Emerging therapeutic options for advanced enteropancreatic neuroendocrine tumors

Introduction: Several chemotherapy agents and combinations have proven effective in the therapy of advanced enteropancreatic neuroendocrine tumors (EP-NETs). However, their toxicity can be significant. Recent understanding of the molecular mechanisms of these tumors, especially the central role of tumor angiogenesis, has led to the identification of new therapeutic targets and agents directed at the molecular level.

Areas covered: This paper gives a comprehensive evaluation of the existing therapeutic armamentarium for EP-NETs. Narrated in a historical perspective, this review analyzes the available information on traditional chemotherapy agents, interferon-α and somatostatin analogs, as well as newer therapies and experimental agents.

Expert opinion: Despite recent advances, a curative approach for metastatic EP-NETs is yet to be discovered. To date, sunitinib and everolimus have been shown to impact progression-free survival only in pancreatic NETs, and the duration of this benefit has not yet been established. Further research is necessary to determine whether a combination of these drugs, either together or with other therapies, may yield superior outcomes. Moreover, sequential use of these agents should be explored in an attempt to improve survival. Efficacy of a variety of experimental agents is also being tested in clinical trials.     

Emerging therapies for the treatment of patients with advanced neuroendocrine tumors

Patients with neuroendocrine tumors may pursue a number of treatment options, but there is little consensus on a single, standard treatment approach. Somatostatin analogs are generally administered to patients with symptoms of hormonal secretion, and are often highly effective in this regard. However, the administration of somatostatin analogs is only rarely associated with tumor regression, and randomized trials demonstrating a survival benefit associated with their use have not been performed. Selected patients with hepatic metastases may undergo surgical debulking, embolization or other ablative therapies. The clinical benefit associated with administration of systemic agents such as IFN-α or cytotoxic chemotherapy has been limited. With the possible exception of streptozocin-based therapy in patients with pancreatic neuroendocrine tumors, the widespread use of standard cytotoxic regimens has been limited by their relatively modest antitumor activity, as well as concerns regarding their potential toxicity. The modest efficacy seen with these agents in patients with advanced neuroendocrine tumors has led to great interest in the development of novel treatment approaches. One such approach is the use of radiolabeled somatostatin analogs. Recently, agents targeting the VEGF pathway and mammalian target of rapamycin have also shown promise in patients with advanced neuroendocrine tumors. Ongoing randomized studies should help better define the role these agents will play in the future treatment of patients with this disease.     

The emerging role of targeted therapies for advanced well-differentiated gastroenteropancreatic neuroendocrine tumors

Introduction: Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) are unique and complex neoplasms, exhibiting a wide spectrum of diverse clinical behaviors. The contemporary management of well-differentiated GEP-NETs is marked by the availability of a wide range of targeted therapies.

Areas Covered: For patients with localized or oligometastatic disease, surgical resection remains the preferred approach and is associated with excellent long-term outcomes. For patients with unresectable but isolated liver metastases, multiple liver-directed therapies, including hepatic arterial based therapies and ablative techniques, exist. For patients with metastatic and progressive disease, a number of systemic therapies exist: molecular targeted agents, peptide receptor radionuclide therapy (PRRT), and systemic chemotherapy. Furthermore, somatostatin analogs (SSA) are an important component of therapy, both effectively controlling symptoms of hormonal overproduction and contributing to slowing tumor progression.

Expert Opinion: In the near future, advances in our understanding of tumor biology, genetics, immunology, nanotechnology, and radiation pharmacology should only continue to expand the availability of targeted therapies, improving the outcomes of patients with GEP-NETs. We herein review the management of advanced well-differentiated GEP-NETS with a particular emphasis on the role of targeted therapies.     

A review of the current clinical trials for gastroenteropancreatic neuroendocrine tumours

Neuroendocrine tumours of the gastroenteropancreatic axis include carcinoid tumours and islet cell tumours of the pancreas (pancreatic endocrine tumours). Standard medical therapies prescribed for these malignancies include long-acting somatostatin analogues (octreotide and lanreotide) for the palliation of hormonal syndromes; cytotoxic agents (streptozocin, dacarbazine, adriamycin and 5-fluorouracil), which are primarily for the management of advanced islet cell tumours; and hepatic artery embolisation or chemoembolisation for the treatment of liver metastases. Clinical research promises to expand this therapeutic armamentarium. Most of the experimental treatments that are being evaluated in human clinical trials fall into the following categories: angiogenesis inhibitors, novel somatostatin analogues, radiolabelled somatostatin analogues, mTOR inhibitors and novel cytotoxic agents. This review summarises the present scope of clinical research in this field.     

