【作者】 张帅；

【导师】 胡立宽；

【作者基本信息】 山东大学 ， 肿瘤学（放射治疗）（专业学位）， 2016， 博士

【摘要】 第一部分加速超分割调强适形放疗在鼻咽癌中的临床应用背景：鼻咽癌(nasopharyngeal carcinoma, NPC)起源于鼻咽黏膜,对放射线中度敏感。NPC放疗结束后的局部残留率约10%,局部复发率范围约16.8-23%。肿瘤克隆干细胞的加速再增殖是放疗失败的主要原因,一定总剂量下全疗程时间延长,肿瘤存活的干细胞再增殖抵消了一部分放疗剂量对肿瘤细胞杀灭作用。头颈部肿瘤的加速增殖发生在放疗开始后的第3-4周,在保持局控率不变的前提下,如果放疗的疗程每延长1天需要补充一个0.66Gy额外的剂量才能抵消肿瘤细胞加速再增殖所“浪费”的剂量。使用常规放疗技术治疗NPC,每周六次组疗效明显优于每周五次组。随着调强适形放疗(intensity modulated radiotherapy, IMRT)技术的运用和普及,单次放疗剂量得到提高,总疗程缩短的这种加速分割模式得到临床广泛的认可和推广。那么增加每周IMRT次数的分割模式疗效和毒副反应如何,并没有相应的文献报道。目的：本研究的主要目的是分析NPC患者接受加速分割(每周六次)IMRT的近期与远期疗效及早晚期毒副反应,从而评价其临床应用的可行性。方法：本研究共入组89例NPC患者。调强适形放疗(IMRT)的方案为：PGTVnx 68-72 Gy, PGTVnd 66-70Gy, PTV1 62Gy,每日一次,每周六次,共33次；PTV252Gy,每日一次,每周六次,共28次,针对放疗结束残存的颈部转移淋巴结使用局部9Mev电子线小野推量2～6Gy。对于Ⅲ/Ⅳ期的患者给予顺铂单药增敏化疗,具体方案为：顺铂75mg/m2 dl,每21天为一个周期。Kaplan-Meier法用于计算总生存率(Overall survival, OS)、无远处转移生存率(Distant metastasis-free survival,DMFS)、局部与区域控制率(Local-regional control, LRC)和无进展生存率(Progression-free survival, PFS)。运用卡方检验进行相关因素筛选,并使用Cox比例风险模型进行分析独立的危险因素。结果：鼻咽部原发肿瘤和颈部转移淋巴结治疗的近期有效率均为100%。T1和T2组的CR率高于T3和T4组,但无统计学差异(卡方值=3.3683,P=0.0665)。本组患者的3年OS、DMFS、LRC和PFS分别为83.6%、80.2%、94.4%和75.7%。没有观察到区域淋巴结复发或未控。多因素分析显示,性别、年龄、放疗前是否贫血、T分期、肿瘤直径≥2.5cm. EBV-DNA表达高低、放射治疗的规律性和放射治疗的严重并发症(≥Ⅲ级)均与患者的预后没有显著的相关性(均P>0.05)。N分期(P=0.002, HR=9.526,95% CI=1.305～3.327)为预测DMFS独立的预后因素,临床分期(P=0.003, HR=9.557,95% CI=1.713～11.194)是预测OS独立的预后因素。复发的时间为23～50个月,中位复发时间为31个月；远处转移的时间为3～38个月,中位远处转移时间为11.5个月。最严重的急性毒副反应是黏膜炎,0至Ⅳ级的发生率分别为2.2%,27.0%,47.2%,20.2%,和3.4%,而晚期毒副反应主要表现为59例I级和18例II级的口干症状。结论：每周六次IMRT这种加速分割模式在鼻咽癌治疗中是切实可行的,取得了非常满意的局部和区域控制率,早晚期放疗不良反应均可耐受。远处转移是治疗失败的最主要因素。第二部分多西他赛联合洛铂方案新辅助化疗序贯同期放化疗在高危鼻咽癌治疗中的疗效初探背景：鼻咽癌(NPC)是东南亚地区一种常见的头颈部恶性肿瘤,其发病、发展与EB病毒感染密切相关。近几十年来,包括放疗技术的更新和化疗药物的换代都取得了巨大的进步,使局部晚期NPC的5年局部控制率达到90%以上,5年总生存率达到80%以上,然而仍有15-25%的远处转移率并未得到改善,如何提高无远处转移率是目前研究的热点和难点。淋巴结分期是影响有无远处转移生存率最重要的预后因素。NPC远处转移的高风险因素包括T4N2,N3和在多个肿大淋巴结中,至少一个淋巴结直径>4厘米。新辅助化疗的优势在于杀灭存在体循环中的肿瘤细胞,从而减少亚临床转移灶。目的：本次研究主要目的是评价高危NPC患者接受多西他赛联合洛铂方案新辅助化疗两个周期,序贯调强适形放疗(IMRT)同步洛铂单药化疗的临床疗效和毒副反应。方法：本研究共入组37例高危NPC患者。新辅助化疗方案为多西他赛(75mg/m2,第1天,静脉滴注)联合洛铂(30mg/m2,第1天,静脉滴注)两个周期。同步化疗方案为洛铂(50mg/m2,第1天,静脉滴注)。在整个化疗期间,监测血常规、肝肾功能和血浆EBV-DNA的变化,每21天为一个周期。调强适形放疗(IMRT)的方案为：PGTVnx 70-74 Gy, PGTVnd 66-70Gy, PTV162-64Gy,每日一次,每周五次,共33次；PTV2 52-56Gy,每日一次,每周五次,共26-28次,针对放疗结束残存的颈部转移淋巴结使用局部9Mev电子线小野推量2-6Gy。使用Kaplan-Meier法计算总生存率(OS)、无远处转移生存率(DMFS)、无局部复发生存率(LRFS)和无进展生存率(PFS)。不同组间率的比较用卡方检验。结果：随访时间为4-52个月,中位随访时间为31个月。3年OS、DMFS.LRFS和PFS分别为74.3%、67.4%、91.5%和61.2%。新辅助化疗和放化疗的有效率分别为83.8%和100.0%。最严重的急性放疗不良反应是放射性黏膜炎,Ⅰ、Ⅱ、Ⅲ级分别为14(37.8%)、18(48.6%)、4(10.8%)。观察到血液学毒性大多属于Ⅰ、Ⅱ级,耐受性良好。其毒性主要表现为白细胞减少(97.3%)、血小板减少(83.8%)和贫血(81.1%)。治疗失败最主要的原因是远处转移,最常见的转移部位是骨,中位远处转移时间为10个月(3-31)。结论：在高危的鼻咽癌患者中,多西他赛联合洛铂新辅助化疗序贯IMRT同步洛铂单药化疗是一种高效、可行的治疗方案,取得了非常满意的短期疗效,使用简易且重复性好,毒副反应可耐受。更多还原

