【作者】 王培培；

【导师】 王军；

【作者基本信息】 河北医科大学 ， 肿瘤学， 2012， 硕士

【摘要】 目的：直肠癌是较为常见的恶性肿瘤，手术是直肠癌的主要治疗手段。尽管外科技术不断进步，其5年生存率仍徘徊于50%，治疗失败的原因主要为局部复发和远处转移。多年来实践证明，各期直肠癌术后辅助放化疗是直肠癌综合治疗的标准手段。但目前直肠癌术后辅助放化疗尚存在一些问题，术后辅助放化疗的经典研究均是在常规放疗的基础上完成。随着放射治疗技术的进展，采用精确放疗技术如三维适形/调强放疗是否较常规术后放疗能进一步提高局控率，减少毒副作用。哪些患者是辅助放化疗的最佳获益人群？本研究回顾性分析226例直肠癌Ⅱ、Ⅲ期患者术后TNM分期、辅助放化疗与辅助化疗、同步放化疗与序贯放化疗、手术与放疗间隔时间、化疗周期数等因素对局部复发率、总生存率（OS）和无病生存率（DFS）的影响，同时对其预后影响因素进行分析，观察三维适形/调强放疗技术进行盆腔预防性照射的毒副作用，以期更深入地了解直肠癌的局部复发、生存情况及治疗副反应，为临床制定更科学的、个体化的治疗方案提供一定理论依据。方法：收集2006年6月至2010年12月于河北医科大学第四医院行直肠癌根治术患者226例，其中pTNM分期Ⅱ期51例，Ⅲ期患者175例。辅助化疗组116例，辅助放化疗组110例，放疗剂量45～54Gy，中位剂量50Gy，其中采用三维适形放疗88例，调强放疗22例。全组患者化疗周期数为2～8周期，中位4周期。191例以FOLFOX方案（奥沙利铂+亚叶酸钙+5-氟尿嘧啶/替加氟）化疗，24例行LF方案（亚叶酸钙+5-氟尿嘧啶/替加氟）化疗，11例口服单药希罗达。中位随访期30月。分析TNM分期、辅助放化疗与辅助化疗、同步放化疗与序贯放化疗、手术与放疗间隔时间、化疗周期数等因素对局部复发率、OS和DFS的影响，并进一步探讨Ⅱ～Ⅲ期直肠癌根治术后影响预后的主要因素。结果：1全组治疗状况：全组1、2、3年局部复发率和远处转移率分别为9.8%、20.7%、22.8%和15.2%、31.2%、39.4%，全组1、2、3年OS和DFS分别为94.4%、71.7%、61.5%和78.8%、59.8%、53.1%。全组59.3%患者出现1～2级胃肠道毒副反应，46.9%患者出现1～2级血液学毒副反应，无3级及以上毒副反应发生。术后放化组的胃肠道、血液学毒副反应发生率分别为78.2%和64.5%，明显高于术后化疗组的41.4%和30.2%（χ²=31.683，P=0.000；χ²=26.786，P=0.000）。术后放化组中，20.9%患者出现放射性肠炎，其中1级占11.8%，2级占9.1%；10%患者出现放射性膀胱炎，1级占8.2%，2级占1.8%。2T₂期、T₃期患者的1、2、3年局部复发率、DFS无明显差异（χ²=1.041，P=0.314；χ²=2.295，P=0.130），T₂期患者OS高于T₃期患者（χ²=4.278，P=0.039）。3N₀期、N₁期、N₂期患者的1、2、3年局部复发率、OS及DFS均有显著差异（χ²=14.599，P=0.001；χ²=47.196，P=0.000；χ²=38.885，P=0.000），随N分期增加，局部复发率高，OS及DFS均有下降。4Ⅱ期患者的1、2、3年局部复发率明显低于Ⅲ期患者（χ²=13.800，P=0.000）。OS、DFS均明显高于Ⅲ期患者（χ²=18.610，P=0.000；χ²=14.993，P=0.000）。5术后放化组1、2、3年局部复发率分别为3.8%、10.5%、10.5%，明显低于术后化疗组的15.5%、29.7%、33.2%（χ²=11.213，P=0.001），术后放化组与术后化疗组1、2、3年OS分别为94.2%、76%、70.7%和95.6%、68.4%、53.5%，1、2、3年DFS分别为81.9%、60%、54.1%和76%、59.2%、52.3%，组间差异不显著（χ²=3.579，P=0.059；χ²=0.263，P=0.608），但术后放化组有延长OS的趋势。6化疗周期数：化疗≥4周期组1、2、3年局部复发率低于化疗＜4周期组（χ²=4.631，P=0.031），化疗≥4周期组OS、DFS均高于化疗＜4周期组，统计学有显著性差异（χ²=5.306，P=0.021；χ²=3.941，P=0.047）。7将手术与放疗时间间隔分为≤30天（26例）、31～60天（36例），＞60天（48天）三组，结果显示不同时间间隔组1、2、3年局部复发率、OS、DFS均无明显差异（χ²=1.170，P=0.557；χ²=3.831，P=0.147；χ²=4.051，P=0.132）。8同步放化组和序贯放化组1、2、3年局部复发率、OS、DFS均无明显差异(χ²²=0.000，P=0.992；χ²=1.596，P=0.207；χ²=0.230，P=0.631)。9Ⅱ期患者术后放化组和术后化疗组1、2、3年OS、DFS均无显著差异（χ²=0.058，P=0.810；χ²=3.356，P=0.067）。Ⅲ期患者术后放化组1、2、3年局部复发率分别为3.8%、13%、13%，明显低于术后化疗组的19.8%、39.2%、44.9%（χ²=13.230，P=0.000）。术后放化组的1、2、3年OS高于术后化疗组，统计学差异显著（χ²=3.875，P=0.047）。术后放化组1、2、3年DFS与术后化疗组差异不明显（χ²=1.632，P=0.201）10多因素分析显示：淋巴结转移数目、术后辅助治疗方式是直肠癌术后局部复发的独立影响因素；肿瘤浸润深度、淋巴结转移数目是直肠癌术后OS的独立影响因素；淋巴结转移数目是直肠癌术后DFS的独立影响因素。结论：1术后放化疗组可显著降低Ⅲ期患者的局部复发率，提高OS，是Ⅲ期直肠癌患者术后综合治疗的最佳模式。2Ⅱa期患者术后局部复发率低，术后放化疗价值不显著，建议术后辅助化疗作为综合治疗模式。3术后放化疗血液学及胃肠道毒副作用显著高于术后单纯化疗。4放疗与手术间隔时间、同步放化疗和序贯放化疗对本组患者未显示出局控率和生存率的差别。5化疗周期数对Ⅱ期和Ⅲ期患者的局部复发和生存影响显著，若化疗周期数不足，局部复发率高，生存状况差。6术后盆腔照射采用三维适形或调强放疗技术，可显著降低盆腔复发率，在提高疗效的同时可显著降低放射性膀胱炎和放射性肠炎的发生机率和程度。7淋巴结转移数目、术后辅助治疗方式是直肠癌术后局部复发的独立影响因素；肿瘤浸润深度、淋巴结转移数目是直肠癌术后OS的独立影响因素；淋巴结转移数目是直肠癌术后DFS的独立影响因素。更多还原