晚期鼻咽癌放疗联合辅助性化疗的临床研究

目的 分析评价晚期（N2,N3期）鼻咽癌放疗加辅助化疗的疗效.方法 86例N2,N3期鼻咽癌患者随机分为放化组（A组,46例）和单放组（B组,40例）,均首先接受根治性放疗,其后放化组46例接受辅助化疗（LV＋5Fu＋DDP）3～4个疗程.结果 放化组5年生存率43.5%,单放组37.5%（P＞0.05）;放化组远处转移发生率19.6%,单放组45%（P＜0.05）;放化组远处转移发生时间平均放疗后18.3个月,单放组7.8个月;放疗后达到CR的放化组与单放组的5年生存率为42.9%、56.5%（P＞0.05）,非CR的放化组与单放组的5年生存率为44.4%、11.8%（P＜0.05）.结论 放疗加辅助性化疗N2,N3期鼻咽癌有助于延缓远处转移发生时间,减少远处转移;对于根治性放疗后未达CR者,辅助化疗能提高生存率.     

Lanreotide for the treatment of gastroenteropancreatic neuroendocrine tumors

Introduction: The prevalence of gastropancreatic neuroendocrine tumors (GEP-NETs), a largely sporadically occurring group of neoplasms, has rapidly increased. NET diagnoses often occur late and entail treatment challenges; treatment beyond surgical resection is typically required. Somatostatin analogs (SSAs), the cornerstone of GEP-NET therapy, target somatostatin receptors on NET cell surfaces and can ameliorate NET-related symptoms and prevent tumor progression.

Areas covered: This expert review summarizes the development of the SSA lanreotide and its role in treating NETs. Key lanreotide preclinical and clinical findings in acromegaly, carcinoid syndrome, and NETs are discussed, along with future treatment goals and therapeutic prospects.

Expert opinion: The role of SSAs in NET treatment was historically one of symptom management. Although this is a critical therapeutic component, ideal treatment would include prevention of tumor progression. As GEP-NETs are biologically diverse, progression prevention can be difficult, depending on primary tumor site and functional status. Recent data indicate that lanreotide significantly prolonged progression-free survival in metastatic GEP-NET patients. Practice patterns seem to be shifting toward using SSAs as first-line therapy. Response to SSAs has typically been categorized as either symptomatic or biochemical. However, SSA use to prevent tumor progression will lead to a new, objective response category based on tumor growth.     

恩度与化疗联合治疗多种晚期恶性肿瘤的临床疗效观察

目的 探讨多种晚期恶性肿瘤应用恩度与化疗联合治疗的临床效果.方法 82例恶性肿瘤患者,以抽签形式分为研究组与对照组,每组41例.对照组患者采用化疗进行治疗,研究组患者采用恩度与化疗联合治疗.比较两组患者的治疗效果、生活质量.结果 研究组患者治疗总有效率73.17％显著高于对照组的51.22％,差异具有统计学意义.(P<...     

局部晚期宫颈癌新辅助化疗22例临床分析

目的观察局部晚期宫颈癌新辅助化疗的疗效及应用价值。方法宫颈癌22例中Ⅰb期（巨块型直径≥4cm）10例,Ⅰ／a期6例,Ⅱb期6例,均采用VBP方案化疗,根据近期疗效予以进一步手术或放疗。结果近期有效率90．9％（20／22）,其中Ⅰb期1例,Ⅱa期1例,经两周期化疗后属病理完全缓解,完全缓解率9％,化疗结束后手术切除率90．9％。结论宫颈癌术前化疗使癌灶缩小,提高了手术切除率及患者的生存质量。     

Investigational drugs for neuroendocrine tumours

Background: Neuroendocrine tumours (NETs) are usually slow-growing neoplasms, which arise in the gastrointestinal tract, endocrine pancreas, lungs or thymus. The majority are malignant. The treatment of patients with metastatic disease consists of biotherapy with alpha-interferon and somatostatin analogues, various chemotherapy combinations or liver embolization. Objective: To review and discuss new treatments for patients with metastatic NETs. Method: Review of the published literature during the last 5 years on treatment of patients with NETs. Results/conclusion: Several new drugs with various mechanisms of action including cytotoxic drugs, tyrosine kinase receptor inhibitors and antiangiogenic drugs as well as radiolabelled substances have been introduced during recent years. Many of these compounds have shown promising results in patients with NETs.     

