【作者】 张文东；

【导师】 王秀问；

【作者基本信息】 山东大学 ， 肿瘤学（专业学位）， 2014， 博士

【摘要】 鼻咽癌(Nasopharyngeal carcinoma, NPC)是起源于鼻咽狭窄管腔的常见肿瘤。在西方国家NPC的发生率很低,然而,在我国南方以及东南亚的一些国家和地区,是常见的恶性肿瘤。长期以来NPC一直是威胁我国人民健康的主要疾病之一,也是我国南部男性三大恶性肿瘤之一,年发病率高达15～50/10万。更重要的是,NPC高发于中年男性,严重影响了社会劳动力资源。由于解剖部位的原因,NPC很难进行手术治疗,目前的治疗手段是以放疗为主,适时配合化疗的综合治疗模式。然而,影响NPC疗效和预后的因素很多,如年龄、性别、种族、分期、病理类型、初始治疗手段、是否解救治疗等,许多因素交织给患者的疗效和预后判断带来困难。为此,我们对澳门特别行政区NPC病例资料进行随访研究分析,以期能对各期NPC的疗效和预后有更准确的判断。第一部分影响鼻咽癌远期生存的随访资料多因素分析研究目的：鼻咽癌(NPC)是东南亚地区常见的恶性肿瘤,尤其是我国东南沿海及港澳台地区。高发病地区NPC的流行病学特征与低发病地区明显不同,亚裔人群NPC的治疗方式及预后也与欧美地区有所不同。目前NPC对综合治疗手段的疗效评价及各种因素对预后的影响仍未达成共识。本研究目的在于评价澳门地区NPC患者的流行病学特征及远期治疗效果,并分析与预后有关的临床病理因素。病例和方法：本项回顾性研究收集了2005年～2009年期间澳门Conde S. Januario General Hospital新确诊治疗的所有NPC患者资料。既往已确诊后治疗并在该段时间复发再次诊治的病例被剔除,然而,资料包含了该段时间内在澳门以外地区确诊为鼻咽癌后转到该院治疗或随访的病例。资料收集内容包括患者人口特征、分期、病理类型、治疗方式、治疗效果及生存时间。患者人口特征包括性别、年龄、婚姻等。治疗方式包括单纯放疗、诱导化疗、同步放化疗、辅助化疗和姑息化疗等。姑息治疗包括晚期肿瘤的联合或单药化疗、姑息放疗等。患者治疗前及疗后随访检查包括完整的病史和体格检查、颅面部检查(包含牙齿和颅神经)、纤维鼻咽镜、全血常规、血清生物化学、胸部X线片、鼻咽部和颅底及可疑转移部位(含副鼻窦)CT或MRI。为了确定鼻咽癌患者的预后影响因素,研究分析患者的生存期与年龄、性别、疾病分期、病理类型、治疗方式、初治疗效等的相关性。数据统计分析中,生存分析用Kaplan-Meier法,组间生存曲线比较用Log-rank检验。各主要预后因素分析用Cox比例风险模型。结果：研究共收集248例各期NPC患者,中位年龄49.0岁,男女之比为184：64,所有患者中位随访时间为47.5月(1～109月)。91.13%的患者为WHO Type Ⅲ型,WHO Type Ⅰ和Ⅱ型仅占8.87%。AJCC分期为Ⅰ期病例只占8.47%,59.7%的病例为Ⅲ期或Ⅳ期患者。所有患者5年生存率为68.70%,中位生存期未达到。Ⅰ～Ⅳ期患者的5年生存率分别是90.48%,76.71%,76.89%和33.87%(P=0.000),差异有统计学意义。所有患者5年无进展生存率为61.04%,中位PFS未达到。而5年无进展生存率分别是85.15%,72.36%,63.88%和26.26%(P=0.000),差异有统计学意义。放疗联合化疗组和单纯放疗组的5年生存率分别为：Ⅰ～Ⅱ期81.67%和79.59%(P=0.753),Ⅲ期79.91%和70.38%(P=0.143),Ⅳ期35.22%和0%(P=0.000),仅有Ⅳ期患者的差异有统计学意义；而两种治疗组患者的5年无进展生存率分别是：Ⅰ～Ⅱ期75.83%和74.98%(P=0.814),Ⅲ期74.08%和42.25%(P=0.027),Ⅳ期27.31%和0%(P=0.000),Ⅲ、Ⅳ期患者差异均有统计学意义。结论：与其它临床病理指标相比,NPC患者的AJCC分期是最重要的预后因素,随着分期升高,5年生存率和无进展生存率均明显降低。治疗方式中在放疗基础上加入化疗对早中期患者没有任何优势,对于晚期(Ⅳ期)患者加入化疗后无论是总生存期还是无进展生存期均明显优于单纯放疗,而对于局部晚期(Ⅲ期)患者,加入化疗后可改善无进展生存期,但对总生存期改变没有任何意义。第二部分辅助化疗对中-晚期鼻咽癌远期生存影响的回顾性分析目的：对于早期NPC,标准的治疗方案是单纯放疗。然而,对于晚期患者,目前标准的治疗是放射治疗和顺铂为基础的全身化疗。目前的资料显示,同步放化疗(concurrent chemoradiotherapy, CCRT)对中期和局部晚期(Ⅱ期、Ⅲ期、ⅣA+B期)鼻咽癌的局部控制和治疗结果有明显地改善。然而,对CCRT结束后辅助化疗(adjuvant chemotherapy, AC)的作用和价值一直有争议。本研究目的在于通过分析不良反应和临床远期预后来评价中期和局部晚期NPC患者治疗中CCRT后加入AC的意义。病例和方法：共收集澳门特别行政区Conde S. Januario General Hospital血液肿瘤科2003年5月～2007年4月间接诊的189例确诊为AJCC分期Ⅱ期-ⅣB期NPC患者的资料,所有病例都接受了CCRT,部分患者放疗后还接受了AC。放疗期间患者于每周一至周五接受调强放疗(intensity-modulated radiation therapy, IMRT),总剂量可达62-70Gy。所有合格病例中,96例只接受了CCRT,而93例在完成CCRT后又做了AC。患者在CCRT期间均接受了每周30mg/m2的顺铂化疗,共用6～8周。CCRT/AC组患者随后用顺铂80mg/m2第1天,氟尿嘧啶1000mg/m2第1至4天辅助化疗,每4周为一周期,共用3周期。研究对所有病例的临床病案记录和放射影像学资料进行了复习。对最早出现的症状、头颈部检查、放射治疗计划、化疗方案等资料进行了分析。治疗前的评价包括完整的病史、包含脑神经功能在内的体格检查、纤维鼻咽镜检查、全血细胞计数、血生化检查(包括肝肾功能)、胸部X线、鼻咽(含颅底)及颈部CT或MRI扫描和牙科检查。对于高转移风险(淋巴结阳性,特别是N3期)和伴有临床症状怀疑有远处转移的患者,还要考虑加做骨同位素扫描和胸腹CT。CCRT组患者疗效评价在末次放疗后4周进行,而CCRT/AC组患者在末次化疗结束后2周进行,4周后再次疗效确认。评价手段依据临床体检、纤维鼻咽镜或影像学检查(CT或MRI),评价标准参照WHO实体肿瘤疗效评价标准。每次随访时患者临床特征、纤维鼻咽镜、和放射影像检查(CT或MRI扫描)。放、化疗导致的毒性评价参照WHO实体肿瘤毒性分级标准。患者在放化疗期间,每周就诊一次接受常规诊视检查。疗程结束后半年内每四周一次门诊随访检查,半年后改为每三月一次,两年后改为每六月一次。随访记录并分析患者一般特征、治疗不良反应、依从性和远期治疗结果,后者包括治疗近期有效率、总生存期(overall survival, OS)、无进展生存期(progression-free survival, PFS)、无复发生存期(relapse-free survival,RFS)、无局部复发生存期(freedom from local recurrence survival, FLRS)、无远处复发生存期(freedom from distant metastasis survival, FDMS)研究的主要目的为比较两组患者的5年生存率。其它研究目的包括评价和比较两组患者的客观有效率、治疗毒性、无复发生存期(RFS),无局部复发生存(FLRS)和无远处复发生存(FDMS)。计算OS、RFS. FLRS和FDMS用Kaplan-Meier法。两组患者生存曲线差异性比较用Log-rank检验。用Cox比例风险回归模型进行多因素分析,用可信区间(confidence intervals, CIs)和风险比(hazard ratios, HRs)评价不同的因素间的差异。用卡方检验(或Fisher’s exact检验)比较两组患者的OS. PFS及局部和远处控制率。结果：CCRT和CCRT/AC两组患者的中位随访期限为分别为49月(范围6-82月)和41月(范围3-82月)。