【Abstract】 Part Ⅰ:Clinical efficacy of intensity modulated radiotherapy with accelerated fractionation in patients with nasopharyngeal carcinomaBackground:Nasopharyngeal carcinoma (NPC) arises from the epithelia of the nasopharynx, moderately sensitive to radiation. The local residual rate of NPC is about 10% and local recurrent rate ranges from 16.8-23%, depending on the initial tumor status. Accelerated proliferation of clonogenic tumor cells is the main reason for radiotherapy failure. Longer courses of treatment cause an increase in proliferating cells under certain total dose. To extend radiotherapy one day requires an additional 0.66 Gy to offset tumor cell proliferation for Tpot=3d cancer. Using conventional radiotherapy, the efficacy of six times weekly group was significantly better than the efficacy of five times weekly group. With the intensity modulated radiotherapy (IMRT) technology widely used, a single dose of radiation is improved, the total course should be shortened corresponding. This acceleration segmentation model has been widely recognized in clinical. How is the efficacy and toxicity to increase the fractionation number of IMRT weekly, and no corresponding literature.Introduction:The purpose of this study was to analyze the efficacy and safety of IMRT with accelerated fractionation (Six times weekly) in patients with NPC.Methods:This study included 89 NPC patients treated with six fractions of IMRT per week. The IMRT doses were planning target volume (PTV) 68-72 Gy for gross disease in the nasopharynx, and 66-70 Gy for positive lymph nodes in 33 fractions. The doses for high risk and low risk region PTV were 62 Gy in 33 fractions and 52 Gy in 28 fractions. For the end of radiotherapy residual cervical lymph node were pushed on 2-6Gy using 9Mev electron beam. Concurrent with chemoradiotherapy, stage Ⅲ/Ⅳ NPC patients received a chemotherapy program consisting of Cisplatin 75 mg/m2, day 1. The cycle repetition was every 21 days. The Kaplan-Meier test was used to calculate overall survival (OS), distant metastasis-free survival (DMFS), local-regional control (LRC) and progression-free survival (PFS). Relevant factors were screened using a chi-square test, and independent risk factors were analyzed using the Cox proportional hazards model.Results:The 3-year OS, DMFS, LRC and PFS were 83.6%,80.2%,94.4% and 75.7%, respectively. No regional lymph node recurrence was detected. Further analyses revealed that gender, age, anaemia, T stage, tumor diameter≥2.5cm, the level of EBV-DNA, regularity of radiotherapy and severe radiotherapy complication were not significantly associated with the prognosis of patients (all P> 0.05). N stage (P=0.002, HR=9.526,95% CI=1.305～3.327) were independent prognostic factors for DMFS, clinic stage (P=0.003, HR=9.557,95% CI=1.713～11.194) was independent prognostic factors for OS. The median recurrent time was 31 months (range,23-50 months). The median distant metastasis time was 11.5 months (range, 3-38 months). The most serious acute toxicity was mucositis, with prevalence of Grades 0 to Ⅳ being 2.2%,27.0%,47.2%,20.2%, and 3.4%, respectively. Late toxicity manifested as Grades Ⅰ and Ⅱ xerostomia in 59 and 18 patients.Conclusion:In patients with NPC, IMRT with accelerated fractionation yielded an excellent local control rate, and the toxicities were mild and tolerable. Distant metastasis was the main cause of treatment failure.Part Ⅱ:Docetaxel combined with lobaplatin neoadjuvant chemotherapy followed by concurrent lobaplatin with intensity modulated radiotherapy increases the efficacy of