多西他赛单药一线治疗晚期非小细胞肺癌临床研究

目的探讨多西他赛单药一线治疗晚期非小细胞肺癌临床疗效及不良反应。方法48例晚期非小细胞肺癌患者,多西他赛75m4g／lm2静脉滴注,第1天。21d为1个周期,治疗2～4个周期后评价临床疗效及不良反应。结果48例患者共化疗140个周期,中位化疗2．9个周期。RR为25．O％,DCR为56．3％,中位无进展生存期5．3个月,中位生存期8．6个月,1年生存率35．4％。不良反应以粒细胞减少、贫血、腹泻、脱发为主。结论多西他赛单药一线治疗晚期非小细胞肺癌临床疗效良好,患者耐受性较好。     

Ramucirumab for the treatment of advanced or metastatic non-small cell lung cancer

ABSTRACT

Introduction: On 12 December 2014, the U.S. Food and Drug Administration (FDA) approved ramucirumab for use in combination with docetaxel for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy.

Areas covered: This review discusses the best treatment strategy for ramucirumab, a vascular endothelial growth factor receptor-2 inhibitor for patients with advanced NSCLC.

Expert opinion: The addition of ramucirumab to docetaxel in the treatment of patients with metastatic NSCLC who have progressed on or after platinum-based chemotherapy confers a 1.4-month improvement in overall survival, with an acceptable toxicity profile. The potential impact of the approval of the programmed death receptor-1 (PD-1)-blocking antibody nivolumab or pembrolizumab on the use of ramucirumab plus docetaxel in advanced NSCLC patient population is uncertain in clinical practice. In order to improve overall outcomes for patients with advanced NSCLC, both ramucirumab plus docetaxel and the PD-1-blocking antibody should be used in any treatment line.     

晚期非小细胞肺癌免疫治疗进展

肺癌是我国最常见的恶性肿瘤之一,其中非小细胞肺癌(NSCLC)约占85%,且大部分NSCLC患者在确诊时疾病已进展至晚期,病死率较高。近年来,临床对于晚期NSCLC的治疗已从传统的手术治疗、化学治疗、放射治疗、靶向治疗走向了免疫治疗。免疫检查点抑制剂(ICIs)治疗晚期NSCLC体现出了良好的抗肿瘤活性,尤其体现在细胞毒性T淋巴细胞相关抗原-4(CTLA-4)、程序性死亡受体-1(PD-1)、程序性死亡配体-1(PD-L1)抑制剂。基于此,本文将重点综述CTLA-4、PD-1、PD-L1抑制剂在晚期NSCLC中的治疗进展,以期提高患者的临床获益率,为临床选择合理治疗方案提供参考。     

DC-CIK细胞联合化疗治疗晚期非小细胞肺癌的临床研究

目的探讨DC-CIK联合化疗治疗晚期非小细胞肺癌的疗效及安全性。方法 112例晚期非小细胞肺癌患者随机分为实验组(n=56)和对照组(n=56),实验组给予DC-CIK细胞联合化疗治疗,对照组仅给予化疗治疗,比较2组的疗效及安全性。结果 2组有效率分别为60.7%和48.9%,差异无统计学意义(P0.05);实验组疾病控制率为89.3%,显著高于对照组的73.2%(P0.05);治疗后实验组KPS评分提高率显著高于对照组(P0.05);实验组患者的毒副反应显著轻于对照组,中位生存期显著长于对照组(P0.05)。结论 DC-CIK细胞与化疗联合用于晚期非小细胞肺癌的治疗,能够有效提高疾病控制率,延长患者生存期,改善患者生存质量。     

Immunotherapy for non-small-cell lung cancer

Activation of the host immune system represents an attractive treatment approach for cancers. In non-small-cell lung cancer (NSCLC), a variety of immunotherapies, including nonspecific immune stimulants, vaccines and checkpoint inhibitors, have been evaluated in clinical trials. Several randomized Phase III trials have failed to demonstrate clinical benefit from nonspecific immune stimulants and vaccines in the overall trial populations. Activity of vaccines in subsets of patients in these trials needs further evaluation. Unlike vaccines aimed at stimulating a cellular immune response to antigens differentially expressed in cancers, checkpoint inhibitors aim at overcoming immune inhibitory signals in the tumor microenvironment via pharmacological inhibition of immune checkpoints – a crucial tumoral immune escape mechanism. Early clinical trials of checkpoint inhibitors showed promising results with some durable responses. Better understanding of the mechanisms of immunosuppression specific to NSCLC will be crucial for successful patient selection for immunotherapy.     