在CCRT治疗期间,每周对患者病变评价一次。放疗完成后,最初的半年每4周评价一次,以后每3月评价一次至两年。随后每6个月进行病变评价。所有患者5年生产率为71.45%,5年无进展生存率是70.31%。CCRT和CCRT/AC组总有效率分别是97.92%和97.83%(P=0.643)。5年生存率分别为68.2%和75.9%(P=0.53)；因随访结束时未到达半数(50%)病例死亡,中位生存期未达到。CCRT组有30例死亡,而CCRT/AC组有21例。两组患者的5年PFS率分别为66.7%和71.4%(P=0.96)。CCRT和CCRT/AC两组患者的5年RFS率分别为66.6%和80.1%,差异没有统计学意义(P=0.39)。两组患者的无局部复发生存率(FLRS)分别为88.6%和94.6%(P=0.48)。两组5年无远处复发生存率(FDMS)分别为75.2%和84.7%(P=0.57)。两组患者的RFS、FLRS和FDMS均没有统计学差异。CCRT/AC组患者辅助化疗期间,有7例患者发生Ⅳ度毒性(危及生命),而39例患者发生Ⅲ度毒性(严重)。该组中相对高发的Ⅲ-Ⅳ度毒性包括白细胞降低、恶心、呕吐和胃炎。12例患者因毒性不能耐受而放弃治疗；2例患者在接受1周期AC后因非毒性原因主动放弃化疗；1例患者在第二周期化疗中死于重症感染,被定义为致死性毒性相关病例。只有78例(83.9%)患者完成了全部3周期的辅助化疗。结论：本研究显示,对于高发地区的中期和局部晚期NPC患者,CCRT后加或不加辅助化疗对两组患者的总生存期和无进展生存期均没有影响,即没有证据显示证明CCRT后加用AC使患者局部控制和临床远期疗效受益。而且,CCRT结束后再进行三周期AC使患者很难耐受,AC组有16.1%的患者因不能耐受治疗所致的不良反应提前结束治疗,降低了患者的生活质量,也导致了治疗依从性降低。因此,除非做临床试验,AC不应在CCRT后的NPC患者中常规应用。更多还原

【Abstract】 Nasopharyngeal carcinoma (NPC) is the most common malignant tumor originated in the nasopharyngeal stenosis cavity. NPC is low incidence In western countries, however, it is very popular in southern China and countries (regions) of Southeast Asia. NPC is one of the main diseases threatening people’s health in our country in a long time, and also is one of three malignant tumors of China’s southern male inhabitant. It has an incidence rate of15-50/100,000in men in these areas. More importantly, NPC often occurs in middle-aged men which seriously affected the social labor resources.Surgical resection of NPC is very difficult for the reason of special anatomic site, therefore, the mainstay strategies for the treatment of NPC are radiotherapy-based, comprehensive therapies, including chemotherapy. However, many factors influenced the curative effect and prognosis of NPC, such as age, gender, race, clinical stage, histological type, original treatment methods and salvage treatment or not, etc. All of above Interlocking factors brings difficulties to our curative effect and prognosis judgment. For this purpose, we performed this retrospective study which included the clinical data of all NPC patients who were newly diagnosed and treated in Macao Special Administrative Region between2005and2009, in order to obtain a more accurate judgments to curative effect and prognosis of different stage NPC.PART I Multivariate Analysis of Long-term Follow-up Result of Nasopharyngeal CarcinomaObjective Nasopharyngeal carcinoma is a common malignancy in Southeast Asia, especially in the southern coastal area of China’s mainland and in Hong Kong, Macao and Taiwan. However, the epidemiological characteristics of NPC are significantly different from those in low incidence regions. The therapeutic method and prognosis of Asian are different from that of Western either. Full consensus has not been reached regarding the value of comprehensive treatment. This study was designed to evaluate the epidemiological characteristics and long-term treatment efficacy in patients with NPC in Macao and to analyze the clinicopathological prognostic factors.Patients and MethodsThis retrospective study includes the clinical data of all NPC patients who were newly diagnosed and treated in Macao Conde S. Januario General Hospital between2005and2009. Patients that had been previously diagnosed with NPC and treated, but who had relapsed during this period, were excluded. However, the study did include patients that had been diagnosed with NPC outside of Macao during that time, who then underwent subsequent treatment and follow-up