头颈部癌的靶向治疗进展

近十年中,靶向治疗逐渐成为头颈部综合治疗策略中重要的组成部分.靶向药物包括各种单克隆抗体、小分子化合物以及反义寡核苷酸等.西妥昔单抗是目前唯一获得批准用于头颈部癌治疗的靶向药物,其他靶向药物如吉非替尼、拉帕替尼等在头颈部癌的Ⅰ～Ⅲ期临床试验中亦获得令人鼓舞的结果.     

Combination therapy with molecular targeting drugs for head and neck cancer

Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for advanced head and neck cancer (HNC). Intensive combination chemotherapy has been re-considered for neo-adjuvant chemotherapy in functional preservation protocol. Molecular targeting drugs (MTG) have proved effective for HNC not only in basic study but in many clinical phase II trials. Cetuximab, an anti-EGFR monoclonal antibody, is a key drug for regimens including MTG. Phase III trials with CDDP/carboplatin+5-FU vs CDDP/carboplatin+5-FU+cetuximab proved the combination with cetuximab was statistically effective for survival of patients with recurrent/metastatic HNC. Combination with cetuximab prolonged survival from 7.4 months to 10.1 months in this report. A good response rate and survival rate are reported in phase II study for chemoradiotherapy with CDDP and cetuximab. The three-year overall survival and local control rate were 76% and 71%, respectively. The combination with MTG will be important in CCRT for advanced HNC. It may well be considered the standard treatment for recurrent/metastatic HNC patients in future.     

Laryngeal preservation in head and neck cancer: multidisciplinary approach

Since the first total laryngectomy was undertaken, efforts have been made to avoid removing the entire larynx. For a long time, partial surgery and radiotherapy were the only options that could preserve the larynx. Development of active chemotherapy regimens has prompted an era of intensive clinical research. Induction chemotherapy followed by radiotherapy in patients with objective responses has been shown to allow conservation of the larynx in nearly two-thirds of individuals, without any effect on survival; concurrent chemoradiotherapy also provides high rates of laryngeal preservation, again without affecting survival; and induction chemotherapy followed by concurrent chemoradiotherapy is under investigation. In the meantime, partial open surgery and endoscopic carbon dioxide laser procedures are feasible in selected moderately advanced laryngopharyngeal cancers as an alternative to destructive surgery. Altered fractionation radiotherapy can also be used in management of these tumours, and targeted treatments have opened a new area of clinical research. Findings of basic research and modern imaging should provide useful approaches for selection of patients for various strategies.     

靶向药物治疗晚期肾癌的meta分析

目的:系统评价靶向药物治疗晚期肾癌的有效性和安全性。方法:计算机检索PubMed、EMBASE、Cochrane Library、中国期刊全文数据库(CNKI)、中国生物医学文献数据库(CBMdice)等,同时追查纳入的参考文献,收集靶向药物治疗晚期肾癌的随机对照试验。根据Cochrane Handbook 5.0的质量评价标准评价,采用RevMan 5.0软件进行统计学分析。结果:最终纳入5个随机对照试验,共2946例患者。meta分析结果显示,与干扰素相比,靶向药物单药虽未能提高晚期肾癌的有效率,却显著提高了晚期肾癌的疾病控制率(OR=2.89,95%CI:2.22-3.77,P<0.001)。靶向药物联合干扰素不但显著提高了晚期肾癌的疾病控制率(OR=2.14,95%CI:1.70-2.69,P<0.00001),还显著提高了有效率(OR=2.52,95%CI:1.90-3.33,P<0.00001)。与干扰素相比,靶向药物的不良反应明显增加,尤以3/4级心血管不良事件(OR=6.29,95%CI:1.77-22.27,P=0.004)、3/4级皮肤不良事件(OR=8.28,95%CI:3.91-17.56,P<0.0001)以及重度疼痛(OR=2.41,95%CI:1.38-4.24,P=0.002)的发生率增加最为明显。靶向药物与干扰素联用组的3/4级胃肠道反应(OR=2.08,95%CI:1.56-2.78,P<0.00001)、心血管(OR=8.67,95%CI:1.86-40.41,P=0.006)不良事件以及疲劳、无力等全身症状(OR=1.48,95%CI:1.20-1.83,P=0.0002)的发生率显著高于干扰素组。结论:与干扰素相比,靶向药物单用能更有效地控制晚期肾癌的进展,靶向药物联合干扰素可进一步提高疗效,是晚期肾癌较好的解救方案,但也伴随更多不良反应的发生。     

