吉西他滨单药及联合用药治疗晚期胰腺癌的疗效对比:一项针对Ⅲ期随机对照临床试验的荟萃分析

背景与目的：晚期胰腺癌的治疗效果较差，生存期也较短。吉西他滨是治疗晚期胰腺癌的一线药物，有研究表明吉西他滨联合用药对患者的生存有益。本研究通过荟萃分析对比吉西他滨单药和联合用药在治疗晚期胰腺癌中的疗效。方法：检索MEDLINE、EBMreviews、EMBASE等数据库，查阅有关文献。所选Ⅲ期随机对照试验的研究对象为晚期胰腺癌，单药治疗组接受吉西他滨单药化疗，联合治疗组接受吉西他滨联合（铂类、喜树碱类，抗代谢素或靶向类）药物治疗。两名评价员独立检索资料。评价指标包括6个月、1年生存率及ORR（客观缓解率）等。结果：共检索出19篇符合要求的文章。荟萃分析结果显示联合治疗组1年生存率较单药治疗组高，两组间差异有显著性（RR：0．87，95％可信区间：[0．78，0．96]，P=0．008）。结论：吉西他滨联合用药可能有效提高晚期胰腺癌患者的生存率。     

吉西他滨为基础的化疗方案治疗进展期胰腺癌的临床研究

背景与目的:进展期胰腺癌预后差.吉西他滨可以改善胰腺癌患者的生存质量,但吉西他滨联合方案疗效是否优于单药,还存在争议,国内更缺乏相关的临床研究.本研究目的是比较吉西他滨为基础的联合化疗方案与吉西他滨单药治疗进展期胰腺癌的疗效.方法:回顾性分析2000～2005年收治的40例经临床或病理确诊的进展期胰腺癌临床资料,其中吉西他滨单药组15例,吉西他滨剂量为1 000 mg/m2,每周1次,连用7周,休息2周,之后每周1次,连用3周,4周重复;吉西他滨联合治疗组25例,联合化疗方案包括吉西他滨1 000 mg/m2,每周1次,连用2周,分别联合:(1)氟尿嘧啶425～600 mg/m2,静脉滴注或持续静脉泵入,d1-5,3周重复;(2)顺铂60～75 mg/m2,分第1、2天,3周重复;(3)奥沙利铂85～130 mg/m2,d1,3周重复;(4)卡培他滨l000 mg/m2,2次/天,d1-14,3周重复.采用Kaplan-Meier生存曲线分析患者的生存期,并比较两组间的临床受益反应、中位疾病进展时间、中位生存时间和不良反应.结果:吉西他滨联合组与单药组患者的临床受益反应均得到改善(56.0% vs.46.7%),但疾病控制率、中位生存时间、临床受益反应在两组之间差异无统计学意义(P＞0.05),不良反应的发生率也相似(P＞0.05).对Ⅲ～Ⅳ期患者进行分层分析,发现吉西他滨联合组疾病控制率高于单药组(75.0% vs.45.5%),但无统计学意义(P=0.13).结论:吉西他滨联合方案与单药治疗进展期胰腺癌相比,疗效、临床受益反应、中位生存时间两组相似.     

晚期胰腺癌姑息性化疗进展

胰腺癌的恶性程度极高且预后极差,其病死率约占年发病人数的98％。以联合放化疗为主的综合治疗是局部晚期及转移性胰腺癌主要的治疗手段,但疗效有限。多项研究结果以及荟萃分析证实了吉西他滨在晚期胰腺癌中应用的优势,目前吉西他滨已成为晚期胰腺癌一线化疗的首选药物。虽然以吉西他滨为基础的联合方案被广泛应用于晚期胰腺癌的治疗,但仍缺乏足够的循证医学证据支持联合方案优于单药,所以最佳化疗的手段及方案仍需进一步研究证实。随着新的化疗药物以及靶向药物的出现,给晚期胰腺癌患者带来了新的希望。     