【Abstract】 Objectives: Rectal cancer is a common malignant tumor, whose maintherapy is surgery. Despite of development of surgical technique, the5-yearoverall survival rate is still about50%, and local recurrence and distantmetastasis are main causes of treatment failure. It has been testified thatpostoperative adjuvant radiochemotherapy is a standard mean to rectal cancer.However, there are still some problems about it. All classical studies arecompleted based on conventional radiotherapy. With the improvement ofradiotherapy technology, whether accurate radiotherapy such as three-dimensional conformal/intensity modulated radiotherapy （IMRT） used canenhance local control rate and lower toxic reactions? Which patients areoptimum benefited villagers?226cases with stage II and stage III rectalcancer are retrospectively analyzed, and effects of TNM stage, adjuvantradiochemotherapy and chemotherapy, concurrent and sequentialradiochemotherapy, interval between surgery and radiotherapy, cycles ofchemotherapy on local recurrence, overall survival （OS） and disease freesurvival （DFS） are also analyzed. Meanwhile, their prognostic factors areanalyzed as well. To investigate side effect of three-dimensionalconformal/IMRT used for preventional irradiation on pelvic cavity, in order tofurther understand the local recurrence, survival conditions and side effects oftreatment, and Provide a theoretical basis for making a more scientific andreasonable therapeutic scheme.Methods:226rectal cancer cases after resection in the fourth hospital ofHebei medical university from June2006to December2010, including51cases in II stage, and175cases in III stage, according to PTNM.116casesunderwent adjuvant chemotherapy, and110cases underwent adjuvant radiochemotherapy. The total dose was45⁵4Gy （median50Gy）, including88cases underwent three-dimensional conformal radiation, and22casesunderwent IMRT. The total cycles of chemotherapy was2⁸（median4）.191cases received FOLFOX chemotherapy,24cases received LF,11casesreceived xelox orally. The median follow-up was30months. Effects of TNMstage, adjuvant radiochemotherapy and chemotherapy, concurrent andsequential radiochemotherapy, interval between surgery and radiotherapy,cycles of chemotherapy on local recurrence, OS and DFS were analyzed, andfurther to exlore the prognostic factors for rectal cancer with II^III stages.Results:1Treatment status: The1-,2-,3-year local recurrent rates and distantmetastasis were9.8%,20.7%,22.8%, and15.2%,31.2%,39.4%respectively.The1-,2-,3-year OS and DFS were94.4%,71.7%,61.5%, and78.8%,59.8%,53.1%respectively. I^II grades of gastrointestinal reaction occurred in59.3%cases, and I^II grades of hematological reaction in46.9%, no III gradeoccurred. The incidence of gastrointestinal and hematological reaction in casesunderwent postoperative radiochemotherapy was78.2%and64.5%, whichwere higher than those underwent chemotherapy （χ²=31.683, P=0.000andχ²=26.786, P=0.004）. Radiation enteritis occurred in20.9%cases underwentpostoperative radiochemotherapy, including I grade （8.2%） and II grade（9.1%）. Radiocystitis occurred in10%, including I grade （8.2%） and II grade（1.8%）.2The1-,2-,3-year local recurrent rates and distant metastasis between T₂and T₃had no significant difference （χ²=1.014, P=0.314and χ²=2.295,P=0.130）, but OS was higher （χ²=4.278, P=0.039）.3The1-,2-,3-year local recurrent rates, OS and DFS had significantdifference （χ²=14.599, P=0.001, χ²=47.196, P=0.000, and χ²=38.885,P=0.000）. With N stage raised, local recurrent rates enhanced, and OS andDFS lowered.4The1-,2-,3-year local recurrent rates of cases in II stage were lower thanthose in III stage （P=0.000）, while OS and DFS higher （P=0.000, P=0.000）. 