patients with high-risk nasopharyngeal carcinomaBackground:Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus-associated cancer with high incidence in Southeast Asia. In recent decades, great advancements have been made in NPC treatment, including the renewal of radiotherapy technique and the replacement of chemotherapy drugs. Therefore 5-year local control rate of locally advanced NPC was raised to 90%,5-year overall survival rate was more than 80%, but still 15-25% of distant metastasis rate did not improve. Currently it is the hot and difficult research how to improve the rate of distant metastasis-free survival (DMFS). The lymph node stage was the most important prognosis factor affecting DMFS. High risk factors of NPC distant metastasis include T4N2, N3 and in multiple lymph nodes, at least one lymph node diameter> 4 cm. Neoadjuvant chemotherapy can reduce subclinical metastases by killing tumor cells in circulation.Purpose:To evaluate the efficacy and safety of docetaxel combined with lobaplatin as neoadjuvant chemotherapy followed by concurrent lobaplatin with intensity-modulated radiotherapy (IMRT) for high-risk positive lymph node (N+) nasopharyngeal carcinoma (NPC).Methods:This study enrolled 37 primary high-risk N+NPC patients. The neoadjuvant chemotherapy program was docetaxel (75 mg/m2, day 1,ivgtt) plus lobaplatin (30 mg/m2, day l,ivgtt) for two cycles. Concurrently with IMRT, patients received a chemotherapy program of lobaplatin (50 mg/m2, day l,ivgtt), Cycle repetition was every 21 days. The IMRT doses were planning target volume (PTV) 70-74 Gy for gross disease in the nasopharynx, and 66-70 Gy for positive lymph nodes in 33 fractions. The doses for high risk and low risk region PTV were 62-64 Gy in 33 fractions and 52-56 Gy in 26-28 fractions. For the end of radiotherapy residual cervical lymph node were pushed on 2-6Gy using 9Mev electron beam. The Kaplan-Meier method was used to calculate OS, DMFS, LRFS and PFS. Comparisons of the frequency of data between groups were carried out using the chi-square test.Results:The median follow-up duration was 31 months (range 4-52). The 3-year overall survival (OS) was 74.3%. The 3-year distant metastasis-free survival (DMFS) was 67.4%. The 3-year locoregional relapse-free survival (LRFS) was 91.5%, and the 3-year progression-free survival (PFS) was 61.2%. The efficiency of short-term effects of neoadjuvant chemotherapy and chemoradiotherapy were 83.8% and 100.0%, respectively. The most serious acute adverse reactions of radiation is radiation mucositis, with Ⅰ level 14 (37.8%), Ⅱ level 18 (48.6%), Ⅲ level 4 (10.8%). Hematologic toxicity was well tolerated. Its toxicity mainly as leukopenia (97.3%), thrombocytopenia (83.8%) and anemia (81.1%). The main reason for treatment failure is distant metastasis, the most common site of metastasis is bone, the median time to distant metastasis was 10 months (3-31).Conclusions:In patients with high-risk NPC, docetaxel combined with lobaplatin neoadjuvant chemotherapy followed by concurrent lobaplatin with IMRT yielded excellent short-term results with mild and tolerable toxicities.更多还原