晚期胰腺癌一线联合化疗研究进展

吉西他滨单药是晚期胰腺癌化疗的金标准,但疗效仍差强人意。目前在晚期胰腺癌的治疗上联合化疗方案有广泛研究,Meta分析多显示联合方案较单药更有优势。联合治疗方案有较高的临床缓解率,较长的无进展生存时间,而且对一般状况较好的患者有明显的生存优势。     

吉西他滨单药化疗与联合化疗治疗进展期胰腺癌的疗效观察

目的观察比较吉西他滨单药与联合化疗治疗进展期胰腺癌的疗效。方法回顾性分析了大连医科大学附属一院2002年至2009年收治的45例进展期胰腺癌患者的临床资料,吉西他滨单药组17例,剂量为1000mg/m2,d1、8,三周为一周期;吉西他滨联合治疗组28例,联合化疗方案包括吉西他滨1000mg/m2,d1、8,分别联合：（1）氟尿嘧啶425～600mg/m2,静滴或持续静脉泵入,d1～5;（2）顺铂60～75mg/m2,分3～4d静脉滴入;（3）奥沙利铂85～130mg/m2,d1,静脉滴入;（4）卡培他滨1000mg/m2,每天两次口服,d1～14。21d为一周期。采用Kaplan-Meier生存曲线分析患者的生存期,并比较两组间的临床受益率、中位疾病进展时间、中位生存时间及不良反应。结果吉西他滨联合组及单药组的临床收益率均得到提高,但两组间比较临床受益率、疾病控制率、中位生存时间均无统计学意义。结论吉西他滨联合化疗方案与吉西他滨单药治疗进展期胰腺癌相比,疗效、临床受益率、中位生存期均相似。     

替吉奥联合吉西他滨治疗晚期胰腺癌的疗效观察

目的:探讨替吉奥(S-1)胶囊联合吉西他滨(GEM)化疗与吉西他滨单药治疗进展期胰腺癌的疗效.方法:对2011年5月至2013年5月收治的37例晚期胰腺癌患者的临床资料进行回顾性分析,其中18例采用替吉奥胶囊联合吉西他滨方案治疗(治疗组);19例采用吉西他滨单药治疗(对照组).采用Kaplan-Meier法分析患者的生存时间,并比较两组患者的客观缓解率、临床受益反应(CBR)、中位疾病进展时间、中位生存时间和不良反应.结果:治疗组有效率明显高于对照组(33.3％vs 21.1％),差异有统计学意义(P =0.032).治疗组疾病控制率(DCR)高于对照组(72.2％vs 63.2％),但差异无统计学意义(P =0.450).治疗组患者CBR缓解率高于对照组(71.8％ vs 45.7％),差异无统计学意义(P=0.421).治疗组的中位生存时间为10.1个月(95％CI:8.0-11.5个月),高于对照组的8.02个月(95％ CI:3.7-10.8个月),差异有统计学意义(P=0.043);两组的中位疾病进展时间分别为3.5个月和3.0个月(P=0.720).治疗组的6个月生存率(72.5％)略高于对照组(66.5％),但差异无统计学意义(P＞0.05).两组不良反应的发生率也相似(P＞0.05).结论:替吉奥胶囊联合吉西他滨治疗方案与单药治疗晚期胰腺癌相比,在客观疗效、中位生存时间方面表现出一定优势,疾病控制率及临床受益反应也有所提高,且不良反应可耐受,是晚期胰腺癌的有效治疗方案.     