5The1-,2-,3-year local recurrent rates of cases underwent postoperativeradiochemotherapy were3.8%,10.5%and10.5%, which were lower thanthose underwent postoperative chemotherapy （P=0.001）. The1-,2-,3-year OSwere94.2%,76%,70.7and95.6%,68.4%,53.3, and1-,2-,3-year DFS were81.9%,60%,54.1%and76%,59.2%and52.3%, respectively, which had nosignificant difference （P=0.059, P=0.608）, but there was prolong trend aboutOS.6Cycles of chemotherapy: The1-,2-,3-year local recurrent rates of caseswith cycle≥4were lower than those with cycle＜4（χ²=4.631, P=0.031）, andOS and DFS were higher （χ²=5.306, P=0.021and χ²=3.941, P=0.047）.7The1-,2-,3-year local recurrent rates, OS, and DFS of cases whose intervalbetween surgery and radiation≤30days,31⁶0days and＞60days had nosignificant difference （χ²=1.126, P=0.557, χ²=3.831, P=0.147, and χ²=4.051,P=0.132）.8The1-,2-,3-year local recurrent rates, OS, and DFS of cases underwentconcurrent or sequential radiochemotherapy had no significant difference（χ²=0.000, P=0.992, χ²=1.596, P=0.207, and χ²=0.230, P=0.631）.9The1-,2-,3-year OS and DFS in cases in II stage underwentradiochemotherapy or chemotherapy had no significant difference （χ²=0.058,P=0.810, and χ²=3.356, P=0.067）. The1-,2-,3-year local recurrent rates were3.8%,13%and13%, which were lower than those underwent chemotherapy（χ²=13.230, P=0.000）. The1-,2-,3-year OS were higher （χ²=3.875, P=0.047）,but the1-,2-,3-year DFS had no significant difference （χ²=1.632, P=0.201）.10Multivariate analysis: Metastatic lymph node number and adjuvanttreatment modality were independent prognostic factors for local recurrence ofrectal cancer after surgery; Invasive depth and metastatic lymph node numberwere independent prognostic factors for OS; Metastatic lymph node numberwere independent prognostic factors for DFS.Conclusions:1Postoperative radiochemotherapy can lower local recurrent rate, andincrease OS, so it is optimum choice for patients in III stage. 2Local recurrent rate in II a stage is low, and postoperativeradiochemotherapy is not helpful to it, and postoperative chemotherapy isrecommended for this stage.3Gastrointestinal and hematological reactions were higher in casesunderwent radiochemotherapy than those underwent chemotherapy alone.4Interval between surgery and radiation, concurrent or sequentialradiochemotherapy has no difference for local control and survival.5Cycles of chemotherapy have effect on local control and survival. If cyclesare insufficient, they are both Poor.6Three-dimensional conformal/IMRT used for preventional irradiation onpelvic cavity can lower pelvic recurrence, meanwhile, radiocystitis andradiation enteritis are also lowered.7Metastatic lymph node number and adjuvant treatment modality wereindependent prognostic factors for local recurrence of rectal cancer aftersurgery; Invasive depth and metastatic lymph node number were independentprognostic factors for OS; Metastatic lymph node number were independentprognostic factors for DFS.更多还原