Everolimus for the treatment of pancreatic neuroendocrine tumors

Introduction: Pancreatic neuroendocrine tumors (PNET) represent the second most common primary malignancy of the pancreas. Until recently, therapeutic options for advanced PNET have been limited.

Areas covered: A recently published Phase III clinical trial demonstrated striking therapeutic activity of the mTOR inhibitor everolimus in advanced PNET and led to its approval for this indication by the FDA. This review discusses this landmark discovery in the context of currently available therapeutic options, pathophysiology and molecular genetics of PNET.

Expert opinion: The approval of everolimus for the treatment of PNET marks a major step forward in the clinical management of this disease and represents a notable example of the successful translation of a targeted therapy that was initially developed based on findings at the lab bench, into everyday clinical practice. These results encourage hopes that the overall therapeutic efficacy of such approaches can be further enhanced by the introduction of combinatorial regimens, simultaneously targeting more than one oncogenic signaling pathway, as well as by stratification of patients based on the individual genetic setup of their tumors.     

Somatostatin analogs in the treatment of neuroendocrine tumors: current and emerging aspects

Introduction: Neuroendocrine tumors (NETs) harbor somatostatin receptors and there is a strong rationale for using somatostatin analogs (SSAs) for treatment of NETs.

Areas covered: This article discusses i) pharmacology of somatostatin and its analogs; ii) antisecretory and anti-proliferative effects of SSAs in NETs; iii) efficacy and safety of emerging therapeutic regimens with first generation SSAs administered at either high doses or in combination with antineoplastic drugs; iv) efficacy and safety of pasireotide and chimeric molecules; v) efficacy of radionuclide therapy of NETs using SSAs.

Expert opinion: SSAs are the first-line medical therapy for functioning and non-functioning well-differentiated NETs. In patients not responder to first generation SSAs, the increase of drug dose over the conventional regimens, the combination of SSAs with other biotherapies or molecular targeted therapies, the switch to pasireotide or the use of SSAs in radionuclide therapy may improve the therapeutic success.     

Investigational drugs targeting somatostatin receptors for treatment of acromegaly and neuroendocrine tumors

Introduction: Octreotide long-acting release (LAR) and lanreotide Autogel (ATG) are the two somatostatin analogs currently approved for treatment of acromegaly and neuroendocrine tumors (NETs). The strength of these drugs has been their specificity for somatostatin receptor subtype 2. However, this peculiarity may become a weakness in some patients with tumors harboring somatostatin receptors different from the subtype 2. Another clinically relevant aspect related to the use of octreotide LAR and lanreotide ATG is the burden of injectable drug regimen that may adversely impact the quality of life of patients with acromegaly and NETs.

Areas covered: The authors review the recently published evidence on novel drugs targeting somatostatin receptors developed for treating acromegaly and NETs. Within this article, the authors discuss: i) the pharmacology of somatostatin and traditional somatostatin analogs; ii) the efficacy and safety of multireceptor-targeted somatostatin analogs in acromegaly and NETs; iii) the efficacy of chimeric molecules in acromegaly and NETs; iv) the preliminary data on the use of new injectable, oral and transdermal formulations of octreotide in acromegaly.

Expert opinion: The development of new somatostatin analogs and new formulations has opened a new scenario for treatment of acromegaly and NETs. That being said, even though there have been big steps taken in the development of new therapies for acromegaly, there are still a number of unresolved issues, while more trials are necessary for the use of somatostatin anaologs in the treatment of NETs.     

重组人血管内皮抑素联合化学疗法治疗晚期非小细胞肺癌临床观察

目的探讨紫杉醇、顺铂联合重组人血管内皮抑素(恩度)一线治疗晚期非小细胞肺癌(NSCLC)的疗效和不良反应。方法 53例晚期NSCLC患者随机分组:26例接受紫杉醇、顺铂联合恩度(试验组)治疗,27例接受紫杉醇、顺铂治疗(对照组),每2个周期行影像学评价疗效。结果试验组和对照组的有效率为30.8%vs 22.2%(P<0.01),疾病控制率为61.5%vs 44.4%(P<0.01),试验组中位进展时间为7.5个月,对照组中位进展时间为4个月,差异显著(P<0.01)。结论 YH-16联合TP方案与单独TP比较,能进一步增加疗效。     