吉西他滨联合替吉奥胶囊治疗晚期胰腺癌的疗效观察

目的探讨吉西他滨联合替吉奥胶囊化疗方案与吉西他滨单药治疗进展期胰腺癌的疗效。方法对2008年1月至2011年1月收治的52例晚期胰腺癌患者的临床资料进行回顾性分析,其中28例采用吉西他滨联合替吉奥胶囊方案治疗(A组);24例采用吉西他滨单药治疗(B组)。采用Kaplan-Meier法分析患者的生存时间,并比较两组患者的客观缓解率、临床受益反应(CBR)、中位疾病进展时间、中位生存时间和不良反应。结果 A组有效率明显高于B组(32.1%vs.20.8%),差异有统计学意义(P=0.039)。A组疾病控制率(DCR)高于B组(67.9%vs.45.8%),但差异无统计学意义(P=0.230)。A组患者CBR缓解率高于B组(72.1%vs.46.9%),差异无统计学意义(P=0.41)。A组的中位生存时间为10.2个月(95%CI:8.0～11.8个月),高于B组的8.03个月(95%CI:3.8～10.9个月),差异有统计学意义(P=0.045);A、B两组的中位疾病进展时间分别为3.6个月和3.0个月(P=0.721)。A组的6个月生存率(72.7%)略高于B组(66.8%),但差异无统计学意义(P>0.05)。两组不良反应的发生率也相似(P>0.05)。结论吉西他滨联合替吉奥胶囊治疗方案与单药治疗晚期胰腺癌相比,在客观疗效、中位生存时间表现出一定优势,疾病控制率及临床受益反应也有所提高,且不良反应可耐受,是晚期胰腺癌的有效治疗方案。     

吉西他滨联合奥沙利铂治疗晚期胰腺癌疗效观察

目的:观察GEMOX联合方案治疗晚期胰腺癌的疗效和毒副反应。方法:19例确诊晚期胰腺癌患者接受至少2个周期的GEMOX联合方案化疗,吉西他滨1000mg/m2,静脉滴入,d1、d8;奥沙利铂130mg/m2,静脉滴入,d1。每21d重复。结果:1例CR,5例PR,8例SD,5例PD,总有效率为31.6%(6/19),毒副反应可以耐受,没有化疗相关的死亡。结论:吉西他滨加奥沙利铂联合化疗是治疗晚期胰腺癌安全有效的方案,可以使部分患者得到临床受益。但需要有Ⅲ期的随机临床试验与吉西他滨单药化疗进行比较,以明确此联合方案的优势。     

吉西他滨联合奥沙利铂治疗晚期胰腺癌疗效观察

目的：观察GEMOX联合方案治疗晚期胰腺癌的疗效和毒副反应。方法：19例确诊晚期胰腺癌患者接受至少2个周期的GEMOX联合方案化疗，吉西他滨1000mg／m^2，静脉滴入，d1、d8；奥沙利铂130mg／m^2，静脉滴入，d1。每21d重复。结果：1例CR，5例PR，8例SD，5例PD，总有效率为31．6％(6／19)，毒副反应可以耐受，没有化疗相关的死亡。结论：吉西他滨加奥沙利铂联合化疗是治疗晚期胰腺癌安全有效的方案，可以使部分患者得到临床受益。但需要有Ⅲ期的随机临床试验与吉西他滨单药化疗进行比较，以明确此联合方案的优势。     

晚期胰腺癌的分子靶向治疗

胰腺癌的药物治疗目前仍以吉西他滨为主,但是晚期胰腺癌患者的总体预后极差,故其有效治疗亟待新型药物的研发。表皮生长因子受体（EGFR）及其配体的过度表达对肿瘤包括胰腺癌的细胞生存、增殖、血管生成、细胞迁移、细胞的入侵及转移等起到重要作用;此外,胰腺癌的进展、局部浸润及转移均有赖于新生血管的生成。因此,针对EGFR与血管内皮生长因子受体（VEGFR）或其配体的分子靶向治疗药物目前己成为晚期胰腺癌药物治疗的临床研究重点。加拿大国立癌症研究所完成的1项Ⅲ期随机双盲临床研究（NCIC PA．3）结果显示,接受酪氨酸激酶抑制剂厄洛替尼与吉西他滨联合方案治疗的晚期胰腺癌患者的1年总生存率与中位生存期均优于仅接受吉西他滨单药治疗者,分别为24％vs17％与6．4个月vs5．9个月,且差异有显著性。目前美国FDA己经批准了厄洛替尼联合吉西他滨治疗晚期胰腺癌的适应证。然而,厄洛替尼作为二线药物用于经吉西他滨治疗失败的胰腺癌,尚未获临床研究结果的支持。目前已完成的其他多项临床研究结果,尚未能证实其他酪氨酸激酶抑制剂或针对EGFR及其配体的单克隆抗体对晚期胰腺癌的疗效。虽然Ⅱ期临床研究结果提示了抗新生血管药物贝伐单抗对晚期胰腺癌的治疗作用,但其疗效未获Ⅲ期随机临床研究结果的支持。旨在研究吉西他滨与厄洛替尼基础上加用贝伐单抗对晚期胰腺癌疗效的AVITA研究,也未能证实该组合可进一步延长患者的中位生存期。其他分子靶向治疗药物如索拉非尼、axitinib与舒尼替尼等药物在晚期胰腺癌的应用目前亦仍有待临床研究结果的证实。本文基于目前己发表的最佳临床证据,就目前在晚期胰腺癌治疗中己获初步进展的抗表皮生长因子及抗新生血管治疗的相关研究及临床应用予以介绍。     

