38.Watanapa P,Williamson RCN.Surgical palliation for pancreatic cancer:developments during the past two decades.Br J Surg 1992;79:8-20.
39.Smith AC,Dowsett JF,Russell RCG,et al.Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction.Lancet 1994;344:1655-60.
40.Shepherd HA,Royle G,Ross APR,et al.Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct:a randomised trial.Br J Surg 1988;75:1166-8.
41.Trede M,Schwall G,Saeger HD.Survival after pancreatoduodenectomy.118consecutive resections without an operative mortality.Ann Surg 1990;211:447-58.
42.Livingston EH,Welton ML,Reber HA.Surgical treatment of pancreatic cancer: The United States experience. Int J Pancreatol 1991;9:153-7.
43. Haycox A, Lombard M, Neoptolemos JP, et al. Current treatment and optimal patient management in pancreatic cancer. Aliment Pharmacol Ther 1998; 12:49-964.
44. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997;15:2403-13.
45. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.nice.org.uk/article.asp?a = 16790 (accessed March 2005).
46. NCCN(National comprehensive cancer network. Clinical Practice Guidelines in Oncology-v.1.2006
2. Rosewicz S, Wiedenman B .Pancreatic carcinoma. Lancet, 1997 349:485-489
3. Evans DB, Abbruzzese JL, Rich TA .Cancer of the pancreas, Principles andPractice of Oncology. Cancer, 1997, pp 1054-1087
4. Howard S, Daniel G, Aimery G, et al. Consensus report of the internationalsociety of astro intestinal oncology on therapeutic progress in advanced pancreatic cancer,cancer. 2006, 107:676-685
5. Burris HA, Moore MJ, Andersen J, et al: Improvements in survival and clinicalbenefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer:A randomized trial. J Clin Oncol. 1997, 15:2403-2413
6. CHUNG PIN LI, YEE CHAO, KWAN-HWA CHI, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study.Int. J. Radiation Oncology Biol. Phys. 2003, 57 (1) 98-104
7．王俊杰，黄毅，冉维强等。放射性粒子组织间种植治疗肿瘤近期疗效．中国微创外科杂志，2003，2(3)：148
8．张福君，吴沛宏，赵明等．CT导引下~(125)I粒子植入治疗胰腺癌．中华医学杂志，2006，86(4)：223—227
9. Sun S, Lu Q, Guo Q, et al. EUS-guided interstitial brachytherapy of the pancreas: a feasibility study. Gastrointest Endosc, 2005,62: 775-779.
10. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004.CA Cancer J Clin. 2004;54:8-29.
11. Van Cutsem E, Aerts R, Haustermans K, Topal B, Van Steenbergen W, Verslype C. Systemic treatment of pancreatic cancer. Eur J Gastroent Hepatol. 2004; 16:265-274
12. Willett CG,Safran H ,Abrams RA ,et al. Clinical research in pancreatic cancer : the Radiation Therapy Oncology Group trials. Int J Radiat OncolBiol Phys ,2003 ,56:31237.
13. Moore MJ . pancreatic cancer : what the oncologist can offer for palliation. Can J Gastroenterol ,2002 ,16 :1212124.
14．申文江，王绿化，夏延毅，主编．放射治疗学新技术进展[M]。北京：北京科学技术出版社，2003．155．
15. Peretz T, Nori D, Nilaris B, et al. Treatment of p rimaryunresectable carcinoma of the pancreaswith 12125 imp lantation. Int J Radiat Oncol Biol Phys, 1989,17: 9312935.
16. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399— 403
17. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.mce.org.uk/article.asp?a = 16790 (accessed March 2005).
18. Bums HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997; 15:2403-13.
1. Von Hoff DD ,Goodwin AL,Garcia L. Advance in the treatment of patient with pancreatic cancer: improvement in symptoms and survival time. The San Antonio Drug Development Team[J] .Br J Cancer ,1998,78 [ Suppl 3 ] :92131
2. Stephen CD. Gemcitabine :a new approach to treating pancreatic cancer [J] Oncol Nur Forum, 1998 ,25(1) :872931
3. Carmichael J . Clinical response benefitin patients with advanced pancreatic cancer. Role of gemcitabine [J ]. Digestion ,1997,58 (6): 5032-5071
4. Burns HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997;15:2403-13.
5. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.nice.org.uk/article.asp?a = 16790 (accessed March 2005).
6. Louvet, R. Labianca, PH,. Lledo, G,et al. Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial. JOURNAL OF CLINICAL ONCOLOGY,2005,23:3509-3516
7. Peretz T, Nori D, Nilaris B, et al. Treatment of p rimaryunresectable carcinoma of the pancreaswith 12125 imp lantation. Int J Radiat Oncol Biol Phys, 1989,17:9312935.
