西妥昔单抗在复发性/转移性头颈部鳞癌治疗中的应用

全球范围内,头颈部鳞癌(head and neck squamous cell carcinoma,HNSCC)年发病率超过500 000人,占所有恶性肿瘤发病率的5%.烟草、酒精的滥用以及人乳头瘤病毒(HPV)是HNSCC发病的危险因素;HPV相关的HNSCC具有分化低、基底细胞样特征明显和T分期较低的特点,疗效较好,总体生存率较高[1-2].局部复发是HNSCC治疗失败的主要原因,随着局部治疗手段的改进,远处转移的患者也日益增多.     

头颈部鳞状细胞癌的肿瘤微环境及免疫治疗研究进展

头颈部鳞状细胞癌（HNSCC）是最常见的一类异质性恶性肿瘤。超过60%的HNSCC患者在确诊时已处在肿瘤晚期或转移阶段,针对复发性或转移性HNSCC(R/MHNSCC)患者可选择的治疗方式及其疗效有限。肿瘤免疫治疗是治疗HNSCC的重要手段之一,尽管免疫治疗持久的反应率较高,但目前只有很低比例的HNSCC患者作出反应,临床上仍存在免疫治疗耐药等挑战。HNSCC肿瘤微环境（TME）的生物学特征、动态抑制性变化和异质性等特点,在HNSCC的发生与发展、免疫逃逸和治疗耐药中起重要的作用。在综述中,论述了抗肿瘤免疫细胞以及细胞外成分在HNSCC的TME中的作用及其机制,总结了HNSCC相关免疫治疗策略,并展望了免疫治疗与放射或化学治疗等传统肿瘤治疗方式组合提高HNSCC个体精准化免疫治疗的疗效。     

抗PD-1/PD-L1和CTLA-4免疫治疗在头颈鳞癌中的研究进展

头颈鳞癌(Head and neck squamous cell carcinoma,HNSCC)患者被诊断时多为晚期,传统方案治疗后复发率约为60%、转移率约为30%。而复发/转移性头颈鳞癌(Recurrent/metastasis HNSCC,R/M HNSCC)患者的治疗手段有限,长期生存率有待提高。免疫检查点抑制剂的出现有效的提高了这些患者的总生存期,为HNSCC患者带来了希望。本文总结了近年来程序性死亡蛋白1(PD-1)、程序性死亡蛋白1配体(PD-L1)和细胞毒性T淋巴细胞相关抗原4(CTLA-4)抑制剂及其组合疗法在头颈鳞癌中的研究进展,希望为临床医师提供新的治疗方案。     

铁死亡在头颈部鳞状细胞癌中的研究进展

头颈部鳞状细胞癌(HNSCC)作为全球发病率极高的癌症之一,由于晚期HNSCC手术治疗后易发生术后复发及对部分化疗药物的耐药性,患者预后情况并不乐观.因此,提高化学药物治疗HNSCC的效率,改善HNSCC患者预后成为目前亟需解决的问题.最新研究发现铁死亡对部分类型的肿瘤细胞的生长增殖具有调节作用,一定程度上降低了肿瘤治...     

基于TCGA数据库分析FTH1在头颈部鳞状细胞癌中的表达和临床意义

目的 探究重链多肽亚基由铁蛋白重链多肽1(ferritin heavy chain polypeptide 1,FTH1)在头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）中的表达和临床意义。方法 基于癌症基因图谱（The Cancer Genome Atlas,TCGA）数据库分析FTH1在HNSCC组织和癌旁组织中的差异表达情况，并分析其表达与肿瘤分期的关系和对总生存的影响。采用Cox比例风险模型评估影响HNSCC患者预后的因素。使用GSEA软件预测FTH1可能参与调控的信号通路。结果 FTH1在HNSCC中高表达，且与肿瘤分期有关（均P<0.05）。FTH1高表达的HNSCC患者总生存率降低（P<0.05）。单因素Cox分析结果显示，高表达的FTH1和肿瘤分期均是影响HNSCC患者的预后因素(均P<0.05)。多因素Cox分析结果显示，肿瘤分期和性别均是影响HNSCC患者的预后因素(均P<0.05)。FTH1的通路富集分析显示，FTH1的高表达样本显著富集到溶酶体、谷胱甘肽代谢、磷酸戊糖途径及癌症通...     