Chemotherapy for advanced pancreatic cancer: Past,present, and future

Advanced pancreatic cancer is a devastating illness characterized by significant morbidity and a brief median survival. Although standard chemotherapy with gemcitabine achieves only modest improvements in survival and quality of life, classic cytotoxic agents, such as 5-fluorouracil, pemetrexed, irinotecan, exatecan, cisplatin, or oxaliplatin, given alone or in combination with gemcitabine, have not proved superior. Thus, more recent trials have focused on targeting the biologic characteristics of pancreatic cancer. Although phase III trials of farnesyl transferase and matrix metalloproteinase inhibitors have not improved survival, encouraging preliminary results have been observed in phase II studies of inhibitors of the vascular endothelial growth factor and the epidermal growth factor receptor.     

Novel advances in pancreatic cancer treatment

Little progress has been made on the treatment of advanced pancreatic cancer. Gemcitabine has been an acceptable standard for more than a decade. The benefit of single-agent gemcitabine in advanced and metastatic pancreatic cancer is small. Adding other chemotherapy agents to gemcitabine has not resulted in meaningful improvement in survival. The randomized trials studying the addition of molecular targeting agents (cetuximab, bevacizumab, farnesyl transferase inhibitors and metalloproteinase inhibitors) to gemcitabine compared with gemcitabine alone have been disappointing. A small gain in median survival by adding erlotinib to gemcitabine has recently been reported. We herein review novel agents in pancreatic cancer that may change the current nihilistic approach in the management of this challenging disease.     

Developments in the systemic therapy of pancreatic cancer

Pancreatic adenocarcinoma is the fourth leading cause of cancer mortality in the United States of America. Progress in the treatment of this disease in the past several decades has been very modest. Several new agents with activity against pancreatic cancer have been identified. Of these, gemcitabine is the most promising agent when used in combination with other drugs. Pilot phase II studies combining gemcitabine with 5-flourouracil, irinotecan, docetaxel, or cisplatin show improved outcomes in objective response rates and survival that need to be confirmed in larger randomized studies. Advancement in the understanding of the molecular biology of neoplasia in recent years has helped identify several molecular targets for future new drug development in pancreatic cancer. Assessment of response to therapy of pancreatic cancer has been a difficult challenge. Functional imaging with techniques such as positron emission tomography (PET) may yield a more precise and timely objective evaluation of response to treatment.     

局部进展期胰腺癌的多学科综合治疗

胰腺癌是恶性程度高且预后极差的消化系统肿瘤。对可手术切除的局限性胰腺癌,因其术后局部复发儿率也较高,故建议采用以手术为主的多学科综合治疗。外放射治疗是无法手术胰腺癌的主要治疗手段。对无法切除的局部进展期肿瘤,主要采用局部外放射治疗联合全身化疗的多学科综合治疗。Ⅲ期随机临床研究结果已经证实,同期联合放化疗较单一放射治疗对患者的生存具显著优势。与放射治疗同步应用的化疗药物目前主要包括5-FU、卡培他滨与吉西他滨等。同期联合放化疗中应用多药联合化疗方案可明显增加治疗相关的不良反应,但临床研究结果并未显示多药方案对疗效及患者预后有所助益。放疗技术目前推荐三维适形放射治疗或调强放疗（IMRT）。靶区范围建议包括临床影像检查可见肿瘤外放安全边界,对未被侵及的淋巴引流区域不行预防性照射。IMRT不仅可减低周围正常组织的照射剂量,还可提高肿瘤靶区的照射剂量,实现剂量递增。     

