Biologic therapies for advanced pancreatic cancer

Patients with metastatic pancreatic cancer have poor prognosis and short survival due to lack of effective therapy and aggressiveness of the disease. Pancreatic cancer has widespread chromosomal instability, including a high rate of translocations and deletions. Upregulated EGF signaling and mutation of K-RAS are found in most pancreatic cancers. Therefore, inhibitors that target EGF receptor, K-RAS, RAF, MEK, mTOR, VEGF and PDGF, for example, have been evaluated in patients with pancreatic cancer. Although significant activities of these inhibitors have not been observed in the majority of pancreatic cancer patients, an enormous amount of experience and knowledge has been obtained from recent clinical trials. With a better inhibitor or combination of inhibitors, and improvement in the selection of patients for available inhibitors, better therapy for pancreatic cancer is on the horizon.     

晚期胰腺癌二线治疗的研究进展

一线使用吉西他滨已成为晚期胰腺癌治疗的标准方案，但是目前尚无标准的二线化疗方案。支持二线治疗优于最佳支持治疗的数据少之又少。我们总结已公布的二线化疗方案，大部分为Ⅱ期临床试验，以摘要的形式发表居多，没有单药的广泛研究。以药物的副作用作为代价，二线化疗的益处是非常有限的，但Ⅲ期随机试验还需要继续进行。未来的二线化疗将不仅以有效率或生存期作为评价，还将把临床受益率作为治疗目标。     

胰腺癌综合治疗的研究进展

胰腺癌发病隐匿,进展迅速,预后极差,病死率高。手术是主要治疗手段,但因早期诊断困难,大部分患者确诊时已无手术机会。随着新型化疗药物和方案的不断涌现;放疗技术及设备的明显改进和以基因治疗和免疫治疗为代表的生物疗法的发展,胰腺癌的治疗手段更加多样化和正规化。正确运用综合治疗有望改善胰腺癌的预后。     

晚期胰腺癌的内科治疗进展

胰腺癌是恶性程度极高、预后极差的消化系统肿瘤。由于发现时多为晚期,因此化疗、放疗、靶向等内科治疗是目前晚期胰腺癌的主要治疗手段。以吉西他滨、氟尿嘧啶、铂类为基础的传统化疗在晚期胰腺癌治疗中疗效有限,白蛋白结合型紫杉醇、厄洛替尼、尼妥珠单抗等药物尚处于临床试验阶段。因此,寻求新的靶标及治疗手段显得尤为重要。本文就晚期胰腺癌的内科治疗进展作一综述。     

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.     

Radical reoperation for advanced pancreatic carcinoma

The indications and outcomes of aggressive reoperation in patients referred to the National Cancer Institute (NCI) for protocol therapy of locally advanced pancreatic carcinoma were investigated. Twenty-nine patients referred to the NCI after exploration and determination of unresectability elsewhere were considered to have localized disease after a metastatic work-up. These patients were then entered onto NCI adjuvant therapy protocols and taken to exploratory laparotomy. Intraoperatively, patients underwent complete resection if possible; otherwise varying palliative surgical procedures were performed. Of the 29 patients, 16 underwent complete resection of their disease, and 13 were unresectable. Two patients suffered postoperative mortality. Disease-specific survival of the resected patients was significantly better than that of the unresectable patients (P < 0.01). The two long-term survivors (53 and > 109 months) underwent definitive surgery after a palliative procedure elsewhere. Complete resection of pancreatic carcinoma contributes to increased survival. The intraoperative definition of unresectability in pancreatic cancer varies with the degree of pancreatitis present, the surgical expertise of the surgeon, and the available ancillary services. Given the extremely grave prognosis of patients with unresectable pancreatic carcinoma, locally unresectable patients without peritoneal seeding or distant metastases at exploration should be considered for referral for protocol therapy to centers where expertise in radical surgery for pancreatic cancer exists. (This article is a US Government work and, as such, is in the public domain in the United States of America.) © 1996 Wiley-Liss, Inc.     

不可切除晚期胰腺癌的综合治疗

胰腺癌（Pancreatic cancer,PC）恶性度高,肿瘤生长迅速,是癌症死亡常见病因之一,在欧美国家排名第4位,我国排名第9位.尽管目前在诊断方面有所进展,但80％以上患者确诊时已为不可切除的局部晚期或转移患者,所以在治疗上必须接受多学科综合治疗,如化疗、放疗、靶向治疗等.本文就目前各学科治疗进展进行综述,以期为不可切除晚期PC的临床综合治疗提供参考和依据.     

