尼妥珠单抗联合多西他赛和顺铂治疗中晚期鼻咽癌的临床研究

目的 探索尼妥珠单抗联合多西他赛和顺铂治疗中晚期鼻咽癌的有效性和安全性.方法 入组46例经病理学确诊的中晚期鼻咽癌患者分为对照组和试验组,每组23例,对照组给予单纯多西他赛和顺铂化疗治疗,试验组在对照组的基础上联合使用尼妥珠单抗.结果 试验组有效率为60.9％,高于对照组的34.8％ (P ＜0.05).试验组生活质量改善率为56.5％,高于对照组的34.8％ (P ＜0.05).入组患者不良反应均为消化道反应、血液学毒性、肝功能损伤、肾功能损伤等,且不良反应均为Ⅰ、Ⅱ度,2组不良反应发生率比较差异均无统计学意义(P均＞0.05).结论 尼妥珠单抗联合多西他赛和顺铂化疗治疗中晚期鼻咽癌的有效性高,且不良反应可控,值得在临床中进一步探索.     

尼妥珠单抗联合白蛋白结合型紫杉醇治疗复发性头颈部鳞癌一例

头颈部鳞癌是一种异源性疾病,类型复杂而多样.不仅对患者外貌和基本生理功能、感觉功能和语言功能产生破坏和影响,还影响患者生活质量.尽管近年来对头颈部鳞癌的诊治取得显著进展[1],但由于其是易局部复发或远处转移的难治性恶性肿瘤,绝大多数复发性头颈部鳞癌患者需要接受姑息性系统治疗,但目前可用的系统治疗方案疗效仍不理想.     

尼妥珠单抗联合放疗的临床研究进展

表皮生长因子受体（epidermalgrowthfactorreceptor,EGFR）在多种肿瘤中存在高表达,与肿瘤的进展、耐放化疗有关。抑制EGFR信号传导通路可控制肿瘤的发展。尼妥珠单抗作为一种新型的抗EGFR单克隆抗体．已应用于多种恶性肿瘤中。全文就尼妥珠单抗联合放疗在肿瘤治疗中的相关临床研究作一综述。     

尼妥珠单抗联合化疗治疗恶性胶质瘤

目的 评价尼妥珠单抗联合化疗治疗恶性胶质瘤的疗效及不良反应.方法 尼妥珠单抗200 mg/次,每周1次,连续8周后改为每2周1次;根据患者O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)蛋白表达状况和既往化疗效果,采用个体化的化疗方案.结果 14例恶性胶质瘤患者共接受尼妥珠单抗治疗122次,中位治疗7.5次(2～20次).联合的化疗方案中,替莫唑胺21 d方案10例,替莫唑胺5 d力案2例,替尼泊甙联合顺铂方案1例,替尼泊甙联合尼莫司汀方案1例.PR 3例(21.4%),SD 6例(42.9%),客观有效率为21.4%,疾病控制率(PR+SD)为64.3%.中位无进展生存期(PFS)为4个月(95%CI0.7～7.3),6个月的疾病无进展生存率为30.6%.主要的不良反应为Ⅰ～Ⅱ度的中性粒细胞下降(2例)、血小板下降(2例)、淋巴细胞下降(1例)、恶心呕吐(3例)和无症状的转氨,升高(1例).1例替尼泊甙联合顺铂方案化疗的患者发生Ⅳ度中性粒细胞下降和血小板下降.1例患者出现尼妥珠单抗治疗相关痤疮样皮疹.结论 尼妥珠单抗联合化疗治疗恶性胶质瘤有一定疗效,患者耐受性好,值得进一步扩大病例数开展临床研究.

