诱导化疗及分子靶向治疗在局部晚期喉癌和下咽癌治疗中的应用[综述]

对于局部晚期喉癌和下咽癌传统治疗方案多以手术治疗辅以放疗或放化疗为主,然而患者的5年生存率未得到明显提高,且常以牺牲喉功能为代价,严重影响患者的生活质量和心理健康。因此非手术治疗逐渐成为研究热点,其中诱导化疗在器官保留及减少远处转移方面展现出明显优势,而分子靶向治疗特异性高、不良反应少,已逐渐应用到头颈鳞状细胞癌的治疗中。本文总结相关临床试验,探讨诱导化疗及分子靶向治疗在局部晚期喉癌和下咽癌中的应用,旨在总结比较不同的治疗方案,为临床决策提供参考。     

诱导化疗及其联合靶向药物在下咽癌中的应用

下咽癌的治疗理念多为延长生存期、保留喉功能、改善生存质量。诱导化疗后根据患者反应情况进行放化疗或手术的个性化、综合化治疗模式是临床研究关注的热点之一，靶向药物的加入可进一步改善患者预后。值得注意的是，因人种、患者身体状况等差异，药物的选择及用药剂量存在争议。本文分析以往的临床试验资料，总结诱导化疗在下咽癌中的治疗历程，探讨诱导化疗及靶向治疗的应用价值，为未来下咽癌的临床诊疗提供参考。     

下咽-食管同时性多原发癌的临床分层治疗策略

目的　探讨下咽-食管同时性多原发癌分层治疗策略。方法　回顾性分析2012年1月~2018年6月收治的21例下咽-食管同时性原发癌患者,分析分层治疗的预后情况。提出下咽-食管原发癌分层治疗策略,两种癌以分期更晚的肿瘤为主线治疗：下咽癌和食管癌同属早期病变,行手术治疗,术后病理为低分化鳞状细胞癌行放疗;若下咽癌和食管癌任一病变为局部晚期则行2~3周期诱导化疗再行手术治疗,术后辅助放疗;若局部晚期患者拒绝行诱导化疗,可行手术+综合治疗（放疗或化疗）。结果　21例下咽- 食管同时性多原发癌患者,20例完成上述分层治疗,1例局部晚期患者因下咽肿物侵犯颈内动脉行放化疗。所有患者随访1~7年,中位随访时间2年,因远处转移死亡5例,2例下咽术后局部复发,2例颈部淋巴结转移,2例咽瘘,1例吞咽困难,1例进食后反流。21例患者随访1年,2例死亡,1年生存率90.5%（19/21）;19例患者随访2年,死亡4例,生存率78.9%（15/19）。结论　下咽-食管同时性多原发癌行分层处理可取得良好的临床疗效。     

局部晚期头颈部鳞状细胞癌的化疗及靶向进展

局部晚期头颈部鳞状细胞癌目前主要采用手术、放疗和化疗相结合的综合治疗,但是器官功能保留率和5年生存率没有显著提高。从20世纪70年代末开始,以顺铂为基础的化疗药开始应用于局部晚期头颈部鳞状细胞癌治疗中,研究表明,顺铂联合氟尿嘧啶作为诱导化疗方案提高了喉功能保全率。后来随着紫杉醇的应用,有研究证实在PF方案基础上加用紫杉醇可提高诱导化疗的疗效。与PF方案相比,TPF方案在局部控制率及无进展生存期上有显著的优越性,因此,成为诱导化疗的首选方案。20世纪90年代初期,同步放化疗成为非手术治疗及保喉的新方式,因其在总体生存率、保喉率、局部控制率上有明确的优势,已被列入局部晚期头颈部肿瘤非手术治疗的标准治疗方案。2006年分子靶向治疗药物西妥昔单抗经美国食品和药物管理局批准运用于临床,因其预后的优势及较少的不良反应成为无法耐受化疗药物的新选择。就局部晚期头颈部鳞状细胞癌的化疗药物及靶向药物治疗进展进行综述。     

下咽癌远处转移的相关因素研究进展

下咽癌是头颈部最常发生远处转移的肿瘤，一旦发生远处转移往往预后极差。远处转移是影响下咽癌预后的主要决定因素，也是临床决策的重要因素。然而，下咽癌远处转移的预防或早期治疗策略仍然是一个极大的挑战。因此，探索下咽癌远处转移相关影响因素，对下咽癌的临床诊断、治疗及改善预后问题至关重要。本文就下咽癌远处转移的部位，下咽癌远处转移的相关因素以及下咽癌远处转移的过程做一综述。     