8.张福君，吴沛宏，赵明，等．CT导引下~(125)I粒子植入治疗胰腺癌，中华医学杂志,2006,86(4)：223-227
9. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399—403
1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004.CA Cancer J Clin. 2004;54:8-29.
2. Van Cutsem E, Aerts R, Haustermans K, Topal B, Van Steenbergen W, Verslype C. Systemic treatment of pancreatic cancer. Eur J Gastroent Hepatol. 2004; 16:265-274
3. Willett CG,Safran H ,Abrams RA ,et al. Clinical research in pancreatic cancer : the Radiation Therapy Oncology Group trials. Int J Radiat OncolBiol Phys ,2003 ,56:31237.
4. Moore MJ . pancreatic cancer : what the oncologist can offer for palliation. Can J Gastroenterol ,2002,16 :1212124.
5. MorrowM, Hilaris BS , Brennan MF , et al .Comparison of conventional surgicalresection ,radioactive implantation , and bypass procedures for exocrine carcinoma of the pancreas. Ann Surg, 1984,199:125.
6．王俊杰，白静，修典荣，等．放射性~(125)I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志2004；19：512．
7．张福君，吴沛宏，赵明，等.CT导引下~(125)I粒子植入治疗胰腺癌，中华医学杂志,2006,86(4)：223-227
8. Sun S, Xu H, Xin J,et al. Endoscopic ultrasound-guided interstitial brachytherapy of unresectable pancreatic cancer: results of a pilot trial. Endoscopy 2006; 38 (4): 399— 403
9. PaoloM, Ralph D, Francesco C, et al. Interstitial brachytherapy forpa ncreatic cancer: report of seven cases treated with 125 I and a review of the literature . Int J Radiation Oncology Biol Phys, 1991,21:451 - 457.
10. Mohuiddin M, Rosato F , Barbot D , et al .Long2term results of combined modality treatment with 1251 implantation for carcinoma of the pancreas. Int J Radiat Oncol Biol Phys ,1992,23 :3032311.
11.Louvet, R. Labianca, PH,. Lledo, G,et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. Journal of Clinical Oncology,2005,23:3509-3516
1. Koprowski H, Herly M, Steplewski Z, et al. Specific in serum of patients with colon carcinoma. Science 1981 ;212 :53
2. Sperti C, Pasquali C, Guolo P, et al. Serum tumor markers and cystfluid analysis are useful for the diagnosis of pancreatic cystic tumors.Cancer 1996 ;78 :237
3. Kokhanenko Niu, Ignashov AM, Varga EV, et al. Role of the tumor markers CA19-9 and carcinoembryonic antigen (CEA) in diagnosis, treatment and prognosis of pancreatic cancer. Vopr Onkol 2001 ;47 :294
4．陈志南、刘民培。抗体分子与肿瘤。第1版．北京：人民军医出版社。2002；406
5. Sali F, Sch lo sser W, Falk enreck S et al. Prognostic value of CA 19- 9 serum course in pancreat ic cancer[J]. Hepato- Gastroenterology, 1998,45 : 253.
1．万崇华．生命质量测定与评价方法．昆明：云南大学出版社,1999，224-227。
2. World Health Orgnization. The First Ten Years of THE World Health Orgnization[M]. Geneva: World Health Orgnization ,1958
3. COX D R, FITZPATRICK R, FLETCHER A E, et al. Q uality - of- life ssessment: can we keep it simple ? J . R. Statist, Soc. A ,1992,155 :353.
4．洪明晃主编．科研设计测量评价．广州：中山大学出版社，1994：76
5．董宣，李天霖，王滨燕，等．生活质量评价——一种多维的健康评价方法．国外医学社会医学分册，1996，13(3)：118
6. Aaronson NK, Ahmedxai S. The European Organixation for Research and Treatment of Cencer QLQ - C30 : A Quality of life Instrument for use in International Conocal Trials in Oncology. Joureal of the National Cancer Institute, 1993 , 85(5) :365
7. 邱彩锋，赵继军．QLQ2C30的应用及计分方法．国外医学护理学分册,2005,24(11)：701-703
8．陈和年，方积乾，胡孟璇，等．生存质量研究．中华预防医学杂志，1993，27(3)：178
9. Aaronson NK, Cull A, Stein Kaasa, et al. The European Organixtion for Eesearch and Treatment of Cancer (EORTC) Modalar Approach to quality of life Aaaessment in oncology: An update. Int J ment Health, 1994,23 (2) :75
1. Peretz T, Nori D, Hilaris B, et al. Treatment of primary unresectable carcinoma of the pancreas with 1-125 implantation. Int J Radiation Oncology Biol Phys, 1989, 17: 931-935.
