不可切除结直肠癌肝转移的转化性治疗策略

手术是治疗结直肠癌肝转移最有效的也是惟一有可能治愈的手段,但是大多数结直肠癌肝转移病人并不能够行肝转移灶切除手术。近些年,用各种细胞毒药物和（或）靶向药物等使不可切除的肝转移病灶缩小,转化为可切除,继而行手术切除,从而获得治愈的可能。转化性治疗的目的是获得最佳反应率,而不是获得最大反应率。术前转化性化疗应选择高效化疗方案,并尽量缩短疗程。具体方案选择方面,KRAS野生型病人推荐西妥昔单抗联合FOLFOX/FOLFIRI,其中5-氟尿嘧啶持续给药,而KRAS突变型病人考虑贝伐珠单抗联合两药化疗或者三药化疗方案。在行转化性治疗时,一旦转移灶转化为可切除,应积极手术切除。     

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2012年美国国家癌症综合网(National Comprehensive Cancer Network,NCCN)指南中结直肠癌新辅助和解救化疗方案出现了一些变更。由于在两项Ⅲ期随机对照研究中西妥昔单抗无法在奥沙利铂化疗的基础上进一步延长病人生存期,FOLFOX联合西妥昔单抗的方案被从KRAS野生型晚期结直肠癌病人的解救化疗和非转化性新辅助化疗中剔除。但在转化性新辅助化疗中,EGFR单抗联合奥沙利铂为基础的化疗方案仍具有合理性。卡培他滨联合贝伐珠单抗具有良好安全性增加为不能耐受高强度化疗的进展期或转移性结直肠癌的一种初始治疗选择。Ⅱ/Ⅲ期直肠癌术前同步放化疗首选卡培他滨或静脉输注氟尿嘧啶联合放疗。3项研究结果表明,在直肠癌新辅助同步放化疗中卡培他滨或静脉输注5-FU联合放疗为目前首选方案,增加奥沙利铂并不能进一步增加近期疗效。     

胃肠道肿瘤的分子标志物与个体化治疗

胃肠道肿瘤是我国的常见恶性肿瘤．严重影响中国人的健康。随着肿瘤分子标志物研究的深入和新型抗肿瘤药物的开发应用,胃肠道肿瘤的治疗模式正在不断发生着变化．越来越多的分子靶向药物如曲妥珠单抗、西妥昔单抗和贝伐单抗等开始应用于临床。基于肿瘤分子分型制定适合患者的个体化治疗策略必将使更多的患者从治疗中获得益处,是未来胃肠道肿瘤治疗的必然趋势。     

直肠癌的靶向药物治疗

近些年,在晚期结直肠癌中靶向治疗明显延长了患者生存期.但是这些大规模的临床研究数据主要来自以结肠癌为主的欧美人群.在我国,直肠癌发病率高,约占全部结直肠癌50％[1].并且由于直肠的特殊解剖结构,易出现局部复发和血行转移（如肺转移）.同时,直肠癌术式的选择也直接影响着患者长期生存的生活质量.因此直肠癌的治疗较结肠癌而言要更复杂,更需要在多学科指导下进行综合治疗.针对直肠癌如何合理地应用抗血管生成类的靶向药物（如贝伐珠单抗）和抗EGFR单抗类的靶向药物（如西妥昔单抗和帕尼单抗）,是我们临床实践需要关注的重点之一.     

贝伐珠单抗联合化疗治疗进展期结直肠癌的疗效观察

目的:观察贝伐珠单抗联合化疗治疗进展期结直肠癌患者的疗效.方法:将进展期结直肠癌患者92例随机分为贝伐珠单抗组和对照组,每组46例.贝伐珠单抗组患者采用贝伐珠单抗加化疗治疗,对照组患者采用常规化疗,观察2组患者的疗效、血清指标、无进展生存情况及术后不良反应发生率.结果:贝伐珠单抗组总有效率及1年、2年、3年无进展生存率...     

胃癌药物治疗新视角

随着新的化疗药物的应用及相关临床研究的开展,胃癌围手术期化疗研究取得了一定的进步.但是姑息化疗进步甚微,晚期胃癌患者的中位生存期仍徘徊在8～10个月.随着人们对胃癌生物学行为及信号传导通路认知的深入.越来越多的靶向药物如曲妥珠单抗、贝伐珠单抗或西妥昔单抗等开始应用于临床.但同时,胃癌的高度异质性致使临床实践中出现很多困难,如怎样合理地实施围手术期化疗、如何实现细胞毒药物和靶向药物在晚期胃癌中的个体化治疗等,应密切结合我国胃癌的具体情况.开展多中心、随机和前瞻性临床研究,充分认识胃癌的异质性,深入了解其生物学特性,加强转化性研究及多学科协作,真正实现个体化治疗.     