喉癌及下咽癌手术治疗进展

喉癌、下咽癌的治疗应遵循多学科综合治疗的原则。手术治疗只是其中的一个手段,如何综合应用现有的治疗手段,如放疗、化疗,是更好地治疗肿瘤,特别是晚期肿瘤的关键。本文仅就喉癌、下咽癌手术治疗进展加以论述。     

局部晚期下咽癌术前新辅助化疗24例临床分析

目的　探讨新辅助化疗在局部晚期下咽癌术前应用的效果以及对喉功能保留的影响。方法　回顾性分析我院自2014年1月~2018年12月收治的35例局部晚期下咽癌患者,T3级26例,T4级9例,根据患者喉功能保留的愿望、身体状况以及治疗依从性,11例患者采用手术+术后放疗,24例患者采用术前新辅助化疗（TPF）方案+手术+术后放 疗。对两组患者的喉功能保留情况,术后并发症等进行比较分析。结果　所有手术病例均完整切除肿瘤,切缘阴性,手术组的11例患者中喉功能保留率为18.2%（2/11）,辅助化疗组24例喉功能保留率为66.7%（16/24）,辅助化疗组喉功能保留率高于手术组,差异有统计学意义。手术组术后并发咽瘘1例,辅助化疗组术后咽瘘3例,两组咽瘘发生率比较,差异无统计学意义。结论　局部晚期下咽癌术前给予新辅助化疗在不降低生存率的前提下能提高喉功能保留率,且不增加术中术后并发症的几率,可作为下咽癌治疗的有效选择。     

诱导化疗在局部中晚期头颈鳞状细胞癌治疗中的应用进展

局部中晚期头颈鳞状细胞癌患者目前主要采用手术、放疗与化疗相结合的综合治疗模式，但是5年生存率并无显著提高。诱导化疗自20世纪70年代被广泛应用到头颈鳞状细胞癌的治疗中，在保留器官功能及减少远处转移方面显示出明显优势，但在提高生存率方面仍存争议。本文简述了诱导化疗在头颈鳞状细胞癌治疗中的发展历程，比较了诱导化疗、手术和同步放化疗在头颈鳞状细胞癌治疗中的优势与劣势，总结了诱导化疗在肿瘤局部控制率和远处转移率方面的作用，提出了诱导化疗在头颈肿瘤治疗中面临的问题与未来展望。     