2. Lee W, Daly B, Morelli D, et al. Limited resection for lung cancer: improved local control with the implantation of Iodine-125 seeds. Int J Radiation Oncology Biol Phys, 2001, 51(s1): 354.
3. Lah JJ, Kuo JV, Chang KJ, et al. EUS-guided brachytherapy. Gastrointest Endosc, 2005,62: 805-808.
4. Sun S, Lu Q, Guo Q, et al. EUS-guided interstitial brachytherapy of the pancreas: a feasibility study. Gastrointest Endosc, 2005,62: 775-779.
5. Lebovics E, Mittelman A, Del Guercio LR, et al. Pancreaticobiliary fistula and obstructive jaundice complicating 1251 interstitial implants for pancreatic cancer: endoscopic diagnosis and management. Gastrointest Endosc, 1990,36: 610-611.
6．王俊杰，白静，修典荣，等。放射性125 I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志2004；19：512．
1.Blasko JC,Grimm PD,Sylsvester JE,et al.The role of external beam radiotherapy with I125/Pd103 brachytherapy for prostate carcinoma.Radiother Oncol 2000;57:273-278.
2.Lee W,Daly BD,DiPetrillo TA,et al.Limited resection for nonsmallcell lung cancer:observed local control with implantation of I125brachytherapy seeds.Ann Thorac Surg 2003;75:237-243
3.雷光焰,付改发,许建秦等。放射性125I粒子组织间永久植入治疗中晚期肺癌的研究。现代肿瘤医学 2005;13(1):77-78
4.王俊杰,白静,修典荣,等.放射性125I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志 2004;19:512.
5.周伟,洛小林,毛凯等。125I放射性粒子术中植入治疗晚期胰腺癌的疗效评价。中华放射肿瘤学杂志 2005;14(4):307-310
6.MorrowM,Hilaris BS,Brennan MF,et al.Comparison of conventional surgical resection,radioactive implantation,and bypass procedures for exocrine carcinoma of the pancreas.Ann Surg,1984;199:125.
7.Mohuiddin M,Rosato F,Barbot D,et al.Long2term results of combined modality treatment with125I implantation for carcinoma of the pancreas.Int J Radiat Oncol Biol Phys,1992;23:303-311.
8.王俊杰,白静,修典荣,等.放射性125I粒子组织间植入治疗胰腺癌的疗效。中华普通外科杂志 2004;19:512.
9.Maier W,Henne K,Krebs A,et al.Endoscopic ultrasound-guided brachytherapy of head and neck tumors.A new procedure for controlled application.J Laryngol Otol 1999;113(1):41-48
10.Lah J J,Kuo JV,Chang KJ,et al.EUS-guided brachytherapy.Gastrointest Endosc 2005;62(5):805-808
11.Martinez-Monge R,Subtil JC,Lopez-Picazo JM.Transoesophageal endoscopic-ultrasonography-guided 125I permanent brachytherapy for unresectable mediastinal lymphadenopathy.Lancet Oncol.2006 Sep;7(9):781-3.
12.Sun S,lu Q,Guo Q,et al.EUS-guided interstitial brachytherapy of the pancrease:a feasibility study.Gastrointestinal.Endoscopy,2005;62:775-779
13.Sun S,Xu H,Xin Jun,et al.EUS-guided Interstitial brachytherapy of irresectable pancreatic cancer-results of a pilot trial.Endoscopy,2006;38:398-402
14.金震东,李兆申,刘岩等.超声内镜引导下定向植入放射性~(125)I粒子治疗胰腺癌的临床研究。中华消化内镜杂志,2006;23(1):15-17
15.Chang KJ.EUS-guided fine needle injection(FNI) and anti-tumor therapy. Eendoscooy 2006;38(S1):588-593
16.金震东,李兆申主编。消化超声内镜学。科学出版社,2006:10,第一版。
1.Gress FG,Hawes RH,Savides TJ,et al.Role of EUS in the preoperative staging of pancreatic cancer:a large single-center experience.Gastrointest Endosc,1999,50:786-91.
2.Krinsky ML,Binmoeller KF.EUS-guided investigational therapy for pancreatic cancer.Gastroimest Endosc,2000,52:S35-8.
3.Legmann P,Vignaux O,Dousset B,Baraza AJ,et al.Pancreatic tumors:comparison of dual-phase helical CT and endoscopic sonography.A JR Am J Roentgenol,1998,170:1315-22.