Abstract：

Objective Nimotuzumab is a humanized monoclonal antibody targeted against epidermal growth factor receptor (EGFR). Recent clinical studies show that patients with malignant gliomas could benefit from nimotuzumab treatment. The aim of the present study was to evaluate the efficacy and side effects of nimotuzumab in combination with chemotherapy for patients with malignant gliomas. Methods The patients received 200 mg of nimotuzumab infusion intravenously over 60 minutes once weekly for the first eight weeks and then once every two weeks until unacceptable toxicity or tumor progression occurred.Individualized chemotherapy was administered based on O6-methylguanine-DNA methyltransferase (MGMT)expression and previous chemotherapy responses in combined with nimotuzumab. Results Fourteen patients received a total of 122 times of nimotuzumab ranging from 2 to 20 ( median 7.5 times ). Combined chemotherapy regimens included:continuous 21-day temozolomide ( 10 cases), standard 5-day temozolomide (2 cases), teniposide plus cisplatin ( 1 case), and teniposide plus nimustine ( 1 case). Partial response (PR) and stable disease (SD) were found in 3 patients (21.4%)and 6 patients (42.9%), respectively.Disease control rate ( PR + SD) was 64.3%. The median progression-free survival (PFS) was 4 months (95%CI:0.7-7.3) and PFS at 6 months was 30. 6%. The most common toxicities include grade Ⅰ -Ⅱ neutropenia (2 cases), thrombocytopenia ( 2 cases), lymphopenia ( 1 case), nausea and vomitting ( 3case) and asymptomatic transaminase increase ( 1 case). One patient developed grade Ⅳ neutropenia and thrombocytopenia. One patient developed nimotuzumab-related acneiform rash. Conclusions Nimotuzumab in combination with chemotherapy has moderate activity in patients with malignant gliomas and the toxicities are well tolerable, therefore, worth further investigation.     

尼妥珠单抗在鼻咽癌治疗中的研究进展

我国鼻咽癌发病率及病死率均位居世界之首。传统的细胞毒性肿瘤治疗方法与毒性局限性密切相关,且局部晚期及复发转移鼻咽癌的病死率仍居高不下。为此靶向分子治疗成为研究热点之一,表皮生长因子受体（epidermal growth factor receptor,EGFR）及其配体的阻断是一种新型无细胞毒性的肿瘤治疗方法。尼妥珠单抗可特异性结合EGFR,阻断EGFR及其介导的下游信号传导途径,从而发挥抗肿瘤及放疗增敏作用。本文就尼妥珠单抗治疗鼻咽癌的研究进展进行综述,以期为临床工作提供参考。     

抗EGFR单抗类靶向药物在头颈部鳞癌综合治疗中的应用

头颈部肿瘤是世界上第6大常见的肿瘤。超过70%的头颈部肿瘤患者在首次确诊时即为局部晚期。尽管不断地努力改进治疗方法,但晚期病例的死亡率仍然居高不下。为了提高疗效,患者通常接受化疗、手术、放射治疗和分子靶向药物综合治疗。大量研究证实,表皮生长因子受体（epidermal growth factor receptor,EGFR）与肿瘤细胞的增殖和转移密切相关,EGFR在大多数头颈部肿瘤中高表达,对这些患者的预后有显著影响。抗EGFR单克隆抗体已经在一些国家被批准用于治疗局部晚期头颈鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）。本文综述了西妥昔单抗和尼妥珠单抗治疗HNSCC的研究进展。HNSCC的单克隆抗体靶向治疗,是选择西妥昔单抗还是尼妥珠单抗？本综述将围绕这一临床医生尤为关心的问题展开讨论。     

调强放疗联合多西他赛和尼妥珠单抗治疗食管癌的疗效观察

目的:评价调强放疗联合多西他赛和尼妥珠单抗治疗食管癌的疗效和安全性。方法:55例不能手术或拒绝手术的中晚期食管癌患者根据入选标准随机分成调强放疗联合每周多西他赛和尼妥珠单抗(治疗组)和同期放化疗(对照组),治疗组在调强放疗的同时给予多西他赛20-30mg/m2,静脉滴注,尼妥珠单抗200mg,静脉滴注,每周1次,连续6周,在放疗第一天同时进行。两组化疗和调强放疗方法相同。结果:治疗组与对照组完全缓解率(CR)分别为53.8%和46.2%,有效率(CR+PR)分别为84.6%和73.1%。1、2、3年局控率分别为85.7%、67.9%、57.1%和70.4%、63.0%、51.9%;生存率分别为71.4%、53.6%、39.3%和63.0%、40.7%、29.6%。治疗组近期毒副反应尤其是放射性食管炎及Ⅰ、Ⅱ度骨髓抑制较对照组大,有1例因放射性食管炎中断治疗,其他经处理后均能顺利完成治疗。远期并发症以食管狭窄为主,两组无明显差异。结论:调强放疗联合每周多西他赛和尼妥珠单抗治疗较同期放化疗组疗效好,可提高中晚期食管癌的近期和中远期疗效,且毒副反应患者能耐受。     