编辑导读北大核心CSCD

论著《先天性遗传性聋患者基于体素的脑形态学研究》利用基于体素形态学方法探讨先天性遗传性聋(CHHL)患者脑功能改变的生理基础。发现CHHL患者除存在听觉相关脑区结构的异常外,还存在广泛的与听觉相关脑区以外的皮层结构改变,提示CHHL患者全脑结构发生顺应性改变并发生功能重塑。论著《内镜在颍下窝良性肿瘤切除术中的应用》回顾性分析了采用内镜手术治疗的11例颍下窝良性肿瘤患者的临床资料,提出内镜下切除颛下窝良性肿瘤具有损伤小、恢复快、并发症少、疗效确切等优点,可作为该区域良性肿瘤手术治疗的重要供选方法论著《环气管部分切除术及其扩大术式治疗严重喉气管狭窄效果分析》认为环气管部分切除术是治疗严重声门下狭窄并累及上段气管狭窄的有效治疗方法,其扩大术式对累及声门的狭窄也有效,这两种术式为喉气管重建术失败的患者提供了挽救性的治疗方法。论著《继发性甲状旁腺功能亢进甲状旁腺全切除术的探讨》分析了195例维持性透析肾病患者继发性甲状旁腺功能亢进的临床资料,提出清扫式甲状旁腺全切除术治疗维持性透析肾病患者的继发性甲状旁腺功能亢进安全可靠:论著《窄带成像内镜在口腔癌及癌前病变诊断中的应用》探讨了窄带成像(NBI)内镜在口腔癌及癌前病变诊断中的应用价值,认为NBI内镜能较白光内镜更准确地检出口腔癌病灶,倪晓光的NBI分型标准对口腔癌及癌前病变的早期诊断具有重要意义:论著《经口机器人手术治疗口咽癌的安全性及有效性的初步探讨》发现在掌握好适应证的前提下.使用达芬奇机器人经口入路切除口咽癌安全、有效、损伤小,论著《下咽癌预后改变及原因分析:单中心2003—2007年与2010—2014年两个五年间数据对比》探讨2003—2007年与2010—2014年2个五年间收治的下咽癌患者的生存预后改变趋势,并对其原因进行分析.发现保留喉功能手术方式的应用使得早期下咽癌患者的喉功能保留率明显升高,且仍可收获满意的长期生存情况;综合治疗模式尤其是术前诱导化疗和术后辅助治疗尤其是放化疗的使用使得局部晚期下咽癌患者保喉率及生存预后情况得到显著提高:论著《下咽鳞状细胞癌TPF方案诱导化疗敏感性差异基因的初步分析》应用基因表达谱芯片,筛选下咽鳞状细胞癌患者对紫杉醇+顺钳+5-氟尿l ?(TPF)方案诱导化疗敏感性的差异表达基因.并进行初步分析,提出CD44.1L-6R可能是下咽鳞状细胞癌TPF诱导化疗敏感性相关的潜在功能性基因。论著《基于钙离子成像的多波长激光诱发体外小鼠螺旋神经节细胞信号转导的实验研究》探究在安全、可接受的不同波长激光信号作用下小鼠螺旋神经节细胞信号转导功能的反应。发现小鼠螺旋神经节细胞在光信号作用下具有诱发信号转导反应的可能,而且该反应具有激光波长选择性。循证医学之窗《晚期下咽癌手术综合疗法与非手术综合疗法两种治疗策略疗效比较的Meta分析》使用Meta分析的方法.比较手术综合疗法(SRT)与非手术综合疗法(CRT)在治疗晚期下咽癌患者中的远期疗效及喉功能保存率,发现SRT远期疗效更好,CRT的喉功能保存效果更佳继续教育园地《鼻腔鼻窦内翻性乳头状瘤的临床分期》总结并对比了既往7个不同的鼻腔鼻窦内翻性乳头状瘤(SNIP)分期.并着重提出以肿瘤根基部位置为导向的新的SNIP临床分期。     

下咽癌的治疗进展

目的下咽癌恶性程度高,位置隐匿,早期症状不典型,且容易侵犯喉和食管等邻近器官,易发生颈部淋巴结转移和远处转移, 预后较差。对于早期下咽癌的治疗,保留喉功能的下咽癌手术和放/化疗都可获得较好的肿瘤学疗效和功能保留。对晚期下咽癌手术加术后放疗是传统的治疗方式,但需行全喉切除的患者将失去发音功能。而放/化疗等非手术保喉治疗,可以获得与手术加放疗相似的生存率,并有望保留喉功能,但是具有近期和远期的毒副作用。因此推荐多学科参与制定治疗方案。     

Evaluation of overall tumor cellularity after neoadjuvant chemotherapy in patient with locally advanced hypopharyngeal cancer

The aim of this study is to clarify the prognostic value of the pathological overall tumor cellularity after neoadjuvant chemotherapy for locally advanced hypopharyngeal cancer. In consecutive series of 45 operable patients with locally advanced hypopharyngeal cancer, neoadjuvant chemotherapy by cisplatin and 5-fluorouracil was administered. Pathological image analysis was performed in 30 patients using the large cross-section specimen after total resection to evaluate the overall tumor cellularity. The chemotherapeutic responses were classified according to the pathological grading scale by dividing into four categories; more than 70% overall tumor cellularity in Grade 1, between an estimated 10 and 70% in Grade 2, less than 10% in Grade 3, and no identifiable malignant tumor cells in Grade 4. The pathological grades were taken into account for analysis of the survival. In 30 available patients, 40% had Grade 1 pathological response, 30% had Grade 2, and 30% had Grade 3. There was no Grade 4 patient. The overall 5-year survival rate for these 30 patients was 53.33%. The survival rate (61.66%) for patients with Grade 2 and 3 responses was significantly higher than that (27.78%) for patients with Grade 1 response (p?=?0.009). Cox regression analysis revealed that the increasing pathological grade was an independent predictor of a better survival in patients undergoing neoadjuvant chemotherapy. We have shown that the prognosis of patients with locally advanced hypopharyngeal cancer, who had been treated by neoadjuvant chemotherapy followed by total resection, can be predicted by evaluation of pathological overall tumor cellularity from the large section specimen.     