结直肠癌肝转移的分子机制研究进展

目的对近年来国内外就结直肠癌肝转移的分子机制研究进展的文献进行总结,旨在为结直肠癌肝转移的诊治及研究提供帮助。方法复习近年来国内外针对结直肠癌肝转移的文献并进行综述。结果影响结直肠癌肝转移的分子机制复杂,如microRNA-192可通过多个靶点抑制结直肠癌肝转移,microRNA-181a则可以促进结直肠癌肝转移。转化生长因子β(Transforming growth factor beta,TGF-β)通过抑制细胞增殖和Smad依赖性信号传导诱导细胞凋亡,起到抑制肿瘤生长的作用。CEA水平的升高不仅对结直肠癌的诊断提供帮助,作为结直肠癌患者的预后指标,CEA还影响结直肠癌细胞在血管中的存活、改变肝脏微环境以及循环肿瘤细胞在肝脏中的黏附和存活,促进肝转移。结论结直肠癌肝转移的分子机制尚未完全阐明,通过对结直肠癌肝转移机制的深入研究,可为结直肠癌肝转移提供分子靶向治疗靶点,如贝伐单抗、西妥昔单抗、帕尼单抗等。检测结直肠癌患者血清学CEA的变化,可以有助于结直肠癌的诊断、判断复发和预后以及转移情况。     

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根据病人状况和治疗目标设定治疗策略是目前结直肠癌重要治疗原则。对于潜在可切除的转移性结直肠癌,更高的肿瘤缓解率将不可切除病灶转化为可切除病灶的概率进一步提高,达到延长总生存期甚至治愈的目的,因此选择客观缓解率高的联合方案更适合;对于不可切除但肿瘤进展迅速同时合并明显临床症状的病人,缩小肿瘤、延长肿瘤控制时间、改善生活质量应作为主要治疗目标,因此具备近期疗效高的联合方案适于该类病人;对于肿瘤进展缓慢的不可切除的转移性结直肠癌,选择毒性反应相对较小的方案延缓肿瘤增长应作为合理的策略,单药对该类病人也具有一定价值。临床研究证实分子靶向药物联合化疗进一步提高了转移性结直肠癌的客观疗效以及生存期,但在转移性结直肠癌综合治疗中如何根据病人状况及肿瘤特点,通过多学科协作分析,筛选出分子靶向药物敏感的疗效预测因子、探讨分子靶向药物与细胞毒药物之间的相互作用、探寻其耐药机制,合理应用分子靶向药物,优化最佳治疗方案,并选择恰当的时机、是实现治疗目标、改变病人疾病转归的重要保证。     

局部进展期直肠癌术前放化疗中新化疗药物应用进展

基于氟尿嘧啶的术前同期放化疗是局部进展期直肠癌标准治疗模式,而探讨新化疗药物如希罗达、奥沙利铂、伊立替康、贝伐单抗和西妥昔单抗在其新辅助放化疗中的作用越来越引起人们兴趣,并开展了一系列Ⅰ-Ⅲ期临床研究,部分取得了积极结果,而有些并不理想。希罗达在局部进展期直肠癌新辅助放化疗中的地位已普遍获得公认．且有取代常规氟尿嘧啶趋势,而奥沙利铂、伊立替康及生物靶向类药物在其中的作用却存在明确争议,临床获益有限。彼此药物之间或靶点药物与放射线之间的相互作用机制研究、新的治疗反应预测靶点及合适个体的筛选可能是今后发展方向。     

转移性结肠直肠癌分子靶向治疗临床研究进展

结肠直肠癌(colorectal cancer,CRC)是全球最常见的恶性肿瘤之一,约25%的病人在初诊时已转移[1];即使早期发现并接受根治的病人,也有约三分之一最终会出现转移复发,这些转移性结肠直肠癌(metastatic CRC,m CRC)病人的5年生存率常低于50%[2]。近年来分子靶向药物的出现显著改善了m CRC病人的预后,其生存期从单纯化疗的20个月提高到近30个月[1]。迄今为止,已有多个分子靶向药物被美国食品和药品管理局(Food and Drug Administration,FDA)批准使用,包括贝伐珠单抗、西妥昔单抗和帕尼单抗等。现就其各自不同的抗肿瘤作用和临床疗效作一综述。     

