Ⅱ-Ⅲ期可切除直肠癌术后同步放化疗Ⅰ/Ⅱ期临床研究

【作者】 金晶；

【导师】 王绿化； 李晔雄；

【作者基本信息】 中国协和医科大学 ， 肿瘤学， 2008， 博士

【摘要】 目的探讨Ⅱ期和(或)Ⅲ期直肠癌患者根治术后,采用卡培他滨同步放化疗剂量的限制性不良反应(DLT)和最大耐受剂量(MTD)。材料和方法选年龄为18～75岁、KPS评分≥70分、根治性手术后病理证实为Ⅱ期和(或)Ⅲ期的直肠癌患者入组。卡培他滨从放射治疗第1天开始服用,间隔12h,连续服用14d,休息7d,为1个周期。共治疗2个周期。同步进行的盆腔放射治疗5周,共25次,总剂量为50Gy。卡培他滨DLT的定义为≥3度的血液学或非血液学不良反应。结果24例患者分别入卡培他滨每天1000mg/m~2组(3例)、1200mg/m~2组(3例)、1400mg/m~2组(3例)、1500mg/m~2组(3例)、1600mg/m~2组(6例)和1700mg/m~2组(6例)。1600mg/m~2组出现1例DLT(1例3度腹泻),补充3例后,未发现DLT,继而进入每天1700mg/m~2组。1700mg/m~2组相继出现2例DLT(3度和4度腹泻各1例),试验终止。结论Ⅱ期和(或)Ⅲ期直肠癌根治术后卡培他滨同步化放疗是安全、可行的。卡培他滨的最大耐受剂量为每天1600mg/m~2,限制性不良反应为腹泻。目的:Ⅱ/Ⅲ期可手术切除直肠癌根治术后,使用奥沙利铂+卡培他滨同步放化疗时,观察奥沙利铂的剂量限制性不良反应(dose-limiting toxicity,DLT),并得到其最大耐受剂量(maximal tolerated dose,MTD)。材料和方法:自2005年2月9日至2006年8月26日,21例接受直肠癌根治术、病理诊断为Ⅱ或Ⅲ期患者进入本研究。所有患者均接受真骨盆照射DT 50Gy/25次/5周。在放疗同时,接受每周1次的奥沙利铂注射,剂量组分别为40(n=6),50(n=3),60(n=3),70(n=3)和80mg/m~2(n=6),连续注射2周停1周为1个周期,放疗期间接受2周期化疗。同时口服卡培他滨1300mg/m~2/天,分2次,期间间隔12个小时口服,治疗周期与奥沙利铂相同,共2周期。治疗期间出现3或4级以上的血液学或非血液学不良反应定义为DLT。出现DLT的低一级剂量水平为MTD。结果:在同步放化疗过程中,1-3度的白细胞低下、腹泻和恶心/呕吐是最常见的不良反应,但是大多数为1-2级。DLT最初见于奥沙利铂40mg/m~2组,为3度腹泻,增加3例后未再出现DLT。在随后的50-70mg/m~2亦未见DLT发生。当剂量递增到80mg/m~2,该组的6例患者中,3例出现DLT,表现为4度白细胞低下(1例)、3度腹泻(2例)。结论:奥沙利铂与固定剂量的卡培他滨同步放化疗时(卡培他滨1300mg/m~2分2次口服/天),患者的耐受性较好。奥沙利铂的剂量限制性不良反应为白细胞低下和腹泻,其最大耐受剂量为70mg/m~2。目的:比较两个分别进行的非随机、前瞻性临床Ⅱ期研究:卡培他滨术后同步放化疗和奥沙利铂+卡培他滨术后同步放化疗的急性不良反应以及患者的耐受性。材料和方法:为了进一步验证前瞻性临床Ⅰ期研究中同步化疗剂量的耐受性,自2005年3月至2007年11月,分别进行了卡培他滨术后同步放化疗(单药组,n=118)和奥沙利铂+卡培他滨术后同步放化疗(双药组,n=90)的Ⅱ期临床研究。无论在单药组还是双药组,均予真骨盆放疗DT 50Gy/25F/5周,化疗药物予以连用2周停1周,放疗中共用2周期的方法。在单药组中,卡培他滨剂量为1600mg/m~2,分2次口服;双药组中,奥沙利铂70mg/m~2/周,卡培他滨1300mg/m~2。结果:在两组中,1-4度的白细胞下降(70.2%,146/208)、腹泻(65.9%,137/208))和恶心(42.3%,88/208)是最常见的急性不良反应,不过有一定比例患者发生了3、4度以上的严重不良反应,包括3、4度腹泻(24.0%、1%)、白细胞下降(4.3%、0.0%)、放射性皮炎(3.8%、0.0%)、狡诈性腹痛(1.0%、0.0%)和乏力(0.5%、0.0%)。接受双药同步放化疗的患者,1-4度急性不良反应发生率显著高于接受卡培他滨单药同步放化疗者,主要为非血液学不良反应,包括恶心(68.9%vs.22.0%,p=0.000),腹泻(76.7%vs.57.6%,p=0.009),乏力(47.8%vs.23.7%,p=0.000),手足综合症(14.4%vs.4.2%,p=0.029)和食欲下降(0.0%vs.27.9%,p=0.000)。但是血液学不良反应在两组无统计学差异。双药组的3、4度腹泻发生率显著高于单药组(33.3%vs.18.6%,p=0.009),除此以外,其它3、4度急性不良反应发生率在两组相似。尽管接受双药同步放化疗的患者总的急性不良反应和3、4度严重不良反应发生率较卡培他滨同步放化疗患者多,但是该组患者中断放疗(10.2%vs.6.7%,p=0.46)或化疗的比率(9.3%vs.19.1%,p=0.09)与单药组相似。结论:Ⅱ/Ⅲ期直肠癌根治术后,同步放化疗是标准的辅助治疗。在Ⅰ期临床的基础上进行的两个Ⅱ期临床研究进一步证明了无论奥沙利铂+卡培他滨同步放化疗还是卡培他滨同步放化疗都是可行的,绝大部分患者耐受性较好。虽然接受奥沙利铂+卡培他滨同步放化疗患者1-4度急性不良反应发生率显著高于卡培他滨同步放化疗患者,且3、4度腹泻亦多于单药组,但是其它严重不良反应的发生在两组无显著差别。长期生存情况还有待于长期的随诊和Ⅲ期前瞻性随机分组研究。更多还原