The role of chemotherapy for advanced oro and hypopharyngeal cancer

Although important progress continuous to be made in the treatment of oro and hypopharyngeal cancer, the 5-year survival rate for all this disease has remained at less than 30% for the past 30 years. In the early 1980s, chemotherapy was introduced with high expectation of reducing in the incidence of distant metastases and increasing the possibility of local control. This article explores the use of chemotherapy in the treatment of advanced pharyngeal cancer. Thus, the efficacy of chemotherapy are reviewed and treatment options for advanced pharyngeal cancer are made. When advanced carcinoma is still localized, function-preserving surgery is performed. In these cases, the possibility of instituting adjuvant chemotherapy with an active treatment regimen may be taken into account depending on the condition of the patient and the tumor. Patients with surgically resectable tumors are given 1-2 cycles of induction chemotherapy. Cases who respond to the induction chemotherapy are subsequently given concurrent chemoradiotherapy. Residual lymph nodes in the neck are removed surgically. The cases who do not respond to the induction chemotherapy are treated with radical surgery. Patients with unresectable carcinoma are given concurrent chemoradiotherapy because local treatment should be performed in such patients as early as possible. In principle, concurrent regimens should be supplemented with adjuvant chemotherapy in all cases. This is particularly required for those with advanced N-stage patients.     

Rational choice of induction chemotherapy-based larynx preservation for hypopharyngeal cancer

Abstract

Backgroud: Induction chemotherapy, as a larynx preservation treatment, has been available for over 20 years. We conducted a retrospective study to evaluate the efficacy of this protocol with taxene, cisplatin and 5-fluorouracil in Chinese patients with hypopharyngeal cancer that chose preservation strategy.

Material and methods: 170 patients with locally advanced hypopharyngeal cancer were assigned to receive induction chemotherapy. 107 patients (63%) with complete response or partial response received larynx preservation treatment and 63 non-responders (37%) received radical surgery.

Results: Median survival time was 30 months (range: 3–59 months). 63 patients (37%) had local-regional failure and 15 (9%) had distant metastasis. Three-year LFS was 27.8% (95% CI: 23.6–32.0%). The estimated three-year overall survival rate was 44.5% (95% CI: 39.5–49.5%). There was no significant difference in the three-year survival rate between responders (44.8%) and non-responders (43.9%) (p?=?.237), however patients with a partial response had a significant decrease in survival (32.2%) (p?<?.001).

Conclusions: In patients with hypopharyngeal cancer, ICT with TPF regimen followed by RT, as a larynx preservation treatment, may be suitable for complete responders, but not partial responders.     

T4b期下咽癌非手术综合治疗77例回顾性分析

目的:分析非手术综合治疗T4b期下咽癌的有效性、安全性及影响临床预后的因素。方法:回顾性分析2010年1月至2021年6月解放军总医院耳鼻咽喉头颈外科医学部收治的77例下咽癌T4b期患者的临床资料,均为男性,年龄（57.0±8.0）岁。治疗方式均采用诱导化疗+同步放化疗,总结该组患者的治疗完成率和不良反应,并利用Kap...     

Neue Aspekte zur aktuellen Therapie von Oropharynxkarzinomen

Beside the surgical treatment of head and neck cancer, the concept of organ and function preserving therapy of locally advanced HNSCC (head and neck squamous cell carcinoma) especially of oropharyngeal origin is becoming increasingly important. The comparison of induction chemotherapy plus chemoradiation and primary concomitant chemoradiation has recently been the subject of randomized clinical trials. New combinations of different (chemo)radiation regimens and targeted therapies are also under investigation for HNSCC. Molecular markers predicting treatment efficacy as well as new potential targets are also being evaluated in several clinical trials. The good prognosis of HPV-associated HNSCC has sparked efforts to deintensify treatment to minimize therapy-related toxicities. The impact of specific therapies is growing due to the increasing incidence of young patients with HPV-positive carcinomas.     