老年头颈部鳞状细胞癌患者的治疗耐受性及预后情况分析

目的 探讨老年头颈部鳞状细胞癌(HNSCC)患者的治疗耐受性及预后情况.方法 选取42例老年HNSCC患者,采用Cox比例风险回归模型分析其治疗耐受性和不良反应的影响因素,分析导致其治疗中断的根本原因,并对相关因素进行生存分析.结果 不同临床症状老年HNSCC患者原发灶位置比较,差异均有统计学意义(P﹤0.05),其中喉癌患者发生疼痛、吞咽困难和口腔黏膜炎的风险最低(P﹤0.05);美国东部肿瘤协作组(ECOG)体力状况(PS)评分为3～4分患者发生疼痛和吞咽困难的风险较高,而发生口腔黏膜炎的风险较低(P﹤0.05);年龄校正的查尔森合并症指数(aCCI)评分﹥8分的患者发生吞咽困难的风险最高,口腔黏膜炎的风险最低(P﹤0.01);TNM分期为Ⅲ～Ⅳ期的患者发生疼痛、吞咽困难、口腔黏膜炎的风险均较高(P﹤0.05).不同ECOG评分、原发灶位置、TNM分期、治疗方式的选择、治疗中断情况老年HNSCC患者伴或不伴合并症比较,差异均有统计学意义(P﹤0.05).不同治疗中断情况老年HNSCC患者的PFS比较,差异有统计学意义(HR=2.406,95％CI:0.977～5.925,P=0.042);伴或不伴合并症老年HNSCC患者的PFS比较,差异无统计学意义(P﹥0.05).结论 伴有合并症的老年HNSCC患者具有更高的ECOG评分,晚期患者更容易发生各类严重合并症,导致治疗耐受性差,不良反应的发生风险增高,进一步导致治疗中断而造成预后不良.     

基于数据库分析人EIF3C在头颈鳞状细胞癌中的表达及临床意义

目的:通过研究真核翻译起始因子3C（eukaryotic translation initiation factor 3 subunit C,EIF3C）在头颈鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）组织中的表达,阐明EIF3C基因的表达与HNSCC临床病理特征和预后的关系以及其相互作用蛋白参与的生物学过程。方法:采用GEPIA数据库分析HNSCC和对照组织中EIF3C基因的表达差异以及HNSCC患者中EIF3C基因表达的高低与预后之间的关系。采用LinkedOmics数据库分析EIF3C基因的表达与HNSCC的病理分级以及TNM分期之间的关系。采用The Human Protein Atlas数据库分析EIF3C蛋白在正常和HNSCC组织中的表达水平。采用STRING数据库分析EIF3C相互作用的蛋白以及参与的生物学过程。结果:EIF3C的表达水平在HNSCC中显著增高（P＜0.01）,与HNSCC的病理分级相关（P=0.026 6）,且分别与HNSCC的T分期（P=0.261 8）、N分期（P=0.358 8）和M分期（P=0.3413）不相关。EIF3C基因表达的高低与HNSCC的总生存率（P=0.24,HR=1.2）和无病生存率（P=0.66,HR=0.93）无显著性差异。免疫组化结果显示EIF3C蛋白在正常组织中呈中等水平表达,而在HNSCC组织中呈中、高等水平表达。EIF3C主要与其他EIFs蛋白相互作用,主要参与细胞的翻译起始调控。结论:HNSCC中EIF3C的表达显著增高且与临床病理分级相关,可为后续EIF3C的功能研究提供重要的理论基础。     

表皮生长因子受体在人头颈部鳞状细胞癌中的作用研究进展

头颈部鳞状细胞癌（head and neck squamous cell carcinoma,HNSCC）是常见的恶性肿瘤,恶性程度较高,患者常出现复发和转移。表皮生长因子受体（epidermal growth factor receptor,EGFR）是重要的癌基因,在头颈鳞癌中广泛过表达,且与HNSCC患者的预后呈负相关,是重要的治疗靶点。但HNSCC中的EGFR靶向治疗效果却不如在非小细胞肺癌治疗中那么有效。近几年的研究发现,EGFR促进肿瘤细胞对治疗耐受的机制可能与其过表达、突变、单核苷酸多态性、入核和自噬有关。本文将就这几个方面进行综述,并探讨如何在HNSCC的治疗中更有效地利用EGFR这一靶点,为探索HNSCC的治疗策略提供新的方向。      