at Conde S. Januario General Hospital. Data collected included patient demographics, NPC stage, histological type, treatment modalities, treatment efficacy, and survival time. Patient demographic characteristics included gender, age, and marital status.The treatment modalities were radiotherapy alone, neoadjuvant chemotherapy followed by radiotherapy, concurrent chemoradiotherapy plus adjuvant chemotherapy, or palliative treatment. Palliative treatment of advanced tumors included single-agent chemotherapy or combined chemotherapy and radiotherapy.Examinations included a complete medical history and physical examination, a craniofacial examination (including dental and cranial nerve exams), nasopharyngofiberscopy, a complete blood count, serum biochemistry, a chest X-ray, and a CT or MRI examination of the nasopharynx, skull base and any suspicious metastatic sites, including the paranasal sinuses.Prognostic factors for NPC patients were determined by analyzing the associations between patient survival and the following:age, gender, disease-stage, NPC histological type, treatment modalities and primary therapeutic effects. The Kaplan-Meier method was used for survival analysis. The survival curves between groups were analyzed using the Log-rank test. The main prognostic factors were analyzed using the Cox proportional hazards model.ResultsA total of248patients with NPC, at all stages, were included in this study. The median age was49.0years old and the ratio of males to females was184:64. The median follow-up time was47.5months (range:1-109months). Among the patients,91.13%were of Type III according to WHO classification. Patients in stage I according to the American Joint Committee of Cancer (AJCC) accounted for only8.47%of the total, while patients in stages III and IV of the disease accounted for59.7%.The5-year survival rate for all patients that underwent follow-up was68.70%, however, the median survival (5-year) was not reached and could not be calculated. The5-year survival rates for patients in stages I-IV were90.48%,76.71%,76.89%and33.87%(P=0.000), respectively. The5-year PFS rate was61.04%for all patients. Just like the median survival, the median PFS (5-year) was not reached either, while the5-year progression-free survival rates were85.15%,72.36%,63.88%and26.26%(P=0.000), respectively.The5-year survival rates in the group that received radiotherapy combined with chemotherapy and in the group that received only radiotherapy were as follows:Stages Ⅰ and Ⅱ:81.67%and79.59%(P=0.753), stage Ⅲ:79.91%and70.38%(P=0.143), and stage Ⅳ:35.22% and0%(P=0.000), respectively, Only the patients of stage IV had significant difference. The5-year progression-free survival rates in these two groups were as follows:Stages Ⅰ and Ⅱ:75.83%and74.98%(P=0.814), stage Ⅲ:74.08%and42.25%(P=0.027), and stage Ⅳ:27.31%and0%(P=0.000), respectively. Both stage Ⅲ and stage Ⅳ had statistics difference.ConclusionsCompared with other clinicopathological parameters, AJCC staging in NPC patients is the most important prognostic factor. As the stage number increases, the5-year survival rates and5-year progression-free survival rates are both significantly reduced. For patients in the early or mid stage (Ⅰ-Ⅱ), there is no advantage of adding chemotherapy to radiotherapy, however in patients with advanced (stage Ⅳ) NPC, the addition of chemotherapy significantly improves overall and progression-free survival compared to radiotherapy alone. For