化疗与靶向药物联合治疗胰腺癌研究进展

以吉西他滨为基础的化疗是胰腺癌的主要治疗方法。近年来对于胰腺癌化疗的研究除了吉西他滨与其他化疗药物的联合和给药方法的改进之外,主要集中在化疗与分子靶向药物的联合以及不同靶向药物之间联合应用的探讨。     

晚期胰腺癌的化疗

单药吉西他滨是晚期胰腺癌的标准治疗,但疗效并不理想.吉西他滨已与多种细胞毒药物或生物靶向药物组成多个联合方案,但是在大多数Ⅲ期临床研究中这些联合方案对生存时间的延长并没有超过吉西他滨单药.有Ⅲ期临床研究结果显示埃罗替尼联合吉西他滨可延长晚期胰腺癌患者的生存时间.非吉西他滨的化疗方案也正在评估中,并已初步看到了希望.     

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。     

胰腺癌的靶向治疗

不能手术切除的或转移的胰腺癌预后不良,细胞毒药物治疗很少奏效,即使第一线化疗药物吉西他滨也只有中等度生存期益处,联合不同的细胞毒药物并不能明显改善,因此,继续寻找更有效的分子靶向药物和联合应用不同的治疗方法势在必行.埃洛替尼是一种口服、小分子表皮生长因子受体酪氨酸激酶抑制剂,在靶向药物中第一个被批准联合吉西他滨治疗晚期胰腺癌患者.吉西他滨联合其他靶向药物,包括单克隆抗体西妥昔单抗或贝伐单抗也被广泛研究,但迄今很少突出成就.进一步研究应继续探究胰腺癌发生的机制,识别相关的关键分子靶以利治疗.     

局部晚期胰腺癌的治疗进展

局部晚期胰腺癌目前治疗的主要手段是放化疗联合姑息性手术的综合治疗,目的在于延长患者生命的同时提高其生活质量。吉西他滨是目前的标准治疗,以其为基础的联合方案的疗效已得到肯定,与靶向药物联合亦有一定的疗效。新的化疗药物和靶向药物的涌现,为局部晚期胰腺癌的治疗提供了更多的途径。     

靶向药物在进展期胰腺癌中的研究进展

胰腺癌是恶性度最高的恶性肿瘤之一,其发病率与病死率逐年上升,但是治疗进展缓慢。目前进展期胰腺癌的主要治疗手段是全身化疗。靶向药物中除了厄洛替尼联合吉西他滨在Ⅲ期临床试验中取得了具有统计学意义的疗效外,其他靶向药物尚未取得切实的疗效。     

胰腺癌的分子靶向药物治疗

胰腺癌发病率在世界范围内近年来有明显增加趋势,其首选治疗方法为手术切除,但因多数不能早期发现而切除率低.吉西他滨是目前晚期胰腺癌化疗的一线方案.其他化疗药物与吉西他滨联合治疗胰腺癌未发现能显著延长患者生存期,分子靶向药物成为目前研究的焦点.尽管用基质金属蛋白酶抑制剂和法呢基转移酶抑制剂治疗晚期胰腺癌的临床研究未得到满意的结果,但将VEGF和EGFR单克隆抗体,酪氨酸激酶抑制剂,COX-2抑制剂及其他免疫治疗方法用于胰腺癌的临床研究结果都令人鼓舞.     