EML4-ALK在非小细胞肺癌中的研究进展

<正>肺癌是目前世界上发病率和死亡率最高的恶性肿瘤,每年有超过100万患者死于肺癌。非小细胞肺癌(non-small cell lung cancer,NSCLC)患者5年生存率仅为13%,化疗仍为主要的治疗手段。针对酪氨酸激酶的靶向治疗越来越受到重视,2009年     

头颈部鳞状细胞癌转移机制及其影响因素研究进展

头颈部鳞状细胞癌(Head and neck squamous cell carcinoma,HNSCC)是一种主要来源于上呼吸道、消化道的非角化上皮癌性增生的恶性肿瘤.癌症转移为HNSCC患者预后差及病死率高的常见原因,HNSCC转移机制近年来成为众多学者关注与研究的热点之一.HNSCC的转移常常为癌细胞经上皮间质转...     

Evidence-based radiation oncology in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Historically, radiation therapy (RT) has been an available treatment option for patients with early resectable head and neck squamous cell carcinoma (HNSCC) and the sole therapy for those with unresectable or inoperable disease. Recently, four noteworthy strategies have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: they include the development of altered fractionation radiotherapy, integration of chemotherapy with radiotherapy, incorporation of intensity-modulated radiotherapy and the introduction of targeted biological therapy. These strategies are briefly reviewed in an effort to help interpret evidence-based data and to facilitate clinical-decision making in a clinical context. MATERIALS AND METHODS: For patients with early stage HNSCC no level 1 study exists in which radiation therapy is compared with conservative surgery for the evaluation of local control or survival. Only evidence from prospective and retrospective cohort studies is available to evaluate the role external radiotherapy and/or brachytherapy currently play in limited disease. For patients with locally advanced HNSCC the recommendations to address the questions about better treatment in resectable and unresectable tumors are based on more than 100 randomized Phase III trials included in six meta-analyses on chemo-radiotherapy and/or altered fractionation. Data from phase II trials and cohort studies help interpret the advances in intensity-modulated radiotherapy. RESULTS: External radiotherapy and/or brachytherapy are crucial treatment options in patients with early stage HNSCC. For patients with locally advanced HNSCC, where outcome with conventional radiotherapy is poor, meta-analyses and collective data showed that loco-regional control may be improved at high level of evidence by altered fractionation radiotherapy, chemo-radiotherapy with concomitant approach or association of selected hypoxic cell radiosensitizer with radiotherapy. For these patients, overall survival may be improved at high level of evidence by concomitant chemo-radiotherapy or hyperfractionated RT delivered with increased total dose. Also EGFR-inhibitors (cetuximab)-radiotherapy strategy offers at a lower level of evidence better loco-regional control and overall survival than radiotherapy alone. Chemo-radiotherapy programs can achieve an improved larynx-function preservation program without the risk of overall survival reduction, for patients with larynx or hypopharynx tumors who are candidates to radical surgery followed by radiotherapy. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemo-radiotherapy. Despite improved results, a higher severe toxicity has been largely evidenced with concomitant chemo-radiotherapy by reducing the gain in the therapeutic index with new treatment strategies. Three-dimensional conformal radiotherapy is the minimal standard of technique in HNSCC: however, as advances are promising, intensity-modulated radiotherapy should be largely implemented. CONCLUSIONS: Stepwise improvements in HNSCC non-surgical therapy have shown favorable impact on loco-regional control and overall survival. However, despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for altered fractionation regimens, type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.     

KiSS1 mediates platinum sensitivity and metastasis suppression in head and neck squamous cell carcinoma