【Abstract】 Purpose:A phaseⅠstudy was conducted to determine the maximal tolerated dose and the dose-limiting toxicity of capecitabine with standard RT as adjuvant treatment in patients with rectal cancer.Methods and Materials:Patients aged 18～75 years old,Karnofsky scored≥70%,stageⅡ/Ⅲrectal cancer after curative surgery were eligible.Total RT dose was delivered as DT 50 Gy in the fraction of 2.0 Gy per day for 5 weeks to the pelvic area.Capecitabine was administered concurrently with radiotherapy in escalating doses,twice daily with 12 hour interval,consisting of 2 cycles of 14 days separated by a seven day rest.Dose-limiting toxicity （DLT） included grade 3 or grade 4 hematologic and nonhematologic toxicity.Results:From Mar 2004 to May 2005,24 patients were enrolled at the following dose levels:daily 1000 mg/m²（3 patients）,1200 mg/m²（3 patients）, 1400 mg/m²（3 patients）,1500 mg/m²（3 patients）,1600 mg/m²（6 patients）, and 1700 mg/m²（6 patients）.Dose-limiting toxicity was observed in 1 patient at 1600 mg/m²（grade 3 diarrhea）,and in 2 patients at 1700 mg/m²（1 patient had grade 3 and 1 grade 4 diarrhea）.Conclusion:Diarrhea is the most common side effect.The maximal tolerated dose（MTD） of capecitabine given concurrently with RT was daily 1600 mg/m², daily from 1^st to 14^th day with a 7-days rest for 2 cycles. PhaseⅠstudy of oxaliplatin in combination with capecitabine and radiotherapy as postoperative treatment for stageⅡandⅢrectal cancerPurpose:A phaseⅠstudy was conducted to determine the maximal tolerated dose（MTD） and the dose-limiting toxicity（DLT） of oxaliplatin（OXA） combined with capecitabine（CAP） and radiotherapy（RT） as adjuvant treatment in patients with operable rectal cancer.Methods & Patients:A total of 21 patients with stageⅡorⅢrectal adenocarcinoma after curative surgery were treated with RT to total dose of 50Gy in 5 weeks.Oxaliplatin was administered at a dosage of 40（n=6）,50（n=3）,60（n=3）,70（n=3） or 80 mg/m² （n=6） once a week for 2 weeks（1st cycle） followed by a 2nd cycle after 7-day break.Capecitabine at a fixed dose of 1300 mg/m²/d was administered orally with same schedule of OXA.DLT was defined as grade 3 or 4 hematological and non-hematological toxicity.Results:Grade 1-3 leukopenia,diarrhea and nausea/vomiting were the most common toxic side effects,and most were grade 1-2.The dose-limiting toxicity was first observed in 1 of 3 patients at 40 mg/m²（grade 3 diarrhea） and in none of the following 3 patients at the same level,nor in patients who received dose levels of 50-70 mg/m².At 80 mg/m²,DLT occurred in 3 of 6 patients（1 grade 4 leukopenia,and 2 grade 3 diarrhea）.Conclusion:Oxaliplatin combined with a fixed dose of CAP 625mg/m² twice a day by mouth plus RT in adjuvant setting were tolerable and clinically feasible.The MTD of OXA in this setting was 70 mg/m²,comparable to the MTD