Recent advances in molecular-targeted drugs in head and neck cancer

Recently, the integration of radiotherapy and chemotherapy has advanced the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), allowing functional organ preservation while improving locoregional control and overall survival compared with radiotherapy alone. However, as recurrences remain inevitable, there is an absolute need for alternative modes of therapeutic intervention. Moreover, the use of chemotherapy and radiotherapy also increases the incidence of toxicities such as mucositis, myelosuppression, xerostomia, and dysphasia. More recently, the use of molecular-targeted drugs, which minimally adds to the existing toxicities, along with cytotoxic drugs and radiotherapy has been intensively investigated. Cetuximab is a chimeric IgG1 monoclonal antibody that specifically blocks the epidermal growth factor receptor. In a randomized trial of radiotherapy with or without cetuximab for locally advanced SCCHN, the addition of cetuximab significantly improved the locoregional control and overall survival without an increase in adverse events. Furthermore, a randomized trial of 5-FU and cisplatin with or without cetuximab for recurrent/metastatic SCCHN demonstrated a significant survival benefit for cetuximab combination arms compared with 5-FU and cisplatin arms alone. Based on these findings, many molecular-targeted drugs have been investigated in the treatment of the head and neck cancer to ensure better clinical outcomes in the near future.     

A multidisciplinary therapeutic approach for advanced previously untreated epidermoid cancer of the head and neck: preliminary report.

A pilot study was conducted using two courses of cis-diamminedichloroplatinum, vincristine (Oncovin), and bleomycin (COB) every three weeks prior to surgery(s) and/or radiotherapy in 34 patients with advanced previously untreated epidermoid cancer of the head and neck. All patients received at least one course of chemotherapy; 7 are too early for evaluation. Responses to chemotherapy were dramatic and occurred within a few days. Sixteen patients had partial remission (PR) (59.3%), 9 had minimal response (MR) (33.3%) and 2 had stable disease after one course of COB. Twenty-two patients completed a second course of chemotherapy, 6 (27.3%) had complete remission (CR), 13 (59.1%) had PR, 1 had MR and 2 had stable disease. Objective remission correlated with subjective improvement. Drug toxicity were tolerable and acceptable. Eight patients had surgical resection after chemotherapy, followed by post-operative radiation therapy, and one patient had pre-operative radiation therapy before the tumor was considered resectable. Twelve patients underwent radiotherapy, including patients with CR after chemotherapy. Presently there is no evidence of local recurrence with the longest follow-up of 15+ months. In this preliminary report, the effectiveness and feasibility of this combined modality therapy is established; further study is needed to prove its value in prolonging disease-free period and survival.     

Problems associated with molecular targeted drugs for cancer

Molecular targeted drugs have been developed and have come to play a part in the standard treatment of cancers. However, issues such as the optimum dose, selection of patients, and verification of the molecular targets remain to be discussed, because unexpected clinical problems related to the clinical efficacy, adverse events, and development of resistance have appeared. Therefore, proof of principle (POP) studies and pharmacodynamic or pharmacogenomic research to explore new bio-markers for the drugs are essential for clinical progress. On the other hand, the higher cost of development and care must also be discussed as new problems.     

Unknown primary cancer of the head and neck: a multidisciplinary approach

The management of patients with cervical lymph node metastases from an unknown primary cancer (CUP) remains a matter of controversy. Although new advanced diagnostic tools, such as positron emission tomography, have recently been introduced in oncology, the frequency of this tumour entity in clinical practice means it is still relevant. Recently introduced molecular profiling platforms may provide biological classification for the primary tissue of origin as well as insights into the pathophysiology of this clinical entity, including the characterisation of the Epstein-Barr virus and human papilloma virus genomas in the metastatic cervical nodes. Due to the lack of randomised trials, a standard therapy has not been identified yet. Although neck dissection followed by post-operative radiotherapy is the most generally accepted approach, there are other curative options that can be used in some patients: neck dissection alone, nodal excision followed by post-operative radiotherapy or radiotherapy alone. A major controversy remains in the target radiation volumes that range from ipsilateral neck irradiation to prophylactic irradiation of all potential mucosal sites and both sides of the neck. Finally, the administration of concurrent chemotherapy is currently being advised for patients with adverse prognostic factors.     

