加速分割调强适形放疗在鼻咽癌中的临床应用与新辅助化疗的研究及探讨

发布时间：2018-06-27 07:10

本文选题：鼻咽癌 + 调强适形放疗　；参考：《山东大学》2016年博士论文

【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P0.05)。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。
[Abstract]:The first part accelerates the clinical application of hyper fractionated intensity modulated radiotherapy in nasopharyngeal carcinoma: nasopharyngeal carcinoma (nasopharyngeal carcinoma, NPC) originates from the nasopharyngeal mucosa. The local residual rate is about 10% and the local recurrence rate is about 16.8-23 after the end of moderate sensitivity.NPC radiotherapy. The accelerated proliferation of the tumor cloned stem cells is the radiotherapy loss. The main cause of the failure is to extend the total course of the total dose at a certain total dose. The survival of the cancer stem cell proliferation counteracts the killing effect of a part of the radiotherapy dose on the tumor cells. The accelerated proliferation of the head and neck tumor occurs in the 3-4 week after the beginning of the radiotherapy. Taking an extra dose of 0.66Gy to counteract the "wasted" dose of tumor cells to accelerate and re proliferate. The treatment of NPC using conventional radiotherapy is significantly better than a five week group. With the application and popularization of the intensity modulated radiation therapy (intensity modulated radiotherapy, IMRT) technique, the single dose of radiotherapy is improved. The accelerated segmentation model with short total course of treatment has been widely recognized and popularized. Then there is no relevant literature on how to increase the efficacy and side effects of IMRT times per week. Objective: the main purpose of this study was to analyze the short-term and long-term effects of accelerated division of IMRT (6 times a week) for patients with NPC. Late toxicity and side effects to evaluate the feasibility of its clinical application. Methods: a total of 89 patients with NPC were enrolled in this study. The scheme of intensity modulated radiation therapy (IMRT) was: PGTVnx 68-72 Gy, PGTVnd 66-70Gy, PTV1 62Gy, once a day, 33 times a week; PTV252Gy, once a day, a total of 28 times per week, to end the remaining neck for radiotherapy. The metastatic lymph nodes used the local 9Mev electron line Onokazu to push 2 ~ 6Gy. for the patients with phase III / IV for the chemosensitization chemotherapy with cisplatin single drug. The specific scheme was cisplatin 75mg/m2 DL, and a periodic.Kaplan-Meier method was used every 21 days to calculate the total survival rate (Overall survival, OS), and the survival rate of Distant metastasis-free survival (DMFS) was not far away (DMFS). ) local and regional control rates (Local-regional control, LRC) and progression free survival (Progression-free survival, PFS). Correlation factors were screened by chi square test, and a Cox proportional hazard model was used to analyze independent risk factors. Results: the short-term effectiveness of nasopharyngeal primary tumor and cervical metastatic lymph node treatment were all in the near future. The CR rate in group 100%.T1 and T2 was higher than that in group T3 and T4, but there was no statistical difference (=3.3683, P=0.0665). The 3 year OS, DMFS, LRC, and PFS were 83.6%, 80.2%, 94.4%, and 75.7%. did not observe the recurrence or uncontrolled lymph nodes in the region. The expression of V-DNA, the regularity of radiotherapy and the severe complications of radiotherapy (> grade III) were not significantly correlated with the prognosis of the patients (P0.05).N staging (P=0.002, HR=9.526,95% CI=1.305 ~ 3.327) as prognostic factors for DMFS independence, and clinical stages (P=0.003, HR=9.557,95% CI=1.713 ~ 11.194) were predictive of OS independence. The recurrence time was 23~50 months, the median recurrence time was 31 months, the distant metastasis time was 3~38 months and the median distant metastasis time was 11.5 months. The most serious acute side effects were mucositis, and the incidence rate of 0 to IV was 2.2%, 27%, 47.2%, 20.2%, and 3.4%, while the late toxic and side effects