Concurrent chemoradiotherapy with cisplatin and fluorouracil for locally advanced hypopharyngeal carcinoma

CONCLUSIONS: The concurrent administration of cisplatin and fluorouracil (CCRT) during radiotherapy after induction chemotherapy had better results than induction chemotherapy followed by radiotherapy alone (CT+RT) for overall survival, laryngeal preservation, and locoregional control in patients with locally advanced hyopharyngeal cancer. OBJECTIVES: To report treatment results comparing CCRT with CT+RT in locally advanced hypopharyngeal cancer. PATIENTS AND METHODS: Sixty-six consecutive patients treated with curative intent were analyzed retrospectively. Thirty-eight patients were treated with induction chemotherapy followed by definitive RT, and 28 patients with induction chemotherapy followed by concurrent chemoradiotherapy. All patients had more than three cycles of continuous infusion of cisplatin and 5-fluorouracil every 3 weeks. The median dose of irradiation was 70 Gy in the CT+RT group and 68.4 Gy in the CCRT group, respectively. RESULTS: The overall 5-year survival rates were 24% for the CT+RT group and 42% for the CCRT group (p=0.031). The 3-year pharyngolaryngectomy-free survival rates were 32% for the CT+RT group and 63% for the CCRT group (p=0.032). The 3-year locoregional control rate for CCRT was significantly better than that for the CT+RT (52% vs 23%, p=0.004). Acute hematologic toxicity appeared in 39% of the CT+RT patients and 75% of the CCRT patients.     

Contemporary therapeutic management of locally advanced hypopharyngeal cancer: oncologic and functional outcomes – a report on 100 cases

Conclusion: A significant proportion of patients with locally advanced hypopharyngeal cancer could not be managed by larynx-sparing therapy. T4 stage is one of the main predictive factors of oncologic and functional outcomes. Objectives: To analyze the therapeutic management of patients with locally advanced hypopharyngeal cancer in clinical practice and to report oncologic and functional outcomes. Methods: This was a retrospective study of all patients treated for a locally advanced hypopharyngeal squamous cell carcinoma between 2001 and 2012 at our institution. Results: A total of 100 patients were included in this study. Induction chemotherapy (CT) followed by radiotherapy (RT) ± CT, primary RT + CT, and primary total pharyngolaryngectomy (TPL) comprised the initial therapeutic management for 54, 24, and 20 patients, respectively. Two patients received only supportive care. Overall survival (OS) and cause-specific survival (SS) were 50% and 60% at 3 years, respectively. In the group of patients referred for induction CT, the 3-year OS and SS were 58% and 70%, respectively. In multivariate analysis, T stage (p = 0.05) and ASA score (p = 0.02) were significant predictive factors of OS. T4 tumor stage had a pejorative impact on swallowing function after therapy (p = 0.006). The rate of patients alive, disease-free, and with a functional larynx at 2 years was 23%.     

Aktuelle Therapieoptionen bei Larynx- und Hypopharynxkarzinomen

The prognosis of squamous epithelial cell carcinoma of the upper aerodigestive tract has improved considerably in the last 30 years. Patients presenting with stage I or II disease are treated with surgery or radiation therapy with curative intent. Although the efficacy is comparable between the two methods, surgery is usually preferred so that the side effects and late toxic effects of radiation can be avoided. For the treatment of advanced stages of disease, surgery, radiotherapy, chemotherapy and immunotherapy are usually combined. The introduction of concurrent administration of chemotherapy and radiotherapy (chemoradiotherapy) has been a major advancement. This has resulted in local control and survival rates comparable to those seen following radical surgery and postoperative radiotherapy, but with preservation of the larynx in most patients. However, recent epidemiological observations have shown declining survival rates in laryngeal cancer patients, raising concern about uncritical and too frequent use of this approach. The rationale for choosing treatment options for patients with laryngeal and hypopharyngeal carcinoma is discussed.     

Clinical analysis of multiple primary malignancies of the hypopharynx and esophagus

PURPOSE: Because the capability to control squamous cell carcinomas of the head and neck has improved recently, the phenomenon of multiple primary malignancies of that region is now recognized with increasing frequency. We reviewed cases of multiple primary squamous cell carcinomas of the hypopharynx and esophagus with regard to their frequency, incidence, and prognosis. PATIENTS AND METHODS: We reviewed 104 cases of hypopharyngeal cancer to determine (1) if and when esophageal cancer occurred, (2) the classification of multiple tumors as metachronous or synchronous, and (3) tumor histology. RESULTS: In most cases of the metachronous type, esophageal cancer followed hypopharyngeal cancer within less than 3 years. Most cases of hypopharyngeal cancer were at an advanced stage, in contrast to esophageal cancer, which were all early stage. These cases had a poor prognosis despite various treatments causing local disease to be well controlled. Endoscopic esophageal mucosal resection was found to be an effective treatment for esophageal cancer, especially in superficial types. CONCLUSIONS: The prognosis and mild systemic damage after endoscopic esophageal mucosal resection compare favorably with surgery, radiation, or systemic chemotherapy.