比较卡铂与顺铂联合化学疗法对晚期恶性肿瘤的疗效

目的：比较卡铂（Ｃａｒ）与顺铂（Ｃｉｓ）联合化学疗法（化疗）对晚期恶性肿瘤的疗效。方法：以Ｃａｒ为主的联合化疗组１２０例（男性１０１例，女性１９例，中位年龄５５ａ）；以Ｃｉｓ为主的联合化疗组１２２例（男性１０５例，女性１７例，中位年龄５４ａ）。结果：Ｃａｒ组缓解率（５４．２％）高于Ｃｉｓ组（４５．１％）（Ｐ＜０．０５），特别对小细胞肺癌、肺鳞癌、卵巢癌和食管癌，Ｃａｒ对胃肠道和肾毒性较Ｃｉｓ为轻，但对骨髓毒性显著为重（Ｐ＜０．０１）。结论：Ｃａｒ可作为上述恶性肿瘤联合化疗的一线药物。     

消瘤平配合化疗治疗中晚期恶性肿瘤的多中心临床疗效观察

目的评价消瘤平配合化疗治疗中晚期恶性肿瘤的有效性和安全性。方法中晚期恶性肿瘤患者150例,随机分为治疗组98例,对照组52例,两组均按常规的化疗方案进行治疗,治疗组在化疗的同时服用消瘤平,4次/d,每次2～3粒,连续服用。结果治疗组和对照组近期有效率分别为62.2%、38.4%,化疗完成率分别96.9%、76.9%,化疗过程中出现的毒副反应发生率治疗组明显低于对照组,两组比较差异有统计学意义（P〈0.05）。结论消瘤平能提高中晚期恶性肿瘤近期临床疗效,减少化疗药物的毒副反应,是一种发展前景较好的抗癌药物。     

褪黑素联合化疗对晚期食管癌患者的影响研究

目的 探讨褪黑素联合化疗对晚期食管癌患者的影响,为临床治疗提供依据.方法 选择2011年6月至2013年5月我院收治的40例初治晚期食管癌患者作为研究对象（观察组）,另外选择同期收治的初治晚期食道癌患者40例作为对照组.观察组采用褪黑素联合化疗的方式进行治疗,对照组仅进行化疗,不使用褪黑素.评价两组患者的临床疗效、Karnofsky行为状况评分、外周血中T淋巴细胞亚群的指标.结果 观察组完全缓解10例,占25.00％,部分缓解17例,占42.50％,总有效率为67.5％;对照组完全缓解9例,占22.50％,部分缓解17例,占42.50％,总有效率为65.0％;两组比较差异无统计学意义（P＞0.05）.观察组Karnofsky行为状况评分改善15例,占37.50％,稳定21例,占52.50％,恶化4例,占10.00％,与对照组比较差异有统计学意义（P＜0.05）.观察组CD3＋和CD4＋水平明显高于对照组,差异有统计学意义（P＜0.05）;两组CD8＋水平比较差异无统计学意义（P＞0.05）;观察组CD＋＋/CD8＋比值明显高于对照组,差异有统计学意义（P＜0.05）.结论 褪黑素联合化疗对晚期食管癌患者临床疗效影响不大,但是能够提高免疫力及降低不良反应,在肿瘤辅助治疗中具有增强疗效、降低毒性等作用.     

高、 低级别胰腺神经内分泌肿瘤的CT及MRI表现

摘要:目的 分析高、 低级别胰腺神经内分泌肿瘤 （PNET） 的 CT 及 MRI 表现。方法 回顾性分析 2011 年 1 月—2017 年 5 月 32 例 PNET 患者的临床、 影像及病理资料, 其中低级别 （G1、 G2） 21 例, 高级别 （G3） 11 例。患者术前行 CT 或 MRI 平扫及增强检查, 术后行病理分析予以确诊。比较高、 低级别 PNET 间影像学表现差异。结果 32 例患者中, 单发 31 例, 多发 1 例。G1 级 12 例, G2 级 9 例, G3 级 11 例。病灶位置： 胰头 10 例 （G3 级 8 例）, 胰体 10 例, 胰尾 12 例。形态： 类圆形 19 例, 不规则形 13 例。内部成分： 实性 16 例, 囊实性 14 例, 囊性 2 例。钙化 5 例。胰、 胆管扩张 3 例 （均为 G3 级）。其他脏器或淋巴结转移 4 例 （均为 G3 级）, 其中肝转移 2 例, 淋巴结转移 2 例。高级别 PNET 通常位于胰头, 肿瘤体积较大, 形态常不规则, CT 或 MRI 增强后一般表现为低强化, 可伴有胰胆管扩张及其他脏器或淋巴结转移。结论 高、 低级别胰腺神经内分泌肿瘤的 CT 及 MRI 表现有一定特征性, 肿瘤的大小、 形态、 位置、 内部成分、 强化程度、 胰胆管的扩张及转移等特征对术前 PNET 病理分级的预测具有重要价值。     