Cetuximab for treating non-small cell lung cancer

Introduction: Epidermal Growth Factor Receptor (EGFR)-dependent signaling plays a crucial role in epithelial cancer biology, and dictated the development of several targeting agents. The mouse-human chimeric antibody Cetuximab was among the first to be developed. After about two decades of clinical research it has gained a significant place in the management of advanced colorectal and head and neck cancers, whereas its development in non small cell lung cancer (NSCLC) has not led to a place in routine clinical practice, because of marginal clinical benefit despite statistically significant Phase III trials. Recent data from ongoing trials suggest that more careful selection based on molecular markers may identify good responders.

Areas covered: In this article, the authors review the literature concerning basic science studies identifying EGFR as a therapeutic target, pharmacological development of Cetuximab, its pharmacodynamics and pharmacokinetics, and clinical trials on Cetuximab in NSCLC, focusing on recent findings on putative predictive biomarkers.

Expert opinion: Cetuximab currently has no role in NSCLC treatment outside of research settings. We argue that failure to identify a predictive biomarker early on has hampered its chances to enter routine practice. Although recent research suggests benefit in highly selected patient subsets, its potential impact is severely dampened by lack of regulatory body approval and the emergence of competitors for the same niches.     

培美曲塞治疗晚期复发性非小细胞肺癌的疗效

目的探讨培美曲塞联合铂类治疗晚期复发性非小细胞肺癌(NSCLC)的疗效以及不良反应。方法经病理学或细胞学确诊的复发性晚期NSCLC患者12例,培美曲塞500 mg/m2第1天静脉滴注,卡铂(AUC=5)第1天静脉滴注或顺铂75 mg/m2每4周重复,至少应用2个周期以上评价疗效及不良反应。结果 12例患者,完全缓解1例,部分缓解2例,稳定5例,进展4例。缓解率25%,疾病控制率66.7%。不良反应主要为轻中度的胃肠道反应和骨髓抑制。结论培美曲塞联合铂类治疗晚期复发性非小细胞肺癌疗效确切,不良反应可耐受。     

Emepepimut-S for non-small cell lung cancer

Introduction: Immunotherapy as a possible therapeutic option for cancer has been of great importance due to the innovative development of vaccines. Various molecules have been tested and emepepimut-S (Biomira Liposomal Peptide 25 (BLP 25)) has emerged as an option, particularly in lung cancer.

Areas covered: A PubMed literature and ClinicalTrials.gov search was conducted using the terms: emepepimut, BLP25, NSCLC, cancer immunotherapy, cancer vaccine and MUC1. This review covers how emepepimut-S acts against the mucin 1 (MUC1) tumor-associated antigen producing a cellular immune response against the cells that express MUC1 and the most important clinical data available that led to the ongoing Phase III trial.

Expert opinion: The results obtained in the Phase I/II trials are promising, showing a favorable toxicity with a benefit in survival in NSCLC patients. As future trials develop, demonstration of the long-term survival benefit, understanding of the various mechanisms of immune response initiated by the drug and the selection of patients that will highly benefit from the immunotherapy will be elucidated. The safety and extension in survival makes emepepimut-S a very interesting drug and could, therefore, offer a possibility of treatment and maintenance, particularly for good performance status patients with locally advanced NSCLC.     

非小细胞肺癌的靶向治疗

肺癌的发病率和死亡率在全球恶性肿瘤中居首位。其中,非小细胞肺癌（NSCLC）占80%~85%。绝大多数NSCLC在临床确诊时正处于复发或转移性的晚期阶段,化疗是这部分人群的主要治疗手段。但是,作为标准一线治疗的含铂两药联合化疗方案已进入平台期,无进展生存期（PFS）为4~6个月,总生存期（OS）仅为8~10个月。近年来,靶向药物的临床应用让人们看到了跨越这一平台的希望和曙光,靶向治疗作为一支生力军正逐渐登上非小细胞肺癌综合治疗的历史舞台。     

CIMAvax-EGF,a therapeutic non-small cell lung cancer vaccine

Introduction: Lung cancer represents the most common cause of cancer death worldwide. While the prognosis remains poor, immunotherapy is giving a positive impact on survival. Cancer vaccines represent a form of active immunotherapy that historically has given modest results in terms of efficacy.