of OXA at the neoadjuvant setting. Preliminary evaluation of acute side effects in two concurrent chemoradiotherapy of capecitabine with or without oxaliplatin in patients with stageⅡandⅢrectal cancerPurpose:To compare the acute toxicity in two prospective,non-randomized trials of adjuvant chemoradiotherapy of capecitabine with or without oxaliplatin in patients with stageⅡandⅢrectal cancer.Materials & MethodsTo further observe the tolerance and toxicity based on two fulfilled phaseⅠstudies,two phaseⅡtrials were launched respectively,from March 2005 to November 2007.118 patients were treated with concurrent capecitabine and radiotherapy（Cap-CRT trial）,with radiotherapy given to the peCFic of DT 50Gy/25F/5wks,and capecitabine at a dosage of 1600 mg/m²,daily in twice, for 2 weeks followed by a 2^nd cycle after a rest of 7 days.In another trial, oxaliplatin and capecitabine plus radiotherapy（Cap-Oxa-CRT trial,n=90） was performed with a same schedule of radiotherapy and chemotherapy,while oxaliplatin at a dosage of 70 mg/m² once a week,and capecitabine of 1300 mg/m²/d,both for 2 cycles.ResultsGrade 1-4 leukopenia,diarrhea and nausea were the most common toxic side-effects among the patients in both trials,accounting for 70.2%（146/208）, 65.9%（137/208） and 42.3%（88/208）.However,some patients experienced grade 3 or 4 side effects,including diarrhea（24.0%;1%）,leukopenia（4.3%; 0.0%）,radiation-induced dermatitis（3.8%;0.0%）,cramping abdominal pain （1.0%;0.0%） and fatigue（0.5%;0.0%）.When comparing the incidence of grade 1-4 side-effects between the two trials,patients in Cap-Oxa-CRT trial experienced significantly more non-hemotological side-effects,mainly in GI, including nausea（68.9%vs.22.0%,p=0.000）,diarrhea（76.7%vs.57.6%, p=0.009）,fatigue（47.8%vs.23.7%,p=0.000）,hand-foot syndrome（14.4%vs. 4.2%,p=0.029） and lost of appetite（50.0%vs.27.9%,p=0.000）,but no significant difference between hematological side-effects,i.e,leukopenia, anemia or thrombocytopenia.If further comparing the incidence of grade 3 and 4 toxicity,the only significant difference was more grade 3 and 4 diarrhea in Cap-oxa-CRT trial（33.3%vs.18.6%,p=0.009）.Although the higher incidence of side-effects in Cap-Oxa-CRT trial,no matter total grade 1-4 or only grade 3 and 4,there was no significant difference in a need to interrupt either radiotherapy（10.2%vs.6.7%,p=0.46） or chemotherapy（9.3%vs.19.1%, p=0.09） in Cap-CRT or Cap-oxa-CRT trial.ConclusionIn patients with stageⅡandⅢrectal adenocarcinoma treated with adjuvant chemoradiotherapy,both concurrent chemotherapy regimens are tolerable.No significant difference for treatment interruption or delay,though patients treated with oxaliplatin,capecitabine and radiotherapy have suffered from more grade 3 and 4 diarrhea.The long-term survival and local control of the two trials is being expected.更多还原