Although surgery and radiotherapy have been the standard treatment modalities for head and neck squamous cell carcinoma (HNSCC), the integration of cisplatin (CDDP)-based therapy has led to improvements in local and regional control of disease for patients. However, many trials show that only 10-20% of patients benefit from this treatment intensification, which can result in profound treatment-associated morbidity and mortality. Moreover, the marginal survival improvement suggests that CDDP resistance is an innate characteristic of HNSCC. To elucidate the biological mechanisms underpinning CDDP resistance in HNSCC, we utilized an experimental model of CDDP resistance in this disease. We first observed significant enhancements in local tumor growth and metastasis, as well as adverse survival, in CDDP-resistant (CR) tumors compared with sensitive tumors. To elucidate the molecular mechanisms of this phenotype, we undertook a systems biology-based approach utilizing high-throughput PCR arrays, and we identified a significant suppression of KiSS1 mRNA and protein expression in the CR cells, but no significant regions of genomic loss with array comparative genomic hybridization. Genetic suppression of KiSS1 in CDDP-sensitive cell lines rendered them CR, an observation that was mechanistically linked to alterations in glutathione S-transferase-π expression and function. We next confirmed that, in human HNSCC tumors, loss of KiSS1 expression was associated with metastatic human HNSCC tumors compared with non-metastatic tumors. Genetic reconstitution of KiSS1 in CR cells abrogated cellular migration and induced CDDP sensitivity. To confirm these findings in a murine model, either CR or KiSS1-transfected CR cells were studied in an orthotopic model of HNSCC, or survival studies revealed significant improvement in survival of the mice bearing CR-KiSS1 tumors. Mechanistically, alterations in apoptotic pathways and CDDP metabolism contributed to KiSS1-associated chemotherapy sensitization. These studies provided further direct evidence for the role of KiSS1 loss in biologically aggressive HNSCC and suggest potential targets for therapy in CR cancers.     

BMSC enhance the survival of paclitaxel treated squamous cell carcinoma cells in vitro

The 5-year survival rate of patients suffering from head and neck squamous cell carcinoma (HNSCC) is unsatisfying despite the advances in carcinoma treatment. Recent studies suggest that stem cells can be used as a gene therapy carrier for cancer treatment. Stem cells produce different cytokines such as growth factors in a paracrine manner and cancer cells may show drug resistance in the presence of such growth factors. Reports in the literature concerning treatment of cancer using bone marrow derived stem cells (BMSC) are controversial, which led us to investigate the effects of paclitaxel on human HNSCC cell lines (FaDu and HLaC 78) cultivated simultaneously with BMSC in a transwell system (co-culture). Co-culture and HNSCC cell lines were treated with 10nM of paclitaxel for 24h. Morphology, viability and apoptosis were measured by microscopy, the MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, and the Annexin V-propidium iodide test. The survival of HNSCC cell lines treated with paclitaxel in co-culture increased significantly compared to control cells. Apoptosis of HNSCC cell lines in co-culture was attenuated significantly. In conclusion, BMSC increase HNSCC resistance to treatment with paclitaxel in vitro. Tumor-stroma interactions are critical components of tumor biology including tumor invasion and metastatic potential. Therefore particular attention must be paid to the complex tumor-stroma interactions to fully understand how tumor cells become chemoresistant.     

Combination of radiation therapy-immunotherapy for head and neck cancers: Promises kept?

Chemoradiotherapy with concurrent cisplatin has been the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC) for over 20 years. Recently, immunotherapy, a new therapeutic class, has emerged for patients with recurrent or metastatic HNSCC and has significantly extended their survival. Will it bring the same benefit to patients with localized tumors? There is a strong rationale for combining radiation therapy and checkpoint inhibitors for HNSCC. Indeed, radiation therapy can have both immunostimulatory and immunomodulatory effects. This is what explains the famous abscopal effect. The aim of this review is to present the data available on the combination of radiation therapy and immunotherapy for HNSCC.     

Gene expression analysis of head and neck squamous cell carcinoma survival and recurrence

The squamous cell carcinomas represent about 90 % of all head and neck cancers, ranking the sixth most common human cancer. Approximately 450,000 of new cases of head and neck squamous cell carcinoma (HNSCC) are diagnosed every year. Unfortunately, because of diagnosis at the advanced stages and early metastasis to the lymph nodes, the HNSCC is associated with very high death rate. Identification of signature biomarkers and molecularly targeted therapies could provide more effective and specific cancer treatment, prevent recurrence, and increase survival rate. We used paired tumor and adjacent normal tissue samples to screen with RT² Profiler™ PCR Array Human Cancer PathwayFinder^TM. Total of 20 up-regulated genes and two down-regulated genes were screened out. Out of 22 genes, 12 genes were subsequently validated to be significantly altered in the HNSCC; the samples were from all 41 patients. Five year survival and recurrence selected genes that could represent the biomarkers of survival and recurrence of the disease. We believe that comprehensive understanding of the unique genetic characteristics of HNSCC could provide novel diagnostic biomarkers and meet the requirement for molecular-targeted therapy for the HNSCC.     

Efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for patients with head and neck squamous cell carcinoma: a systematic review and meta‐analysis of randomized controlled trials

Agents targeting epidermal growth factor receptor (EGFR) are used to treat head and neck squamous cell carcinoma (HNSCC); however, their efficacy and safety is poorly understood. Here we evaluated the efficacy and safety of anti‐EGFR agents administered concurrently with standard therapies for HNSCC. Randomized controlled trials that evaluated addition of EGFR targeted therapy versus standard therapy alone were included. The primary outcome was overall survival (OS). Secondary outcomes were progression‐free survival (PFS), overall response rate (ORR), locoregional control, and severe adverse events (SAEs, grade ≥ 3). Sixteen eligible trials with 4031 patients were included. Addition of anti‐EGFR regimens to standard therapy significantly improved OS of patients with HNSCC (HR = 0.89; 95% CI, 0.82–0.96), with a moderately elevated rate of SAEs (RR = 1.08; 95% CI, 1.03–1.13). Subgroup analysis indicated that the survival benefit was observed when cetuximab was administered concurrently with radiotherapy (RT) for stage III/IV patients (HR = 0.76; 95% CI, 0.61–0.94; p = 0.01), or with chemotherapy for recurrent or metastatic (R/M) HNSCC (HR = 0.86; 95% CI, 0.78–0.95; p = 0.005). Significantly increased ORR (RR = 1.51; 95% CI 1.05–2.18) and PFS (HR = 0.72; 95% CI, 0.59–0.88) were found in R/M HNSCC patients treated with anti‐EGFR plus chemotherapy, while no significant improvements were found in stage III/IV patients treated with anti‐EGFR plus standard therapy. In conclusion, addition of cetuximab to standard therapy may improve outcomes for R/M HNSCC patients, while causing a moderate increase in SAEs. For stage III/IV patients, anti‐EGFR mAb plus RT can improve OS compared with RT alone, while replacement of chemotherapy with EGFR mAb or adding EGFR mAb to combined chemotherapy and RT did not improve outcomes.     

EphB4 provides survival advantage to squamous cell carcinoma of the head and neck

The receptor tyrosine kinase EphB4 and its ligand EphrinB2 play critical roles in blood vessel maturation, and are frequently overexpressed in a wide variety of cancers. We studied the aberrant expression and biological role of EphB4 in head and neck squamous cell carcinoma (HNSCC). We tested the effect of EphB4-specific siRNA and antisense oligonucleotides (AS-ODN) on cell growth, migration and invasion, and the effect of EphB4 AS-ODN on tumor growth in vivo. All HNSCC tumor samples express EphB4 and levels of expression correlate directly with higher stage and lymph node metastasis. Six of 7 (86%) HNSCC cell lines express EphB4, which is induced either by EGFR activation or by EPHB4 gene amplification. EphrinB2 was expressed in 65% tumors and 5 of 7 (71%) cell lines. EphB4 provides survival advantage to tumor cells in that EphB4 siRNA and AS-ODN significantly inhibit tumor cell viability, induce apoptosis, activate caspase-8, and sensitize cells to TRAIL-induced cell death. Furthermore, EphB4-specific AS-ODN significantly inhibits the growth of HNSCC tumor xenografts in vivo. Expression of EphB4 in HNSCC tumor cells confers survival and invasive properties, and thereby provides a strong rationale for targeting EphB4 as novel therapy for HNSCC.     

Immune checkpoint inhibitors in head and neck squamous cell carcinoma: A systematic review of phase-3 clinical trials

BACKGROUNDThe outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using immune checkpoint inhibitors (ICIs). The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-3 trials in the field.AIMTo evaluate the evidence on the effectiveness of ICIs in HNSCC, based on published phase-3 clinical trials.METHODSWe searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). We used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit our results to randomized controlled trials.RESULTSFive phase-3 clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: Four in R/M HNSCC and one in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the second-line treatment setting compared to the standard of care (standard single-agent systemic therapy). While the net gain in overall survival (OS) with nivolumab was 2.4 mo [hazard ratio (HR) = 0.69, P = 0.01], that with pembrolizumab was 1.5 mo (HR = 0.80 nominal P = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the first-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 mo (HR = 0.77, P = 0.0034) in the overall population and a net gain in OS of 4.2 mo in the PD-L1 positive (combined positive score > 20) population compared to standard of care (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.CONCLUSIONAnti-PD-1 agents provide survival benefits in R/M HNSCC in the first and second-line settings, with acceptable toxicity profiles compared to standard therapy. There is no proven efficacy in the curative setting to date.