Update on chemotherapy for advanced bladder cancer

PURPOSE: Recent years have seen several advances in the treatment of locally advanced and metastatic bladder cancer. We summarize the current state of the art for advanced bladder cancer treatment. MATERIALS AND METHODS: A comprehensive review of published, prospective phase II/III clinical trials and retrospective analyses of patients with advanced bladder cancer was performed. RESULTS: Adjuvant and neoadjuvant chemotherapeutic strategies around the time of radical cystectomy have been used to decrease the risk of subsequent metastatic disease. Although the benefit of adjuvant chemotherapy remains unproven, neoadjuvant chemotherapy is associated with a modest 5% to 6% absolute survival benefit in 2 meta-analyses of the available data. Chemoradiation is feasible and effective in some patients, allowing bladder preservation with an acceptable risk of progression. Randomized, phase III data comparing methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy to gemcitabine/cisplatin showed similar response proportions and overall survival with less toxicity in the gemcitabine/cisplatin arm. This has led to the widespread use of gemcitabine/cisplatin as first line chemotherapy for metastatic bladder cancer. The optimal agents and regimens for second line chemotherapy remain undefined. Similarly biological and targeted therapies for advanced bladder cancer remain investigational. CONCLUSIONS: Combination cisplatin based neoadjuvant chemotherapy may benefit patients with locally advanced bladder cancer. Gemcitabine/cisplatin has replaced methotrexate, vinblastine, doxorubicin and cisplatin as the regimen of choice in patients with good renal function. The optimal regimens for the medically unfit patient and second line chemotherapy remain undefined. The development of targeted therapies, less toxic regimens and improved cytotoxic agents are necessary to improve outcomes.     

Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer

OBJECTIVE: In Western populations, long-term survival rates after curative resection of gastric cancer remain extremely poor. The lack of effective adjuvant therapy has prompted the evaluation of neoadjuvant approaches. Since 1988, we have conducted three separate phase II trials using neoadjuvant chemotherapy to treat patients with potentially resectable gastric cancer. The present study was conducted to evaluate whether response to neoadjuvant chemotherapy is predictive of survival in patients with resectable gastric cancer. METHODS: Eighty-three patients with pathologically confirmed gastric adenocarcinoma were treated with neoadjuvant chemotherapy before planned surgical resection. Response was assessed by upper gastrointestinal series, endoscopy, computed tomography scan, and pathologic examination. RESULTS: For the three phase II trials, clinical response rates ranged from 24% to 38%. Three patients (4%) had a complete pathologic response. Sixty-one patients (73%) underwent a curative resection. Median follow-up was 26 months. Univariate analysis revealed T stage, number of positive nodes, and response to chemotherapy to be significant predictors of overall survival. However, on multivariate analysis, response to chemotherapy was found to be the only independent prognostic factor. CONCLUSIONS: Response to neoadjuvant chemotherapy is the single most important predictor of overall survival after neoadjuvant chemotherapy for gastric cancer. These findings support further evaluation of neoadjuvant approaches in the treatment of this disease.     

Multidisciplinary Management of Locally Advanced Breast Cancer

▪ Abstract: The treatment of locally advanced breast cancer is aimed at achieving long-term local control with local surgery and/or radiation therapy and at improving disease-free and overall survival through the application of systemic cytotoxic chemotherapy and hormonal therapy. Studies of local therapy alone with surgery or radiotherapy have demonstrated high rates of local recurrence and low rates of long-term survival. The application of anthracycline-based neoadjuvant chemotherapy has resulted in rates of response ranging from 72% to 97%, clinical complete responses of 12–52%, and pathologic complete responses of 4–33%. Multidisciplinary treatment with neoadjuvant therapy, followed by local surgery and/or radiation therapy, followed by additional chemotherapy, has resulted in rates of local control that exceed 80%, and 5-year survival rates exceeding 50% are not unusual. The use of anthracycline-based neoadjuvant chemotherapy in the treatment of locally advanced breast cancer is thus now firmly established. Research in the treatment of locally advanced breast cancer is needed to further define the optimal method of local therapy and the role of new agents such as the taxanes. ▪     

Advances in the management of recurrent or metastatic squamous cell carcinoma of the head and neck