were mainly 59 I. Level and 18 cases of II - class dry mouth symptoms. Conclusion: six times a week, a six time IMRT accelerated segmentation model is practicable in the treatment of nasopharyngeal carcinoma, with a very satisfactory local and regional control rate and tolerable adverse effects in the early and late stage of radiotherapy. Distant metastasis is the most important factor in the treatment failure. The second part of docetaxel combined with luoplatin scheme. The effect of neoadjuvant chemotherapy sequential concurrent chemoradiotherapy on the treatment of high risk nasopharyngeal carcinoma: nasopharyngeal carcinoma (NPC) is a common head and neck malignant tumor in Southeast Asia. Its incidence and development are closely related to EB virus infection. In recent decades, great progress has been made in the renewal of radiotherapy technology and the replacement of chemotherapeutic drugs. The local control rate of local advanced NPC is above 90% for 5 years, and the total survival rate of 5 years is above 80%. However, the distant metastasis rate of 15-25% is still not improved. How to improve the metastasis rate is the hot spot and difficulty of the present study. The lymph node staging is the most important prognostic factor of distant metastasis,.NPC distant metastasis. High risk factors include T4N2, N3, and at least one lymph node in multiple lymph nodes with a diameter of 4 cm. The advantage of the neoadjuvant chemotherapy is to kill the tumor cells in the existing body circulation and reduce the subclinical metastases. Objective: the main purpose of this study was to evaluate high risk NPC patients to receive docetaxel combined with luoplatin regimen. Two cycles of adjuvant chemotherapy and sequential intensity modulated radiation therapy (IMRT) were used to synchronize the clinical efficacy and side effects of single drug chemotherapy with luoplatinum. Methods: a total of 37 high-risk patients were enrolled in this study. The new adjuvant chemotherapy regimen was docetaxel (75mg/m2, first days, intravenous drip) combined with luoplatinum (30mg/ m2, first days, intravenous drip) in two cycles. Luoplatinum (50mg/m2, first days, intravenous drip). Monitoring blood routine, liver and kidney function and plasma EBV-DNA changes during the whole chemotherapy period, every 21 days as a cycle. The scheme of intensity modulated radiation therapy (IMRT) is: PGTVnx 70-74 Gy, PGTVnd 66-70Gy, PTV162-64Gy, once a day, a total of 33 times a week; PTV2 52-56Gy, once a day, five times a week, A total of 26-28 times, the total survival rate (OS) was calculated using the local 9Mev line Onokazu push 2-6Gy. for the metastatic lymph nodes in the cervical lymph node with the end of the radiotherapy. There was no distant metastasis survival (DMFS), no local recurrence rate (LRFS) and progression free survival (PFS). The comparison of the rates of different groups was checked with chi square test. At 4-52 months, the median follow-up time was 31 months.3 years OS, DMFS.LRFS and PFS were 74.3%, 67.4%, 91.5% and 61.2%., the efficiency of neoadjuvant chemotherapy and radiochemotherapy was 83.8% and 100.0%., respectively, the most serious acute radiotherapy adverse reactions were radioactive mucositis, I, II, and III were 14 (37.8%), 18 (48.6%), 4 (10.8%) respectively. Most of the toxicity mainly manifested as leukocyte reduction (97.3%), thrombocytopenia (83.8%) and anemia (81.1%). The most important reason for the failure of the treatment was the distant metastasis, the most common metastatic site was the bone, and the distant metastasis time was 10 months (3-31). Conclusion: in high-risk nasopharyngeal cancer patients, docetaxel combined. Luoplatinum neoadjuvant chemotherapy sequential IMRT synchronous luoplatinum single drug chemotherapy is an efficient and feasible treatment. It has achieved very satisfactory short-term efficacy, easy to use, good reproducibility, and tolerable toxic and side effects.
【学位授予单位】：山东大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R739.63

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