New approaches in systemic treatment of advanced colorectal cancer: the molecular targets era

The prognosis of advanced colorectal cancer remains poor in spite of the advances obtained in recent years with new therapeutic agents, new approaches in surgical procedures and new diagnostic methods. New treatments directed to molecular targets have emerged and are being developed to improve these results, but there is a need to optimize and define the best use of these new approaches. In this review, the authors examine the most important trials with monoclonal antibodies and tyrosine kinase inhibitors in the treatment of advanced colorectal cancer.     

胰腺癌分子靶向治疗进展

胰腺癌在胃肠道肿瘤中预后差,5年生存率不到5％,发病率呈逐渐上升趋势。治疗主要是外科手术、化疗和放疗相结合的综合治疗,但目前常规治疗效果有限,因此针对胰腺癌生物学特性进行治疗是改善预后的关键。随着靶向治疗的进展,VEGF单克隆抗体和EGFR抑制剂在临床试验中都表现出较好的前景。其他靶向药物,如沙利度胺、基质金属蛋白酶抑制剂、COX-2抑制剂和法尼基转移酶抑制剂还在研究之中。分子靶向治疗将为胰腺癌的治疗提供新的机会。     

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。     

Fast neutron irradiation for locally advanced pancreatic cancer

Nineteen patients with locally advanced pancreatic cancer and one patient with islet cell cancer were treated with 1700–1750 neutron rad alone or in combination with 5-flourouracil to exploit the theoretic advantages of higher linear energy of transfer, and lower oxygen enhancement ration of neutrons. Only 5 of 14 (36%) obtained partial tumor regression. The median survival for all patients with pancreatic cacer was 6 months, which is less than that reported with 5-flouracil and conventional photon irradiation. Gastrointestinal toxicity was considerable; hemprrhagic gastritis in five patients, colitis in two and esophagitis in one. One patient developed radiation myelitis. We therefore, caution any enthusiasm for this modality of therapy until clear evidence of a therapeutic advantage over photon therapy is controlled clinical trials.     

Staging for locally advanced pancreatic cancer

Aim

To address the role of a dedicated radiologist and high quality CT scanning in staging of patients referred with suspected locally advanced pancreatic cancer. Furthermore, the value of laparoscopy in detecting CT-occult metastases in these patients was assessed.

Methods

In a prospective cohort study, 116 patients with suspected unresectable pancreatic cancer referred from peripheral hospitals (107) or our own gastroenterology department (9) were analysed. CT scans from referral centres were reviewed and in case of locally advanced disease or uncertain metastatic disease, patients underwent a laparoscopy to detect CT-occult metastases. Patients without metastases were offered 5-FU based chemoradiotherapy.

Results

After reviewing 107 abdominal CT scans from referral centres, 73 (68%) scans had to be repeated due to unacceptable quality. Locally advanced disease was confirmed in 59 (55%) patients and metastatic disease was found in 24 patients (22%). During laparoscopy, metastases were found in 24/68 (35%) patients with locally advanced disease on CT scan and metastases were confirmed in 3/5 (60%) with suspected metastases.Overall, only 46/116 (40%) patients with suspected unresectable disease appeared to have locally advanced pancreatic cancer after adequate staging including laparoscopy in our centre.

Conclusion

Correct staging is difficult in patients with suspected locally advanced pancreatic cancer and should preferably be performed in centres with technically advanced equipment and experienced radiologists. Laparoscopy should be offered to patients before locoregional therapy.     

Exploiting inflammation for therapeutic gain in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.     

吉西他滨联合奥沙利铂治疗进展期胰腺癌（附40例）

目的：观察吉西他滨（择菲GEM）联合奥沙利铂（艾恒OXA）组成的GEMOX方案治疗进展期胰腺癌的有效性和安全性。方法：进展期胰腺癌40例,应用GEM800mg／m2静滴半小时,d1,d3;OXA60mg／m2静滴2小时,d2,d9;21天重复。至少接受2个周期的化疗,按照WHO标准进行评价。结果：观察化疗后肿瘤原发病灶的变化情况及化疗的不良反应。临床有效率为17．5％,具有较好的耐受性,不良反应主要有骨髓抑制和消化系统反应。结论：健择联合艾恒治疗进展期胰腺癌疗效较好,不良反应可以耐受。     

吉西他滨联合奥沙利铂治疗进展期胰腺癌(附40例)