Most patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) undergo definitive therapy, yet locoregional recurrence and metastasis are common. Most patients ultimately require systemic treatment. Platinum/5‐fluorouracil (5‐FU) has been the standard of care for patients with good performance status (median survival, 6–8 months). Cetuximab, a monoclonal antibody against epidermal growth factor receptor (EGFR), significantly improved median survival in combination with platinum/5‐FU compared with chemotherapy alone, establishing it as a new standard for patients with recurrent or metastatic disease. Cetuximab is also active in platinum‐refractory disease. Ongoing trials are exploring other EGFR inhibitors as well as the use of biologic agents in combination (eg, cetuximab + bevacizumab). Predictive biomarkers may help personalize therapy for SCCHN, and it is unclear whether the favorable prognostic effect of p16 or human papillomavirus in locally advanced oropharyngeal cancer is relevant for advanced disease. Head Neck, 2013     

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??Treatment strategy for unresectable local advanced gastric cancer from a surgical point of view LIANG Han. Department of Gastric Cancer Surgery, Tianjin Medical University Cancer Institute & Hospital??National Clinical Research Center for Cancer??Tianjin 300060??China
Abstract According to Yoshida’s stage IV gastric cancer classification, for some patients with marginally resectable and potentially unresectable metastatic gastric cancer??neoadjuvant intraperitoneal plus systematic chemotherapy (NIPS)??cytoreductive surgery??CRS?? plus hyperthermic intraperitoneal chemotherapy (HIPEC)??palliative surgery plus chemotherapy??conversion therapy with docetaxel based three drug regimen and S1/paclitaxel chemotherapy plus apatinib may be benefited. For patients with moderate amount and more ascites??NIPS regimen may control the ascites, relieve symptoms and prolong the survival time. CRS+HIPEC has been demonstrated to provide survival benefit for patients with PCI (peritoneal cancer index) score≤6. It is still controvertial whether the palliative surgery followed by chemotherapy may benefit for patient or not??but judicious use of surgical resection both gastrectomy and metastasis before chemotherapy in metastatic gastric cancer patients may result in favorable treatment approach. Conversion therapy with docetaxel based three drug regimen and chemotherapy combined with apatinib may result a high conversion rate.     

Neoadjuvant treatments in digestive cancer

Neoadjuvant chemotherapy or chemoradiotherapy is an important concept in the treatment of colorectal liver metastasis, gastric cancer, and esophageal or rectal tumors. This treatment strategy improves disease-free survival and sometimes overall survival. It allows surgical resection of lesions that where not resectable at diagnosis. The new standards of neoadjuvant treatments in gastrointestinal oncology are described in this article.     

结直肠癌同时性肝转移新辅助化疗后手术对比直接手术患者的生存疗效

目的对比结直肠癌同时性肝转移行新辅助化疗后手术与直接手术患者的生存疗效。方法本研究采用回顾性队列研究方法,纳入在2008年1月至2018年12月期间,北京大学肿瘤医院肝胆胰外一科收治的282例初始评估为技术上可切除的结直肠同时性肝转移患者。以肝转移术前是否接受过新辅助化疗,分为新辅助化疗组(244例)和直接手术组(38例),比较两组的总生存时间(OS)和无进展生存时间(PFS)。采用倾向性评分校正后进行Cox多因素生存分析,校正的因素包括:性别、年龄、原发肿瘤部位、原发肿瘤T分期、临床风险评分(CRS)、RAS状态、辅助化疗有无、切缘状态。结果244例新辅助化疗组患者术前完成4(1~15)个周期的化疗,其中207例患者一线选择奥沙利铂为主的化疗方案,37例患者一线选择伊利替康为主的化疗方案,90例患者一线联合了靶向治疗。全组患者中位随访时间为30(5~134)个月,失访率1%。未校正前,新辅助化疗组1、3年OS分别为95.1%和66.4%,直接手术组1、3年OS分别为94.7%和51.5%,差异有统计学意义(P=0.026);新辅助化疗组1、3年PFS分别为51.0%和23.4%,直接手术组1、3年PFS分别为39.5%和11.5%,差异有统计学意义(P=0.039)。经倾向性评分校正后,Cox多因素分析显示,新辅助化疗是PFS的独立保护因素(HR=0.664,95%CI:0.449~0.982,P=0.040),但不是OS的独立保护因素(HR=0.651,95%CI:0.393~1.079,P=0.096)。亚组分析显示:新辅助一线化疗有效组(194例,包括完全缓解、部分缓解及缩小但未达到部分缓解)的1、3年OS分别为96.9%和67.1%,优于直接手术组(94.7%和51.5%),经倾向性评分校正后差异有统计学意义(P=0.026);而新辅助一线化疗无效组(50例,包括肿瘤进展或增大)的1、3年OS分别为90.0%和63.3%,与直接手术组(94.7%和51.5%)相比,经倾向性评分校正后差异无统计学意义(P=0.310)。结论对于可切除的结直肠癌同时性肝转移患者,新辅助化疗后行肝切除手术相对于直接手术可使患者获得更长的疾病控制时间,虽然整体OS获益不明显,但新辅助一线化疗有效患者的OS优于直接手术者。     