The overexpression of the EGFR by tumor cells was reported in more than half of cases of lung cancer, representing a mechanism of cancerogenesis. CIMAvax-EGF, a therapeutic vaccine for non-small cell lung cancer (NSCLC) developed in Cuba, consists of a human recombinant EGF able to induce antibodies against the autologous EGF, resulting in serum EGF withdrawal and lower EGF-EGFR interaction.

Area covered: We critically reviewed the existing literature about CIMAvax-EGF, from the Pilot studies to the efficacy controlled studies. We also overviewed the ongoing trials.

Expert opinion: CIMAvax-EGF demonstrated to be safe and immunogenic. In a phase III randomized study CIMAvax-EGF, used as a switch maintenance treatment after platinum-based chemotherapy, did not significantly improve survival. Current data are not sufficient to recommend CIMAvax-EGF as a treatment option for advanced stage NSCLC. Further studies, conducted in a context of worldwide standardized clinical practice, are needed to better define if a subpopulation of patients can benefit from the vaccination.     

Ipilimumab (MDX-010) in the treatment of non-small cell lung cancer

Respiratory syncytial virus (RSV) is a major cause of bronchiolitis and pneumonia in young children and the elderly. Despite its clinical importance, there is no licensed vaccine available at present. Vaccine development has been hampered by observations of increased pathology after RSV infection in infants vaccinated with formalin-inactivated RSV; incomplete immunity following natural infection; and the need to be effective during the neonatal period when levels of maternal antibody are high. Four categories of RSV vaccine carriers – live-attenuated RSVs, recombinant vectors expressing the protective antigens of RSV, DNA vaccines and subunit vaccines – have been evaluated in animal models and/or clinical trials. So far, studies with live-attenuated virus vaccines highlight the need to improve immunogenicity whilst maintaining a suitable level of attenuation. Studies with recombinant vectors, DNA and subunit vaccines illustrate the pivotal nature of the vaccine carrier in determining the balance between immune-mediated protection against infection and the induction of immune-mediated pulmonary pathology.     

Pembrolizumab for the treatment of non-small cell lung cancer

ABSTRACT

Introduction: Immune checkpoint inhibitors targeting programmed death protein 1 (PD-1) receptor and its ligand, PD-L1, have recently led to significant and durable improvements in the clinical outcomes of some types of cancers including lung cancer.

Areas covered: Pembrolizumab was approved by the US FDA for the treatment of advanced or metastatic NSCLC whose disease has progressed after other treatments and with tumors that express PD-L1. In the phase I KEYNOTE-001 trial, the overall response rate (ORR) was 19.4%, the median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 12.0 months for 495 unselected NSCLC patients. Strong PD-L1 expression (≥ 50%) was associated with higher ORR, longer PFS, and longer OS. The phase II/III randomized KEYNOTE-010 trial demonstrated that pembrolizumab improved OS versus docetaxel in patients with previously treated NSCLC.

Expert opinion: Pembrolizumab, demonstrated durable response and prolonged OS especially in NSCLC patients with high expression of PD-1, thereby suggests a new treatment paradigm. However, many issues remain to be explored, including the identification of other robust biomarkers that can accurately predict the immune-responsiveness of tumors. Along with the identification of predictive biomarkers, further understanding of the tumor microenvironment is necessary to improve treatment outcomes through combinations of immunotherapy or combined with other targeted therapies.     

Immunotherapy for small cell lung cancer: mechanisms of resistance

Introduction: Small cell lung cancer (SCLC) is a highly malignant disease with a dismal prognosis that is currently being tested for theclinical activity of checkpoint inhibitors. SCLC is associated with smoking and exhibits a high mutational burden. However, low expression of PD-L1 and MHC antigens, as well low levels of immune cell infiltration and rapid tumor progress seems to limit the efficacy of anticancer immunity. Nevertheless, long-term survival was reported from studies using anti-PD-1/PD-L1 and CTLA-4 agents.