脱氧核苷酸注射液联合化疗治疗晚期胃癌的随机临床研究

目的比较脱氧核苷酸注射液联合化疗与单纯化疗治疗晚期胃癌的临床疗效及不良反应。方法 68例晚期胃癌患者采用随机数字表法分为治疗组38例和对照组30例。治疗组采用脱氧核苷酸注射液联合化疗,对照组给予单独化疗。随访21 d评估患者的骨髓抑制、体重改变及免疫功能。结果治疗组7 d后WBC计数为（3.9±1.3）×109/L,血小板计数为（65.2±23.7）×109/L,WBC恢复正常人数占63.2%,III度＋IV度骨髓抑制发生率为10.5%;对照组分别为（3.0±1.2）×109/L、（48.8±21.4）×109/L、33.3%、40.0%,两组比较差异具有统计学意义（P〈0.05）。随访14 d,CD3＋（62.3±18.7 VS 55.4±16.8）,CD4＋（39.1±14.2VS 38.3±5.0）,NK细胞（33.5±12.6 VS 24.4±11.2）水平治疗组高于对照组,两组比较差异具有统计学意义（P〈0.05）。另外两组治疗21 d后,治疗组肌肉不良事件发生率、肝损伤事件发生率、医院感染发生率、体重增加量、生活质量（KPS）评分提高≥10分分别为10.5%、5.3%、5.3%、（1.9±0.5）kg、65.8%;对照组则分别为50.0%、20.0%、33.3%、（-0.8±0.2）kg、40.0%,两组比较差异具有统计学意义（P〈0.05）。结论脱氧核苷酸注射液减轻晚期胃癌化疗后的骨髓抑制,激活免疫功能,提高胃癌患者的体重,改善生存质量。     

雷替曲塞单药二线治疗晚期大肠癌疗效观察

目的 评价雷替曲塞单药二线治疗晚期大肠癌的疗效及安全性.方法 对28例经过一线化疗之后出现复发或进展的晚期结直肠癌患者采用雷替曲塞单药方案化疗.雷替曲塞3 mg/m2,d1静脉输注15 min,每三周重复1次.至少进行3周期.观察疗效、不良反应,并随访观察中位无疾病进展生存期(MPFS)、一年生存率.结果 28例患者,总有效率28.6%,中位无疾病进展生存期(MPFS)6.5个月,一年生存率42.9%.最常见不良反应是粒细胞减少、胃肠道反应和转氨酶升高,但副反应可控.结论 雷替曲塞二线治疗晚期复发转移结直肠癌疗效肯定,耐受性好.     

紫杉醇联合卡培他滨一线治疗晚期胃癌

目的评价紫杉醇联合卡培他滨一线治疗老年晚期或转移性胃癌的疗效及毒副反应。方法采用紫杉醇80mg／m^2,静脉滴注3h,第1、8天;卡培他滨2000mg／m^2,分两次口服,连用14d,每3周重复,至少连用2周期后评价疗效。结果32例可评价疗效,其中完全缓解1例（3．1％）,部分缓解17例（53．1％）,稳定10例（31．3％）,进展4例（12．5％）,有效率RR：56．3％（18／32）,中位疾病进展时间：6．2个月,中位生存期11．8个月,1年生存率为43．5％,临床受益率为75％。主要不良反应为骨髓抑制及胃肠道反应,多为Ⅰ度和Ⅱ度毒副反应,其他有肌肉酸痛、脱发、手足综合征等。所有患者无化疗相关死亡。结论紫杉醇联合卡培他滨方案一线治疗老年晚期或转移性胃癌疗效确切,不良反应可耐受,值得进一步临床研究。