Adjuvant treatment strategies for pancreatic cancer

Pancreatic cancer is a difficult and unsolved surgical problem. It remains one of the top five causes of cancer-related deaths and has the lowest 5-year survival of any cancer, largely due to late diagnosis, low resection rates, and local recurrence. Clinical trials examining the optimal timing and delivery of adjuvant therapies for pancreatic cancer have yielded controversial results. Although most experts agree that the addition of chemotherapy has survival benefit in patients with resectable pancreatic cancer, there is no consensus regarding the optimal therapeutic agents, timing (neoadjuvant versus adjuvant), and the addition of radiation therapy to the treatment regimen. Multiple phase III trials are in progress in efforts to examine these issues. Additionally, exciting progress has been made with novel chemotherapeutic combinations, and alternative treatment modalities including interferon-α, immunotherapy, and pancreatic cancer stem cells. Given the high failure pattern after surgical resection, with more than half of patients developing locoregional recurrence, all patients undergoing pancreaticoduodenectomy are candidates for adjuvant therapy.     

Biotherapy in colorectal cancer

Strategies for the treatment of metastatic colorectal cancer must take into account the contribution of monoclonal antibodies. A group of new efficient tools in oncology, these drugs target tumor antigens. Bevacizumab recognizes VEGF. Vascular endothelial growth factor (VEGF) is a key mediator in angiogenesis. This antibody combined with chemotherapy increases the survival of patients treated for metastatic colorectal cancer. Median survival of patients treated with antibodies and chemotherapy is 20 months, compared with only 15 months for patients treated with chemotherapy alone. Cetuximab is a monoclonal antibody that binds competitively and with high affinity to the EGF receptor. Cetuximab is currently approved for use in patients with pretreated colorectal cancer. EGF is a major cell growth factor. The side effects of these new biotherapies are different from chemotherapy: bevacizumab affects vascular elements and the most common side effect of anti-EGFR treatment is acneiform skin rash.     

The Role of Preoperative Chemotherapy in Patients with Resectable Colorectal Liver Metastases

Background  Liver metastases develop in 40–50% of patients with colorectal cancer and represent the major cause of death in this disease. Surgical resection remains the only treatment procedure that can ensure long-term survival and provide cure when liver metastases can be totally resected with clear margins, when the primary cancer is controlled, and when there is no nonresectable extrahepatic disease. Five-year survival rate after surgical resection of colorectal metastases varies from 25% to 55%, but cancer relapse is observed in most patients. Aim  To review the potential benefits and disadvantages of neoadjuvant chemotherapy administered before surgery to patients with initially resectable metastases. Results  European Organization for Research and Treatment of Cancer (EORTC) study 40983 has shown that neoadjuvant chemotherapy could reduce the risk of relapse by one-quarter, and allows to test the chemosensitivity of the cancer, to help to determine the appropriateness of further treatments, and to observe progressive disease, which contraindicates immediate surgery. Neoadjuvant chemotherapy can induce damage to the remnant liver. Oxaliplatin-based combination regimen is associated with increased risk of vascular lesions, whereas irinotecan-containing regimens have been associated with increased risks of steatosis and steatohepatitis. Analysis of EORTC study 40983 showed that administration of six cycles of neoadjuvant systemic chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was associated with moderate increase of the risk of reversible complications after surgery, but mortality rate was below 1% and not increased. If patients are not overtreated, chemotherapy before surgery is well tolerated. The integration of novel targeted agents in combination with cytotoxic drugs is a promising way to improve outcome in patients with advanced colorectal cancer. Preliminary trials have shown that targeted agents combined with cytotoxic regimens can increase tumor response rates. Another impact of preoperative chemotherapy is that metastases that respond to treatment may no longer be visible on computed tomography (CT) scan or at surgery. Patients should be carefully monitored and receive surgery before metastases disappear. Conclusion  Treatment of most patients with liver metastases—those with resectable metastases as well as those with initially unresectable metastases—should start with chemotherapy. If drugs are well chosen and the duration of treatment is monitored with care during multidisciplinary meetings, benefits largely outweigh potential disadvantages.