晚期胃癌分子靶向药物研发的研究进展

近年来,化疗基础上加用抗表皮生长因子受体2 药物、抗血管生成药物及免疫检查点抑制剂,不仅可提高晚期胃癌（GC）患者治疗的有效率,而且可明显改善患者预后。然而,目前晚期GC患者治疗后的生存获益远落后于肺癌、结直肠癌及乳腺癌等实体肿瘤,靶向治疗仍需进一步探索。随着分子生物学技术的发展,新的治疗靶点如Claudin 18.2、基质金属蛋白酶（MMP）、Dickkopf相关蛋白1（DKK-1）、RAD3相关蛋白激酶（ATR）被发现在GC细胞中表达,针对这些靶点的药物逐渐在临床治疗中崭露头角,并显示出较好的临床应用前景。阐述晚期GC治疗中靶点的作用机制及靶向药物的研究进展,对提高GC的临床治疗疗效具有重要意义。     

Cancer of head and neck: a multidisciplinary approach

The head and neck region encompasses structures from the base of the skull to the clavicles which include nasopharynx,oropharynx,hypopharynx,larynx and oral cavity.Tobacco,alcohol,and human papilloma virus (HPV) infection are the three major risk factors for head and neck squamous cell carcinoma (HNSCC) in different countries.     

Locally advanced head and neck cancer

Opinion statement The simultaneous administration of chemotherapy and radiation has produced a significant impact on the treatment of advanced squamous cell carcinomas of the head and neck. Although no single regimen has emerged as the “standard” approach, recent trials have consistently demonstrated the superiority of combined treatment programs over radiotherapy alone for local tumor control and overall survival. More-over, multimodal treatment has emerged with important ancillary goals of organ preservation, improved cosmesis, and enhancement of quality of life. With improving survival in all stages of disease, much attention can be given to identifying effective measures to reduce the risk of metachronous primary cancers in this high-risk group.     

The role of taxanes and targeted therapies in locally advanced head and neck cancer

PURPOSE OF REVIEW: This review presents new data on the role of taxanes and targeted therapies in the management of squamous cell carcinoma of the head and neck. RECENT FINDINGS: Taxane-containing triplets are clearly superior as an induction regimen in locally advanced squamous cell carcinoma of the head and neck when compared with cisplatin/5 fluorouracil which has been the standard for two decades. Preliminary data suggest that the addition of a taxane to cisplatin/5 fluorouracil as induction regimen followed by chemoradiation may be superior to chemoradiation alone. The addition of cetuximab to radiation prolongs locoregional control and survival without increasing mucositis. Areas of active investigation are the search for epidermal growth factor receptor mutations and the optimal way of integrating epidermal growth factor receptor-directed therapies into standard management. Meanwhile new targets are explored. SUMMARY: Taxane/cisplatin/5 fluorouracil induction chemotherapy is clearly superior to cisplatin/5 fluorouracil. Epidermal growth factor receptor directed therapies can safely be combined with radiation and the combination shows encouraging results.     

Recent regimen of chemotherapy for advanced head and neck carcinomas

Standard treatment for squamous cell carcinomas in the head and neck consists of surgery and/or radiotherapy. However, this standard treatment alone has not improved the poor prognosis of advanced head and neck carcinomas. A new curative treatment modality for advanced head and neck carcinomas including chemotherapy with an impact is needed. The clinical results of chemotherapy over the past twenty years have shown chemotherapy including cisplatin (CDDP) and 5-fluorouracil (5-FU) to be the most efficacious for advanced cases. In this paper, the problems with this chemotherapy are discussed in terms of predictive factors of the response to this treatment, and the recent clinical results with chemotherapy including CDDP, 5-FU, and other drugs are reviewed. Furthermore, new chemotherapeutic regimens and the clinical results including commonly applied taxanes, e.g., paclitaxel and docetaxel, are reviewed.     

Combining molecular therapeutics with radiotherapy for head and neck cancer

In the last decade, research focus has shifted to testing rapidly emerging classes of agents that specifically target signaling pathways within tumor cells or microenvironment. Though their effects given as single agents are generally limited, many of these compounds have the capability to sensitize tumors to radiation or cytotoxic drugs. Actively investigated approaches include combining anti-EGFR agents, bioreductive hypoxic cell toxins, anti-angiogenesis agents, or inhibitors of multiple signaling pathways with radiotherapy.