尼妥珠单抗增强食管鳞癌放疗敏感性的研究*

目的:研究尼妥珠单抗（h-R 3）对人食管鳞癌KYSE450 细胞的放射增敏效应。方法:利用四氮唑盐（MTT）比色法分析h-R 3、X 线照射及两者联合对人食管KYSE450 细胞的生长抑制作用,通过流式细胞仪分析细胞周期分布及细胞凋亡的变化。采用克隆形成实验检测h-R 3 对食管癌细胞系放射敏感性的影响,多靶单击模型拟合细胞存活曲线。同时采用基因芯片技术对h-R 3 组、h-R 3 联合照射组两组进行检测,筛选不同组之间的差异基因,用生物信息学分析差异基因功能。结果:h-R 3 组、照射组和h-R 3 联合照射组对KYSE450 细胞生长均有抑制作用,且联合照射组对KYSE450 细胞的生长抑制作用最强（35.25± 5.62）% ,明显高于h-R 3 组（16.12± 8.73）% 和照射组（27.64± 6.66）%（F = 10.953,P < 0.001）。 联合照射组细胞出现明显的G 2 期阻滞和细胞凋亡,G 2期细胞和凋亡细胞所占比例最高,分别达到（29.37± 7.29）%（F = 17.299,P < 0.001）和（18.80± 2.03）%（F = 85.691,P < 0.001）。 多靶单击模型显示,h-R 3 联合照射组的SF2、Do、Dq值均较单纯照射组减小（SER=1.63）,提示h-R 3 对KYSE450 细胞有放射增敏作用。基因芯片分析发现h-R 3 可通过下调EGF/PDGF 信号传导通路的相关基因发挥放疗增敏作用。结论:尼妥珠单抗能有效抑制人食管癌KYSE450 细胞的生长,与X 射线照射联合后能够促进细胞凋亡,增强G 2 期阻滞效应,能够增强食管癌KYSE450 细胞对X 射线的放疗敏感性,此效应与下调表皮生长因子受体（epidermalgrowthfactorreceptor ,EGFR）信号传导通路的相关基因有关。      

尼妥珠单抗联合放疗对人胰腺癌细胞株PANC-1凋亡的影响

目的 观察尼妥珠单抗联合放疗对胰腺癌细胞株PANC-1增殖的影响,并探讨其机制。方法 CCK-8法观察各组细胞生长增殖情况;流式细胞仪(FCM)检测各组细胞凋亡率;实验分组为:对照组(C)、单用尼妥珠单抗组(h-R3)、单纯照射组(R)、尼妥珠单抗联合放疗组(h-R3+R);结果 除对照组外,各组细胞抑制率依次为(2.36±2.08)%、(27.03±13.53)%、(51.19±16.26)%;各组细胞凋亡率依次为:(1.12±0.08)%、(3.94±0.16)%、(5.55±0.16)%、(8.81±0.09)%。结论 尼妥珠单抗可增强单纯照射组对细胞株PANC-1的生长抑制作用;其增敏作用的机制可能与抑制EGFR信号转导通路,诱导细胞凋亡增加等有关。     