Areas covered: Data of clinical trials of checkpoint inhibitors in SCLC show lower success rates compared to NSCLC. The mechanisms of resistance to immunotherapy are discussed for their relevance to SCLC patients.

Expert opinion: Although some factors, such as a high mutation rate, favor immunotherapy for SCLC patients, downregulation of MHC class I, low expression of PD-L1, poor tumor infiltration by effector T cells, presence of myeloid-derived suppressor cells as well as regulatory T lymphocytes counteract the immune system activation by checkpoint inhibitors. Furthermore, this tumor develops avascular regions which have immunosuppressive effects and restrict access of lymphocytes and antibodies. In conclusion, immunotherapy in SCLC is effective in highly selected patients with good performance status and special and unknown preconditions contributing to long-lasting responses.     

培美曲塞治疗老年晚期非小细胞肺癌疗效观察与护理

目的观察培美曲塞治疗老年晚期非小细胞肺癌的疗效和毒副反应,探寻相对应的护理方法。方法通过对32例老年晚期非小细胞肺癌患者静滴培美曲塞,观察其疗效、毒副反应,并实施相应护理措施。结果32例晚期非小细胞肺癌患者应用培美曲塞治疗,完全缓解（CR）2例,部分缓解（PR）17例,稳定（SD）6例,进展（PD）7例。发生的毒副反应主要有骨髓抑制、消化道反应、过敏反应及药物外渗等。其中2例Ⅱ度骨髓抑制,1例Ⅳ度骨髓抑制;11度恶心呕吐19例,5例轻度便秘;2例出现严重皮肤瘙痒。经采取有效的对症治疗及积极的护理措施后都得到了缓解。结论培美曲塞治疗晚期非小细胞肺癌患者,掌握正确的给药方法,及时进行毒副反应的处理和护理干预,能有效地提高患者生活质量。     

晚期非小细胞肺癌综合治疗的前瞻性研究

目的探讨提高Ⅲ期非小细胞肺癌治疗效果的方法。方法85例Ⅲ期非小细胞肺癌患者随机分为3组,并进行不同顺序的治疗,A组(化疗+手术+放疗)28例,放疗后配合辅助化疗;B组(手术+化疗+放疗)28例;C组(手术+放疗+化疗)29例。比较各组3年生存率、局部区域复发率和远处转移率的差异性。结果A、B、C3组3年生存率分别为75.00%,53.57%,44.83%,其中A组与C组比较差异有显著性意义(P<0.05);3组局部区域复发率分别为7.14%,32.14%,17.24%,其中A组与B组比较差异有显著性意义(P<0.05);各组远处转移率分别为7.14%,10.71%,37.93%,其中A组与C组及B组与C组比较,差异均有显著性意义(P<0.05)。结论术前化疗再手术,配合术后放疗及辅助化疗,可提高治疗Ⅲ期非小细胞肺癌的疗效。     

紫杉醇联合奈达铂治疗晚期非小细胞肺癌的临床观察

目的观察紫杉醇（PTX）联合奈达铂（NDP）治疗晚期非小细胞肺癌的疗效及不良反应。方法 48例晚期非小细胞肺癌患者应用紫杉醇（PTX）联合奈达铂（NDP）方案化疗：PTX 135~175 mg/m2,静脉滴注,第1天;NDP 80~100 mg/m2,静脉滴注,第2天,21 d为1个周期。结果全组48例患者中,完全缓解率（CR）3例（6.3%）,部分缓解率（PR）16例（33.3%）,稳定（SD）22例（45.8%）,病情进展（PD）7例（14.6%）。有效率（RR）为39.6%,疾病控制率（DCR）为85.4%。主要不良反应为骨髓抑制及胃肠道反应,肝、肾毒性较轻。结论紫杉醇联合奈达铂治疗晚期非小细胞肺癌不良反应轻,疗效较好,值得临床推广。     