patients with locally advanced (stage Ⅲ) NPC, addition of chemotherapy improves progression-free survival, but not overall survival. PART Ⅱ Retrospective Study of the Effect of Adjuvant Chemotherapy in Intermediate andLocoregionally Advanced Nasopharyngeal CarcinomaObjectiveFor early stage Nasopharyngeal Carcinoma, the standard therapeutic scheme is radiotherapy alone; while for advanced NPC, the current standard treatment is composed of irradiation and cisplatin-based systemic therapy.Concurrent chemoradiotherapy (CCRT) showed a significant improvement in disease control and clinical outcome in patients with intermediate and locoregionally advanced nasopharyngeal carcinoma (NPC)(stage II, III and IVA+B). However, there has been debate about the contribution and application of additional adjuvant chemotherapy (AC) to CCRT regime. This study aims to evaluate the additional value of AC to the treatment of intermediate and locally advanced NPC with regard to toxicity and clinical outcomes.Patients and MethodsFrom May2003through to April2007,189patients with biopsy-proved, intermediate and locoregionally advanced (stage II to Stage IVB) NPC finished CCRT schedule with/without followed by AC at the Department of Haemato-oncology, Conde S. Januario General Hospital, Macao SAR of China. All cases must have received CCRT, part of them had also received AC after radiation. All patients in the two groups had received intensity-modulated radiation therapy (IMRT) from Monday to Friday, with a dose range from62to70Gy (median66Gy). Of all studied patients,96received CCRT after diagnosed; and93received CCRT and followed by AC. The chemotherapy during CCRT consisted of weekly cisplatin (30mg/m2) for6to8weeks. Three cycles of AC were given with cisplatin (80mg/m2) and5-FU (1000mg/m2/d on day1to4) every4weeks to patients of CCRT/AC arm.Clinical records and radiographic study of the patients were reviewed retrospectively. Documented data of the initial presenting symptoms, head and neck examination, radiotherapy protocols, chemotherapy treatment regimens were analyzed. Pretreatment evaluation consisted of a complete history, physical examination including cranial nervous function test, fiberoptic nasopharyngoscopy, complete blood cell count, serum biochemistry (including liver and renal function test), chest X-ray, computed tomography (CT) scan or magnetic resonance imaging (MRI) scan of the nasopharynx and base of skull and neck, dental evaluation. The imaging of distant metastases including isotope bone scan and CT scan of the upper abdomen and chest could be considered for at-risk subsets presented (lymph node positive, especially N3stage) and for those patients with clinical indication.Response was assessed three months after the completion of radiation in the CCRT group and two weeks after the last chemotherapy in the CCRT/AC group. The evaluation standard was in accordance with the WHO response criteria and included CR, partial response (PR), no change (NC) and progressive disease (PD). Clinical characteristics, flexible nasopharyngoscopy and radiological examination (CT or MRI scan) were evaluated at every visit. The toxicity caused by chemotherapy and/or radiotherapy was also assessed in accordance with the WHO standard.Each patient was evaluated every week during CCRT. When radiation was finished, all cases were assessed every three months during the first two years and then every half year until death. Patient