目的:观察吉西他滨(择菲GEM)联合奥沙利铂(艾恒OXA)组成的GEMOX方案治疗进展期胰腺癌的有效性和安全性。方法:进展期胰腺癌40例,应用GEM800mg/m2静滴半小时,d1,d8;OXA60mg/m2静滴2小时,d2,d9;21天重复。至少接受2个周期的化疗,按照WHO标准进行评价。结果:观察化疗后肿瘤原发病灶的变化情况及化疗的不良反应。临床有效率为17.5%,具有较好的耐受性,不良反应主要有骨髓抑制和消化系统反应。结论:健择联合艾恒治疗进展期胰腺癌疗效较好,不良反应可以耐受。     

晚期胰腺癌的分子治疗研究现状

胰腺癌是全球第七大致命的恶性肿瘤,分别是美国胃肠道恶性肿瘤和癌症相关死亡的第二大和第三大原因。与其他恶性肿瘤相比,晚期胰腺癌患者的生存率最低,中位总体生存率为2~8个月,5年生存率为8.5%。治疗十分困难,给临床医生带来极大挑战。目前晚期胰腺癌的治疗药物匮乏,化疗仍然是其主要治疗方法。虽然化疗能短暂的控制疾病的进展,但是在生存期的延长方面却差强人意。分子靶向治疗已在其他的瘤种中取得了里程碑般的成就,譬如肺癌、结直肠癌等,但晚期胰腺癌患者的分子靶向治疗效果并不显著。这需要我们去寻找新的治疗靶点和药物。本文基于胰腺癌信号传导通路及肿瘤微环境,总结和分析晚期胰腺癌分子治疗的研究现状,探索未来胰腺癌治疗的发展方向。     

立体定向放射治疗联合吉西他滨与吉西他滨单药治疗局部晚期胰腺癌疗效比较

  [摘要]　　　目的 评价立体定向放射治疗联合吉西他滨与吉西他滨单药治疗局部晚期胰腺癌的疗效。方法 对治疗组56例胰腺癌患者行立体定向放射治疗(总剂量4000~4500CGY,10次分割)联合盐酸吉西他滨单药化疗(500mg/m2第1、8天)。对照组50例仅行盐酸吉西他滨单药化疗（500mg/m2第1、8、15天）。结果[给出各项主要数据] 治疗结束2个月CT复查,治疗组及化疗组局部控制率分别为98%、78%（P<0.05）,疼痛控制率分别为67%、17%（P<0.05）。治疗组中位PFS为14个月,较化疗组7.5个月明显延长（P<0.05）。治疗组与化疗组中位生存期分别为15.8、13.2个月（P>0.05）。结论 立体定向放射治疗联合吉西他滨治疗局部晚期胰腺癌较单纯化疗组近期疾病控制率较高,能延长患者无病生存期,显著提高患者的生存质量。     

Gefitinib in the treatment of advanced non-small-cell lung cancer

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor, even after platinum-based chemotherapy. EGF receptor (EGFR)-targeted therapies, such as gefitinib, have been subject to comprehensive clinical development. Several Phase II and III trials have evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemo-naive patients. A Phase III trial in heavily pretreated advanced NSCLC patients, 90% of whom were refractory, demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant in the overall population. A second large Phase III trial in patients with pretreated advanced NSCLC (INTEREST) demonstrated the noninferiority of gefitinib in comparison with docetaxel for overall survival together with an improved quality of life and tolerability profiles. As a result, gefitinib is expected to have a large impact in the management of pretreated patients with NSCLC.     

Combined modality treatment of pancreatic cancer: implications for the surgeon

Since pancreatic cancer is still increasing and has a poor prognosis, there is great interest in improving treatment results by combined modality approaches. This paper considers the most appropriate studies to analyze the status of treatment and future implications for surgeons. With new radiation sources and more sophisticated treatment plans, intra- and post-operative radiotherapy now has an established role in local tumor control. Combination chemotherapy has yielded response rates of 40-45% and improved chemotherapy will play a role in the treatment and perhaps in the prevention of disseminated disease. Although it seems likely that chemotherapy combined with newer radiotherapeutic technique could improve treatment results in advanced pancreatic cancer, treatment-related and limiting toxicity still must be defined. There are suggestions that more surgeons become involved in the combined modality approach, as both radiotherapy and chemotherapy may be more valuable in primary management. The unsatisfactory results of surgical treatment imply the need for adjuvant treatment, which must be tested in randomized multicenter trials. Future efforts will require an interdisciplinary approach to this disease.