三种含铂化疗方案治疗晚期非小细胞肺癌的临床观察

目的 观察三种抗癌药(长春瑞滨、吉西他滨和多西紫杉醇)联合顺铂治疗晚期非小细胞肺癌(NSCLC)的近期疗效及毒性反应.方法 经病理组织学或细胞学证实的70例晚期NSCLC患者,随机按治疗方法 分为3组化疗,长春瑞滨联合顺铂(NP)组24例,吉西他滨联合顺铂(GP)组25例,多西紫杉醇联合顺铂(TP)组21例,3组患者资料具备可比性,3组患者采用对应药物进行治疗,均以21d为一周期,连续应用两周期后评价疗效及不良反应.结果 NP组总有效率29.2%(7/24),GP组总有效率40.0%(10/25),TP组总有效率33.3%(7/21),3组方案总有效率比较无统计学差异(P＞0.05);毒性反应方面,3组均以骨髓抑制为主,白细胞下降及贫血发生率相近.NP组Ⅰ～Ⅱ度静脉炎(14.6%)较其他两组多,GP组Ⅲ～Ⅳ度血小板降低(16%)较其他两组严重,TP组Ⅰ～Ⅱ度外周神经毒性(38.1%)较其他两组多.结论 用于晚期NSCLC一线化疗,NP、GP、TP三种方案近期疗效相似,但毒性存在差异,故应根据患者个体情况进行选择.     

The role of talactoferrin alfa in the treatment of non-small cell lung cancer

Importance of the field: Immunotherapeutic approaches to treating NSCLC via either adoptive transfer of immunity or stimulation of the endogenous immune system have shown increasing promise in recent years.

Areas covered in this review: Talactoferrin alfa is an oral immunomodulatory agent currently in late-stage clinical trials that acts through dendritic cell recruitment and activation in the gut-associated lymphoid tissue.

What the reader will gain: Talactoferrin is a recombinant human lactoferrin that is a member of the transferrin family of iron-binding glycoproteins. Lactoferrins have multiple known biological activities including cancer protection, cellular growth and differentiation and antimicrobial and anti-inflammatory properties. This review discusses the proposed mechanism of action of talactoferrin-alfa and outlines the pre-clinical, Phase I and II data in NSCLC. The ongoing Phase III trials are discussed.

Take home message: The current role of Talactoferrin alpha in the treatment of NSCLC is described and we explore potential future roles for this drug in both early stage and advanced stage disease.     

改进的紫杉醇联合顺铂方案治疗晚期非小细胞肺癌的临床观察

目的 为比较紫杉醇联合顺铂改进的3周方案与传统3周方案治疗晚期NSCLC的疗效、毒副反应及1年生存率。方法75例经组织学或细胞学确诊的Ⅲb或Ⅳ期NSCLC患者,随机分为两组,分别接受改进方案（A组）和传统3周方案（B组）化疗。2周期后评价疗效与毒副反应,并随访1年生存率。结果A组无CR,A组总有效率为47．9％（18／37）;B组CR1例,总有效率为52．6％（20／38）。总有效率两组差异无显著性（P〉0．05）,两组1年生存率分别为38．2％和35．6％。两组差异无显著性（P〉0．05）。主要毒副反应为恶心、呕吐、骨髓抑制、脱发、周围神经毒性、肝功能受损、心脏毒性等。A、B组差异无显著性（P〉0．05）。关节肌肉疼痛A组32．4％;B组84．2％,两组差异有显著性（P〈0．05）。结论紫杉醇联合顺铂改进的3周方案治疗NSCLC与传统3周方案相比,疗效相似,但血液学毒性明显下降,耐受性好。     

多西紫杉醇联合顺铂治疗晚期非小细胞肺癌的临床研究

目的观察多西紫杉醇（艾素）联合顺铂治疗晚期非小细胞肺癌的疗效及不良反应。方法对经病理或细胞学证实的60例非小细胞肺癌患者给予多西紫杉醇＋顺铂联合化疗。结果全组无CR病例,部分缓解25例,稳定25例,进展10例,总有效率为83％,中位生存期10．5个月,一年生存率45％,最常见的毒副反应为骨髓抑制。结论多西紫杉醇联合顺铂一线或二线治疗非小细胞肺癌均有较好的疗效,毒性反应可以耐受。