characteristics, toxicity, compliance with treatment and clinical outcomes including response to treatment, overall survival (OS), progression-free survival (PFS), relapse-free survival (RFS), freedom from local recurrence survival (FLRS), and freedom from distant metastasis survival (FDMS) were analyzed.The primary end point of the study was to compare OS at5years in the two groups. The other goals were to assess and compare the objective response rate, toxicity, relapse-free survival (RFS), freedom from local recurrence survival (FLRS), and freedom from distant metastasis survival (FDMS) rates in both arms. The Kaplan-Meier product-limit method was used in the calculation of OS, RFS, FLRS and FDMS rates. The significance of differences between survival curves was estimated by Log-rank test. Hazard rations and CIs were estimated for various end points. Toxicity rates were compared using χ2test.ResultsThe median follow-up duration of the CCRT and CCRT/AC patients was49months (range,6to82months) and41months (range,3to82months), respectively. During the treatment of CCRT, patients were evaluated every week. After completion of radiation, patients were evaluated every four weeks for the started half year, and every three months until the end of two years, then every six months thereafter.The five-year OS rate for the189patients was71.45%, and five-year PFS rate was70.31%. The overall response rate of CCRT and CCRT/AC groups was97.92%and97.83%, respectively (P=0.643). Five-year OS rate was68.2%in CCRT group and75.9%in CCRT/AC group (P=0.53). Neither group reached the median OS duration (50%) due to the long survival time. When we analyzed the data,30patients had died in the CCRT group, and21patients had died in the CCRT/AC group. Five-year PFS rate was66.7%and71.4%in CCRT and CCRT/AC groups, respectively (P=0.96).The5year RFS rates were66.6%for CCRT group compare with80.1%for CCRT/AC group; this difference was no statistical significance (P=0.39). The5-year FLRS rates were88.6%for the CCRT group and94.6%for the CCRT/AC group (P=0.48). The5-year FDMS rates were75.2%for the CCRT group and84.7%for the CCRT/AC group (P=0.57). No statistically significant difference was found in RFS, FLRS or FDMS between the two groups.Grade4(life-threatening) toxicity occurred in eleven patients, and39patients had grade3(severe) side effects from adjuvant chemotherapy. A relative high incidence of grade3or4leukopenia, nausea, vomiting and stomatitis was observed in this group. Twelve went off permanently due to toxicity. Two refused further treatment after completed first cycle of chemotherapy, documented as unrelated to toxicity. One patient was off for died from severe infection during the second cycle of adjuvant chemotherapy and was defined as fatal toxicity related case. So only83.9percent of patients received all three courses of AC finally. ConclusionsResults of this study showed that with or without AC after CCRT had no effect to OS and PFS in both groups, that is to say no evidence of additional value of AC to CCRT treatment in disease control and clinical outcomes in patients with locally advanced NPC in endemic region. Moreover, additional three cycles of AC after CCRT seems poorly tolerated in patients. About16.1percent of patients in AC group had to finish schedule for could not tolerate the adverse reaction. So it cut down the quality of life and compliance. Therefore, AC should not be used routinely after CCRT except for a clinical trial.更多还原