Combination chemotherapy with gemcitabine and S-1 for advanced pancreatic cancer

The incidence and mortality of pancreatic cancer has increased very rapidly in Japan. The five-year survival rate is still poor at less than 10%, because it is commonly considered to be linked to a high incidence of distant metastasis even at the initial diagnosis as well as to the tumor's resistance to anticancer agents. Although gemcitabine has been the most widely used chemotherapeutic agent in patients with advanced pancreatic cancer (APC), gemcitabine monotherapy has obvious limitations. Therefore, various combinations with other agents have been investigated to improving the survival of patients with APC. Under these circumstances, we conducted a phase I /II trial of gemcitabine with S-1, an oral fluorouracil derivative, to determine the maximum tolerated dose and to evaluate the activity and toxicity of such a combination in patients with APC. S-1 was administered orally twice daily each day for 14 days and gemcitabine on days 8 and 15 of each cycle, and this cycle was repeated every 21 days. As a result, S-1 30 mg/m2 orally twice daily and gemcitabine 1,000 mg/m2 were selected as the recommended dose. The toxicities observed were mainly hematological ones with mild non-hematological toxicities. An encouragingly high response rate was observed. This result is very promising, but the survival benefit in comparison with gemcitabine monotherapy needs to be confirmed in a future randomized clinical trial.     

Chemotherapeutic advances in pancreatic cancer

Advances in chemotherapy for pancreatic cancer have been limited. In the past decade, the standard therapy for metastatic disease has switched from 5-fluorouracil (5-FU) to gemcitabine. However, several other cytotoxic agents have shown limited but promising efficacy in pancreatic cancer, and many of these appear to be well suited for combination chemotherapy. Although 5-FU and cisplatin have not demonstrated substantial survival benefits when combined with gemcitabine, results of several phase III trials with other agents are still pending. For locally advanced disease, most recent studies have incorporated gemcitabine into combined-modality therapy. Similarly, in surgically resectable disease, current trials are incorporating gemcitabine into adjuvant therapy. Other trials are using neoadjuvant therapy as a possible means to improve upon current surgical results. However, much hope comes from the development of newer “targeted” therapies for this disease. Although matrix metalloproteinase inhibitors and farnesyl transferase inhibitors did not appear to be effective in initial studies, other targeted therapies are beginning to enter clinical trials.     

Systemic therapy for advanced pancreatic cancer

Death from pancreatic cancer remains high with few long-term survivors. Systemic chemotherapy with 5-fluorouracil-based combinations had minimal impact on natural history of this disease. Several new agents with activity against pancreatic cancer have been identified over the past decade. Gemcitabine has modest activity in this disease. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan show improved outcomes in objective response rates and survival that need to be confirmed in prospectively randomized studies. Advancement in the understanding of the biology of pancreatic cancer has helped identify several molecular targets for the development of novel therapies. Ongoing and future treatment regimens for pancreatic cancer will incorporate traditional cytotoxic drugs and novel targeted therapies.     

Systemic therapy for advanced pancreatic cancer

Death from pancreatic cancer remains high with few long-term survivors. Systemic chemotherapy with 5-fluorouracil-based combinations had minimal impact on natural history of this disease. Several new agents with activity against pancreatic cancer have been identified over the past decade. Gemcitabine has modest activity in this disease. Combination chemotherapy trials incorporating gemcitabine, cisplatin, 5-fluorouracil, oxaliplatin, docetaxel or irinotecan show improved outcomes in objective response rates and survival that need to be confirmed in prospectively randomized studies. Advancement in the understanding of the biology of pancreatic cancer has helped identify several molecular targets for the development of novel therapies. Ongoing and future treatment regimens for pancreatic cancer will incorporate traditional cytotoxic drugs and novel targeted therapies.