4.Harewood GC.Wiersema MJ.Endosonography-guided fine needle aspiration biopsy in the evaluation of pancreatic masses.Am J Gastroenterol,2002.97:1386-1391.
5.Michael JL,Maurits JW.Pancreatic neoplasms.Gastrointest Endoscopy Clin N Am,2005,5:117-142.
6.Sedlack R,Affi A,Vazquez-Sequeiros E,et al.Utility of EUS in theevaluation of cystic pancreatic lesions.Gastrointest Endosc,2002,56:543-547.
7.Gress FG.Barawi M,Kim D,et al.Preoperative localization of a neuroendocrine tumor of the pancreas with EUS-guided fine needle tattooing.Gastrointest Endosc,2002,55:594-597.
8.Levy MJ,Wiersema MJ.Endoscopic ultrasound in the diagnosis and staging of pancreatic cancer.Oncology(Huntington),2002,16:29-38.
9.Hemandez LV,Mishra G,Forsmark C,et al.Role of endoscopic ultrasound(EUS)and EUS-guided fine needle aspiration in the diagnosis and treatment of cystic lesions of the pancreas.Pancreas,2002,25:222-8.
10.Sedlack R,Affi A,Vazquez-Sequeiros E,et al.Utility of EUS in the evaluation of cystic pancreatic lesions.Gastrointest Endosc,2002,56:543-7.
11.金震东.超声内镜在胰腺疾病诊断与治疗中的应用.胰腺病学,2003,3:109-113.
12.Shyam V,Mohamad AE.The Role of Endoscopic Ultrasonography in the Evaluation of Pancreatico-Biliary Cancer.Gastrointest Endoscopy Clin N Am,2005,15:497-511.
1.Haycox A,Lombard M,Neoptolemos J,et al.Current practice and future perspectives in detection and diagnosis of pancreatic cancer.Aliment Pharmacol Ther,1998,12(10):937
2.上海市肿瘤研究所流行病学研究室.1995年上海市市区恶性肿瘤发病率.肿瘤,1998,18(3):封2
3.Van Hoe L,Baert AL.Pancreatic carcinoma:applications for helical computed tomography.Endoscopy,1997,29(6):539
4.Lin Y,Taurakoshi A,Wakai K,et al.Descriptive epidemiology of pancreatic cancer in Japan.J Epidemiol,1998,8(1):52
5.Talamini G,Bassi C,Falconi M,et al.Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer.Dig Dis Sci 1999;44:1303-11.
6.Coughlin SS,Calle EE,Patel AV,et al.Predictors of pancreatic cancer mortality among a large cohort of United States adults.Cancer Causes Control 2000;11:915-23.
7.Bansal P,Sonnenberg A.Pancreatitis is a risk factor for pancreatic cancer.Gastroenterology 1995;109:247-57.
8.Lo"wenfels AB,Maisonneuve P,DiMagno EP,et al.Hereditary pancreatitis and the risk of pancreatic cancer.J Natl Cancer Inst 1997;89:442-6.
9.Howes N,Wong T,Greenhalf W,et al.Pancreatic cancer risk in hereditary pancreatitis in Europe.Digestion 2000;61:300.
10.Tersmette AC,Petersen GM,Offerhaus GJ,et al.Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.Clin Cancer Res 2001;7:738-44.
11.Silverman DT,Schiffman M,Everhart J,et al.Diabetes mellitus,other medical conditions and familial history of cancer as risk factors for pancreatic cancer.Br J Cancer 1999;80:1830-7.
12. Murphy KM, Brune KA, Griffin C, et al. Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res 2002;62:3789-93.
13. Hahn SA, Greenhalf W, Ellis I, et al. BRCA2 germ line mutations in familial pancreatic carcinoma. J Natl Cancer Inst 2003;95:214-21.
14. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000; 119:1447-53.
15. Lynch HT, Smyrk TC, Watson P, et al. Genetics, natural history, tumor spectrum, and pathology of hereditary nonpolyposis colorectal cancer—anupdated review. Gastroenterology 1993; 104:1535-49.
16. Phelan CM, Lancaster JM, Tonin P, et al. Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 1996; 13:120-2.
17. Offerhaus GJ, Giardiello FM, Krush AJ, et al. The risk of upper gastrointestinal cancer in familial adenomatous polyposis. Gastroenterology 1992;102:1980-2.
18. Whelan AJ, Bartsch D, Goodfellow PJ. A familial syndrome of pancreatic carcinoma and melanoma with a mutation in the CDKN2 tumor suppressor gene. N Engl J Med 1995;333:975-7.