尼妥珠单抗联合三维适形放疗及化疗治疗局部晚期鼻咽癌的初步临床研究

  目的   探讨尼妥珠单抗联合同期三维适形放疗(3D-CRT)及化疗治疗Ⅲ、ⅣA期鼻咽癌的疗效及不良反应。   方法  经组织病理确诊的Ⅲ、ⅣA期(2008分期)鼻咽癌初诊患者63例随机分为对照组(33例)和治疗组(30例), 均采用3D-CRT及同期和序贯紫杉醇顺铂方案化疗, 治疗组每周一放疗前行尼妥珠单抗100mg治疗, 共6~7次。   结果   放疗结束后2个月原发灶CR率、颈部淋巴结CR率治疗组分别为100.0%、96.7%, 明显高于对照组的81.8%及75.8%(P均 < 0.05), 放疗后1年局部控制率、无转移生存率在治疗组及对照组分别达到100.0%vs.89.3%、95.5%vs.82.1%(P > 0.05), 两组主要不良反应为放射性咽喉炎、放射性皮炎和恶心呕吐、白细胞减少、疲乏等, 耐受性较好。治疗组发生3度以上放射性咽喉炎(P < 0.05)、放射性皮炎(P > 0.05)较对照组偏高。   结论   尼妥珠单抗联合3D-CRT及紫杉醇及顺铂同期及序贯化疗治疗局部晚期鼻咽癌, 可提高近期完全缓解率及局部控制率, 耐受性较好, 远期生存率有待进一步观察研究。      

Nimotuzumab Combined with Neoadjuvant or Induction Chemotherapy for Head and Neck Squamous Cell Carcinoma: A Retrospective Study

Objective: To assess the efficacy and toxicity of nimotuzumab combined with neoadjuvant or induction chemotherapy for head and neck squamous cell carcinoma (HNSCC). Methods: Patients received intravenous nimotuzumab (400 mg, weekly for 1–3 weeks) combined with chemotherapy (5-fluorouracil/paclitaxel/docetaxel +nedaplatin/cisplatin for 1–2 cycles), prior to definitive surgical resection, radiotherapy or other treatments. Theprimary endpoint was the objective response rate (ORR). The secondary endpoints were tumor downstaging,complete response rate (CRR), partial response rate (PRR), disease control rate (DCR), R0 resection rate, pathological complete response (pCR), larynx preservation rate, overall survival (OS), progression-free survival (PFS),and safety. Results: A total of 71 HNSCC patients with T_1-4N_0-2M₀ were enrolled. After neoadjuvant/inductionchemotherapy, the ORR in patients with hypopharyngeal and laryngeal cancer was 100% and 76.1%, respectively.The DCR was 100% in both groups. The T downstaging in patients with hypopharyngeal and laryngeal cancerwas 64.0% and 50.0%, the N downstaging was 28.0% and 2.2% (p = 0.001), respectively. At the early stage andlocally advanced stage, the T downstaging was 66.7% and 50.0%, the N downstaging was 0% and 16.0% (p =0.128), respectively. The R0 resection rate and pCR in 39 patients receiving surgery were 94.9% and 20.5%, respectively. The larynx preservation rate was 73.2%. The median PFS was 29.2 months in patients with laryngeal cancer. A mild rash occurred in a single patient and no grade 4 adverse events were encountered. Conclusion:Nimotuzumab combined with neoadjuvant or induction chemotherapy achieved similar short-term efficacyand less adverse events compared with previous studies. The N downstaging rate in patients with hypopharyngealcancer was significantly higher compared with patients with laryngeal cancer.     

顺铂和5-氟脲嘧啶联合尼妥珠单抗作为一线方案治疗转移鼻咽癌的临床观察

目的 探究顺铂和5-氟尿嘧啶联合尼妥珠单抗作为一线方案治疗转移鼻咽癌的临床疗效及安全性.方法 将50例鼻咽癌转移患者随机分成对照组和实验组,对照组患者采用顺铂和5-氟尿嘧啶治疗,实验组患者采用顺铂和5-氟尿嘧啶联合尼妥珠单抗治疗,比较2组患者近期治疗有效率、控制率及不良反应发生情况.结果 实验组患者CR及PR均明显高于对照组,PD明显低于对照组,差异均有统计学意义(P＜0.05);实验组患者的治疗有效率及控制率分别为72.0％、92.0％,均明显高于对照组患者(44.0％、72.0％),且有统计学差异(P＜0.05).2组患者均有明显的不良反应发生,但每种不良反应相比均无明显的统计学差异(P＞0.05).实验组患者1年生存率为92.0％,明显高于对照组患者72.0％ (P ＜0.05).结论 采用顺铂和5-氟尿嘧啶联合尼妥珠单抗作为一线方案治疗鼻咽癌转移可以显著提高治疗有效率、控制率及1年生存率,且不会增加不良反应发生率,是1种更为可取的治疗方案.     

Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

Research indicates that a small population of cancer cells is highly tumorigenic, endowed with the capacityfor self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells areconsidered the ‘‘drivers’’ of the tumorigenic process in some tumor types, and have been named cancer stemcells (CSC). Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to theacquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype thatmay contribute to tumor recurrence and metastasis. CSC have been identified in human head and neck squamouscell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase(ALDH) activity. Head and neck cancer stem cells reside primarily in perivascular niches in the invasive frontswhere endothelial-cell initiated events contribute to their survival and function. Clinically, CSC enrichment hasbeen shown to be enhanced in recurrent disease, treatment failure and metastasis. CSC represent a novel targetof study given their slow growth and innate mechanisms conferring treatment resistance. Further understandingof their unique phenotype may reveal potential molecular targets to improve therapeutic and survival outcomesin patients with HNSCC. Here, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells,with a focus on the impact of these cells on head and neck tumor progression, metastasis and recurrence due totreatment failure.     

Wnt Signaling: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Cellular maintenance and development are two fundamental mechanisms regulated by the canonical Wnt signalingpathway. Wnt/beta-catenin signaling pathway controls a myriad of cellular processes that are essential for normal cellfunctioning. Cell cycle progression, differentiation, fate determination, and migration are generally orchestrated bycanonical Wnt signaling. Altered Wnt/beta-catenin signaling has been considered a promoting event for different typesof cancers and the oncogenic potential of Wnt signaling have been discussed in many cancer types, including breast,colon, pancreatic as well as head and neck. Furthermore, Wnt signaling is critical for the maintenance and stemnessof both the normal as well as cancer stem cells. This review sheds new light on Wnt signaling and explains how it canregulate normal physiological processes and curtail the development of cancer. It depicts the vital functions of Wntsignaling in the stem cell growth and differentiation by focusing on current druggable targets that have been ascribedby recent studies. Thus, Wnt signaling pathway retains a tremendous potential in eradicating head and neck squamouscell carcinoma.     

Prognostic Significance of Epidermal Growth Factor Receptor Phosphorylation and Mutation in Head and Neck Squamous Cell Carcinoma

The molecular status of the epidermal growth factor receptor (EGFR) has not been as well studied in head and neck squamous cell carcinoma (HNSCC) as in lung cancer. We examined the frequencies of EGFR mutations as well as the expression/phosphorylation status of the EGFR protein in HNSCC patients. Moreover, we tried to elucidate associations between EGFR molecular status and patient characteristics and disease‐free survival. In this prospective cohort study, clinical data and samples were obtained from 82 consecutive patients who had not been treated with EGFR molecular targeting therapy. Full‐length EGFR was sequenced, and expression and phosphorylation of the EGFR protein were measured by Western blotting. Four novel mutations (E709K, V765G, Ins770G, and G1022S) and one mutation well‐known in lung cancer (L858R) were identified in six HNSCC samples (7%), but we could not find any mutations in the extracellular domain of EGFR, such as EGFRvIII, in this study. E709K and Ins770G as well as L858R appear to be functional mutations based on the use of Ba/F3 cells. In terms of patient characteristics, the number of metastatic lymph nodes and node stage were associated with phosphorylation of EGFR. No patients with EGFR mutations relapsed during the study period. Excluding mutated cases, patients whose tumor samples showed phosphorylated EGFR relapsed significantly earlier than those without phosphorylated EGFR. This finding was still significant after adjusting for mutation and overexpression of EGFR protein using the Cox proportional hazard model. In conclusion, phosphorylated EGFR without mutations may be a marker of poor prognosis in patients with HNSCC.