本文選題：鼻咽癌 + 調(diào)強(qiáng)適形放療�。� 參考：《山東大學(xué)》2016年博士論文

【摘要】：第一部分加速超分割調(diào)強(qiáng)適形放療在鼻咽癌中的臨床應(yīng)用背景：鼻咽癌(nasopharyngeal carcinoma, NPC)起源于鼻咽黏膜,對放射線中度敏感。NPC放療結(jié)束后的局部殘留率約10%,局部復(fù)發(fā)率范圍約16.8-23%。腫瘤克隆干細(xì)胞的加速再增殖是放療失敗的主要原因,一定總劑量下全療程時間延長,腫瘤存活的干細(xì)胞再增殖抵消了一部分放療劑量對腫瘤細(xì)胞殺滅作用。頭頸部腫瘤的加速增殖發(fā)生在放療開始后的第3-4周,在保持局控率不變的前提下,如果放療的療程每延長1天需要補(bǔ)充一個0.66Gy額外的劑量才能抵消腫瘤細(xì)胞加速再增殖所“浪費(fèi)”的劑量。使用常規(guī)放療技術(shù)治療NPC,每周六次組療效明顯優(yōu)于每周五次組。隨著調(diào)強(qiáng)適形放療(intensity modulated radiotherapy, IMRT)技術(shù)的運(yùn)用和普及,單次放療劑量得到提高,總療程縮短的這種加速分割模式得到臨床廣泛的認(rèn)可和推廣。那么增加每周IMRT次數(shù)的分割模式療效和毒副反應(yīng)如何,并沒有相應(yīng)的文獻(xiàn)報道。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的近期與遠(yuǎn)期療效及早晚期毒副反應(yīng),從而評價其臨床應(yīng)用的可行性。方法：本研究共入組89例NPC患者。調(diào)強(qiáng)適形放療(IMRT)的方案為：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,針對放療結(jié)束殘存的頸部轉(zhuǎn)移淋巴結(jié)使用局部9Mev電子線小野推量2～6Gy。對于Ⅲ/Ⅳ期的患者給予順鉑單藥增敏化療,具體方案為：順鉑75mg/m2 dl,每21天為一個周期。Kaplan-Meier法用于計算總生存率(Overall survival, OS)、無遠(yuǎn)處轉(zhuǎn)移生存率(Distant metastasis-free survival,DMFS)、局部與區(qū)域控制率(Local-regional control, LRC)和無進(jìn)展生存率(Progression-free survival, PFS)。運(yùn)用卡方檢驗(yàn)進(jìn)行相關(guān)因素篩選,并使用Cox比例風(fēng)險模型進(jìn)行分析獨(dú)立的危險因素。結(jié)果：鼻咽部原發(fā)腫瘤和頸部轉(zhuǎn)移淋巴結(jié)治療的近期有效率均為100%。T1和T2組的CR率高于T3和T4組,但無統(tǒng)計學(xué)差異(卡方值=3.3683,P=0.0665)。本組患者的3年OS、DMFS、LRC和PFS分別為83.6%、80.2%、94.4%和75.7%。沒有觀察到區(qū)域淋巴結(jié)復(fù)發(fā)或未控。多因素分析顯示,性別、年齡、放療前是否貧血、T分期、腫瘤直徑≥2.5cm. EBV-DNA表達(dá)高低、放射治療的規(guī)律性和放射治療的嚴(yán)重并發(fā)癥(≥Ⅲ級)均與患者的預(yù)后沒有顯著的相關(guān)性(均P0.05)。N分期(P=0.002, HR=9.526,95% CI=1.305～3.327)為預(yù)測DMFS獨(dú)立的預(yù)后因素,臨床分期(P=0.003, HR=9.557,95% CI=1.713～11.194)是預(yù)測OS獨(dú)立的預(yù)后因素。復(fù)發(fā)的時間為23～50個月,中位復(fù)發(fā)時間為31個月；遠(yuǎn)處轉(zhuǎn)移的時間為3～38個月,中位遠(yuǎn)處轉(zhuǎn)移時間為11.5個月。