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。     

低表达miR-33a诱导胰腺癌细胞对吉西他滨的耐药

背景与目的：胰腺癌是一种恶性程度很高的肿瘤。由于其对一线化疗药物吉西他滨的耐受,往往导致预后较差。MicroRNA(miRNA,miR)是一类非编码小RNA,参与肿瘤的多种生物学功能。miR-33a作为代谢相关的miRNA被广泛研究,而与耐药之间关系的报道较少。该研究通过探讨miR-33a参与胰腺癌吉西他滨耐药及其作用解析,为胰腺癌化疗提供新的理论依据。方法：采用原位杂交方法检测胰腺癌组织中miR-33a的表达情况;采用实时荧光定量PCR(Real-time PCR)检测各胰腺癌细胞系中miR-33a的表达情况。利用SW1990和Miapaca-2胰腺癌亲本细胞株,构建吉西他滨耐药细胞株(SW1990^res,Miapaca-2^res)及miR-33a稳定表达细胞株(SW1990-miR-33a,Miapaca-2-miR-33a、SW1990^res-miR-33a和Miapaca-2^res-miR-33a);采用细胞毒性实验检测miR-33a的表达对胰腺癌细胞对吉西他滨敏感性的影响。结果：miR-33a在胰腺癌组织样本中普遍低表达。与HEK293T正常人胚肾细胞相比,其在各胰腺癌细胞系中均呈低表达。miR-33a过表达可以增加胰腺癌细胞对吉西他滨的药物敏感性,能有效逆转胰腺癌细胞对吉西他滨的耐药。结论：miR-33a在胰腺癌组织中低表达,导致胰腺癌患者对吉西他滨获得性耐药。增加miR-33a表达,从而增强了胰腺癌细胞对吉西他滨的药物敏感性,为开发新型胰腺癌分子靶向治疗药物,联合化疗提供新的理论依据。     

胰腺癌的靶向治疗

放化疗联合靶向药物治疗是晚期胰腺癌的主要治疗手段.目前与胰腺癌治疗相关的靶向药物主要有表皮生长因子受体(EGFR)阻断剂、抗血管内皮生长因子(VEGF)单克隆抗体等.其中,厄洛替尼与吉西他滨(GEM)联合已被证实具有延长胰腺癌患者生存期的作用.     

Recent progress and limitations of chemotherapy for pancreatic and biliary tract cancers

Gemcitabine chemotherapy has been the standard for advanced pancreatic cancer for more than a decade. New oral fluoropyrimidines such as S-1 and capecitabine are other key drugs. Gemcitabine plus erlotinib was the only combination therapy that significantly prolonged survival, although the effect was minimal. Little or no improvement in survival with recent molecular-targeted drugs might be attributed to the very high incidence of K-ras gene mutation in pancreatic cancer. Recently, the non-gemcitabine-based-regimen of FOLFIRINOX showed significantly greater overall survival compared with gemcitabine for the first time. For biliary tract cancer, gemcitabine plus cisplatin combination chemotherapy has been proved to significantly prolong survival and will become the standard therapy. Further improvement in survival is expected by the addition of cetuximab.     

Synergistic effects of acyclic retinoid and gemcitabine on growth inhibition in pancreatic cancer cells

Pancreatic cancer is a serious healthcare problem worldwide because of its high mortality. Gemcitabine, a DNA synthesis inhibitor, is the standard first-line treatment for advanced pancreatic cancer and is also expected as a key drug for the combination therapy of this malignancy. Retinoids, which are derivatives of vitamin A, exert anti-tumor effects in various types of human malignancies, including pancreatic cancer. This study examined whether combination therapy with gemcitabine and acyclic retinoid (ACR), a new synthetic retinoid, had enhanced anti-tumor efficacy in pancreatic cancer. ACR, 9-cis-retinoic acid and gemcitabine preferentially inhibited the growth of human pancreatic cancer cells (Panc-1 and KP-2) in comparison to PE normal human pancreatic epithelial cells. The combination of ACR plus gemcitabine synergistically inhibited the growth of Panc-1 cells. The combined treatment with these two agents also acted synergistically to induce apoptosis and to inhibit Ras activation in these cancer cells. In vivo, the combination therapy augmented tumor growth inhibition through the induction of apoptosis and inhibition of cell proliferation in tumor tissue. These results suggest that the combination of ACR plus gemcitabine may therefore be an effective regimen for the chemotherapy of pancreatic cancer.     

胰腺癌的治疗进展

外科是胰腺癌惟一可能治愈的手段。放化综合治疗可提高局部晚期患者的中位生存期。抗血管生成是有吸引力的治疗靶标,生物靶向治疗与化疗联合对局部晚期胰腺癌患者有一定的疗效。     

胰腺癌的治疗进展

外科是胰腺癌惟一可能治愈的手段。放化综合治疗可提高局部晚期患者的中位生存期。抗血管生成是有吸引力的治疗靶标,生物靶向治疗与化疗联合对局部晚期胰腺癌患者有一定的疗效。     

晚期非小细胞肺癌的维持化疗

维持化疗对晚期非小细胞肺癌(NSCLC)可延长生存期.诱导化疗方案中证实有效的药物可用于维持化疗,二线、三线化疗药物及分子靶向药物似乎更适合用于晚期NSCLC维持化疗.     