19. Solcia E, Capella C, Kloppel G, eds. Tumours of the pancreas. Washington DC: Armed Forces Institute of Pathology, 1997:262.
20. Moossa AR, Levin B. The diagnosis of 'early' pancreatic cancer: the University of Chicago experience. Am Cancer Soc 1981;47:1688—97.
21. Gambil EF. Pancreatitis associated with pancreatic carcinoma: study of 26 cases. Mayo Clin Proc 1971;46:174.
22. Karlson BM, Ekbom A, Lindgren PG, et al. Abdominal US for diagnosis of pancreatic tumor: prospective cohort analysis. Radiology 1999;213:107-11.
23. McCarthy MJ, Evans J, Sagar G, et al. Prediction of resectability of pancreatic malignancy by computed tomography. Br J Surg 1998;85:320-5.
24. Griffanti-Bartoli. Malignant tumours in the head of the pancreas and periampullary region. Anti Cancer Res 1994; 14:657-66.
25. Vitellas KM, Keogan MT, Spritzer CE, et al. MR cholangiopancreatography of bile and pancreatic duct abnormalities with emphasis on single-shot fast spin-echo technique. Radiographics 2000;20:1108-12.
26. Palazzo L, Roseau G, Gayet B, et al. Endoscopic ultrasonography in the diagnosis and staging of pancreatic adenocarcinoma.Results of a prospective study with comparison to ultrasonography and CT scan.Endoscopy 1993;25:143-50.
27.Midwinter MJ,Beveridge CJ,Wilsdon JB,et al.Correlation between spiral computed tomography,endoscopic ultrasonography and findings atoperation in pancreatic and ampullary tumours.Br J Surg 1999;86:189-93.
28.Mertz HR,Sechopoulos P,Delbeke D,et al.EUS,PET and CT scanning for evaluation of pancreatic adenocarcinoma.Gastrointest Endosc 2000;52:367-71.
29.Diehl SJ,Lehmann KJ,Sadick M,et al.Pancreatic cancer:value of dual-phase helical CT in assessing resectability.Radiology,1998,206(2):373
30.Bottger TC,Boddin J,Duber C,et al.Diagnosing and staging of pancreatic carcinoma-what is necessary?Oncology,1998,55(2):122
31.袁世珍,徐克强。1988年亚太地区胃肠病学会议简介。国外医学内科学分册,1999,26(5):185
32.Caletti G,Ferrari A.Endoscopic ultrasonography.Endoscopy,1996,28(2):156
33.袁世珍.胰腺癌的研究进展.实用老年医学,1999,13(1):6
34.Brandt KR,Charbonneau JW,Stephens DH,et al.CT and US guided biopsy of the pancreas.Radiology 1993;187:99-104.
35.Lees WR.Imaging diagnosis of pancreatic cancer.Curr Pract Surg 1994;6:143-6.
36.陆星华.胰腺癌研究现状与展望。胰腺病学。2003,6(3):63
37.Polati E,Finco G,Gottin L,et al.Prospective randomised double-blind trial of neurolytic coeliac plexus block in patients with pancreatic cancer.Br J Surg 1998;85:199-201.
38.Watanapa P,Williamson RCN.Surgical palliation for pancreatic cancer:developments during the past two decades.Br J Surg 1992;79:8-20.
39.Smith AC,Dowsett JF,Russell RCG,et al.Randomised trial of endoscopic stenting versus surgical bypass in malignant low bile duct obstruction.Lancet 1994;344:1655-60.
40.Shepherd HA,Royle G,Ross APR,et al.Endoscopic biliary endoprosthesis in the palliation of malignant obstruction of the distal common bile duct:a randomised trial.Br J Surg 1988;75:1166-8.
41.Trede M,Schwall G,Saeger HD.Survival after pancreatoduodenectomy.118consecutive resections without an operative mortality.Ann Surg 1990;211:447-58.
42.Livingston EH,Welton ML,Reber HA.Surgical treatment of pancreatic cancer: The United States experience. Int J Pancreatol 1991;9:153-7.
43. Haycox A, Lombard M, Neoptolemos JP, et al. Current treatment and optimal patient management in pancreatic cancer. Aliment Pharmacol Ther 1998; 12:49-964.
44. Burris HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomised trial. J Clin Oncol 1997;15:2403-13.
45. NICE (National Institute for Clinical Excellence). Guidance on the use of gemcitabine for pancreatic cancer May 2001. http://www.nice.org.uk/article.asp?a = 16790 (accessed March 2005).
46. NCCN(National comprehensive cancer network. Clinical Practice Guidelines in Oncology-v.1.2006