最嚴(yán)重的急性毒副反應(yīng)是黏膜炎,0至Ⅳ級的發(fā)生率分別為2.2%,27.0%,47.2%,20.2%,和3.4%,而晚期毒副反應(yīng)主要表現(xiàn)為59例I級和18例II級的口干癥狀。結(jié)論：每周六次IMRT這種加速分割模式在鼻咽癌治療中是切實(shí)可行的,取得了非常滿意的局部和區(qū)域控制率,早晚期放療不良反應(yīng)均可耐受。遠(yuǎn)處轉(zhuǎn)移是治療失敗的最主要因素。第二部分多西他賽聯(lián)合洛鉑方案新輔助化療序貫同期放化療在高危鼻咽癌治療中的療效初探背景：鼻咽癌(NPC)是東南亞地區(qū)一種常見的頭頸部惡性腫瘤,其發(fā)病、發(fā)展與EB病毒感染密切相關(guān)。近幾十年來,包括放療技術(shù)的更新和化療藥物的換代都取得了巨大的進(jìn)步,使局部晚期NPC的5年局部控制率達(dá)到90%以上,5年總生存率達(dá)到80%以上,然而仍有15-25%的遠(yuǎn)處轉(zhuǎn)移率并未得到改善,如何提高無遠(yuǎn)處轉(zhuǎn)移率是目前研究的熱點(diǎn)和難點(diǎn)。淋巴結(jié)分期是影響有無遠(yuǎn)處轉(zhuǎn)移生存率最重要的預(yù)后因素。NPC遠(yuǎn)處轉(zhuǎn)移的高風(fēng)險因素包括T4N2,N3和在多個腫大淋巴結(jié)中,至少一個淋巴結(jié)直徑4厘米。新輔助化療的優(yōu)勢在于殺滅存在體循環(huán)中的腫瘤細(xì)胞,從而減少亞臨床轉(zhuǎn)移灶。目的：本次研究主要目的是評價高危NPC患者接受多西他賽聯(lián)合洛鉑方案新輔助化療兩個周期,序貫調(diào)強(qiáng)適形放療(IMRT)同步洛鉑單藥化療的臨床療效和毒副反應(yīng)。方法：本研究共入組37例高危NPC患者。新輔助化療方案為多西他賽(75mg/m2,第1天,靜脈滴注)聯(lián)合洛鉑(30mg/m2,第1天,靜脈滴注)兩個周期。同步化療方案為洛鉑(50mg/m2,第1天,靜脈滴注)。在整個化療期間,監(jiān)測血常規(guī)、肝腎功能和血漿EBV-DNA的變化,每21天為一個周期。調(diào)強(qiáng)適形放療(IMRT)的方案為：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,針對放療結(jié)束殘存的頸部轉(zhuǎn)移淋巴結(jié)使用局部9Mev電子線小野推量2-6Gy。使用Kaplan-Meier法計算總生存率(OS)、無遠(yuǎn)處轉(zhuǎn)移生存率(DMFS)、無局部復(fù)發(fā)生存率(LRFS)和無進(jìn)展生存率(PFS)。不同組間率的比較用卡方檢驗(yàn)。結(jié)果：隨訪時間為4-52個月,中位隨訪時間為31個月。3年OS、DMFS.LRFS和PFS分別為74.3%、67.4%、91.5%和61.2%。新輔助化療和放化療的有效率分別為83.8%和100.0%。最嚴(yán)重的急性放療不良反應(yīng)是放射性黏膜炎,Ⅰ、Ⅱ、Ⅲ級分別為14(37.8%)、18(48.6%)、4(10.8%)。觀察到血液學(xué)毒性大多屬于Ⅰ、Ⅱ級,耐受性良好。其毒性主要表現(xiàn)為白細(xì)胞減少(97.3%)、血小板減少(83.8%)和貧血(81.1%)。治療失敗最主要的原因是遠(yuǎn)處轉(zhuǎn)移,最常見的轉(zhuǎn)移部位是骨,中位遠(yuǎn)處轉(zhuǎn)移時間為10個月(3-31)。結(jié)論：在高危的鼻咽癌患者中,多西他賽聯(lián)合洛鉑新輔助化療序貫IMRT同步洛鉑單藥化療是一種高效、可行的治療方案,取得了非常滿意的短期療效,使用簡易且重復(fù)性好,毒副反應(yīng)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.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R739.63

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