Combinational therapy: New hope for pancreatic cancer?

Pancreatic cancer is a devastating disease with a low overall survival rate. Chemotherapy is the most common treatment for patients presenting with advanced pancreatic cancer. Gemcitabine achieves a modest improvement in overall survival and is the gold standard for advanced pancreatic cancer treatment. Capecitabine and S-1, derivatives of 5-fluorouracil (5-FU), offers minimal clinical benefits. Folfirinox represents a new and aggressive regimen that might benefit patients of metastatic pancreatic cancer with good performance status. Other chemotherapy drugs such as platinums and irinotecan do not provide significant improvement in overall survival, but have been used as part of combinational therapies. Comparing to systemically delivered chemotherapy, regional intra-arterial chemotherapy achieves higher local drug concentration in tumors with lower systemic drug toxicity, and may serve as a better treatment regimen. Although there have been progress made in chemotherapeutic strategies against pancreatic cancer, the overall survival is not significantly improved in the last decade. Recently, development of chemotherapy in combination with molecular targeted therapies holds great promise in pancreatic cancer treatment, especially in patients with metastatic disease. Growing bodies of preclinical and clinical evidences indicate that the combination of conventional modalities with specific molecular targeted therapy increase the efficacy of the monotherapy without an increase in toxicity. In this review, we summarized the current regimens of chemotherapy and molecular targeted therapy for advanced pancreatic cancer and highlighted the novel combinational treatments tested in recent clinical trials.     

动脉持续灌注化疗与静脉全身化疗治疗中晚期胰腺癌的疗效分析

Objective: To compare the curative effectiveness of continuous transarterial infusion chemotherapy and systemic venous chemotherapy in treating patients with advanced pancreatic cancer, and to evaluate the value of selective continuous transarterial infusion chemotherapy in treating advanced pancreatic cancer. Methods: Of the 51 patients with advanced pancreatic cancer receiving chemotherapy with gemcitabine and 5-fluorouracil, 25 patients were treated with selective continuous transarterial infusion chemotherapy, 26 were treated with systemic venous chemotherapy, and curative effectiveness was analyzed retrospectively. Curative effectiveness included tumor volume, clinical benefit response (CBR), acute and subacute toxic reactions of antitumor drugs, survival rate and median survival time. Results: The objective effective rate in transarterial group was 32.0% versus 23.1% in systemic group without any significant difference (P = 0.475). Clinical benefit rates in transarterial group and systemic group were 80.0% and 50.0% respectively (P = 0.025). The 6-, 9- and 12-month accumulated survival rates and median survival time in transarterial group were higher than those of the systemic group (P = 0.002), the differences were statistically significant. However, the adverse reactions between the two groups were not statistically significant. Conclusion: Compared with systemic chemotherapy, continuous transarterial infusion chemotherapy with gemcitabine and 5-fluorouracil could improve clinical benefit rate and survival time of patients with advanced pancreatic cancer, it is safe and reliable, and the adverse reactions is less.     

Epidermal growth factor receptor-targeted therapy for pancreatic cancer

Clinical and experimental work supports the view that the epidermal growth factor receptor (EGFR) is a relevant target for cancer therapy. Expression of EGFR is exaggerated in pancreatic adenocarcinoma and activation of EGFR appears to have an important role in the growth and differentiation of this and other types of cancers. EGFR-targeted therapeutic approaches have shown clinical activity in advanced human cancers for which chemotherapy over the last 30 years has sustained a mere palliative role at best. Therefore, the need remains for novel anti-cancer therapies that effectively and specifically target epithelial tumor cells while minimizing the toxic side-effects commonly associated with cytotoxic conventional therapies. Agents capable of inhibiting EGFR activity with resultant inhibition of cell proliferation and angiogenesis have significant potential as chemotherapeutic agents for the treatment of pancreatic adenocarcinomas as well as multiple other malignancies.