Clinical Analysis of Radiotherapy Combined with Cisplatin-based Chemotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma
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摘要:目的
分析局部晚期食管鳞癌进行精确放疗同步顺铂或顺铂联合紫杉醇脂质体化疗的临床疗效及不良反应。
方法收集精确放疗同步含顺铂方案化疗的局部晚期食管鳞癌46例,其中单药顺铂化疗(RT+P组)26例,顺铂联合紫杉醇脂质体化疗(RT+TP组)20例。回顾性分析两种同步放化疗方法的近期疗效,1、2及3年生存率以及放射性食管炎、放射性肺炎、胃肠道反应、骨髓抑制等不良反应发生率,并与同期17例单纯放疗(RT组)病例进行比较。
结果三组患者观察期内均未出现Ⅳ~Ⅴ级不良反应。三组仅12%~15%的患者出现Ⅰ~Ⅱ级放射性肺炎,发生率低、程度轻,三组相互间差异无统计学意义(P=0.939)。RT组的Ⅰ~Ⅱ级胃肠道反应发生率及Ⅲ级骨髓抑制发生率均明显低于其他组。同步放化疗组的治疗有效率高于单纯放疗组,但差异无统计学意义(P=0.161)。同步放化疗组总的1、2、3年生存率及中位生存期均高于单纯放疗组。RT+TP组的生存率明显优于RT组(P=0.019)。
结论精确放疗同步顺铂联合紫杉醇脂质体化疗治疗局部晚期食管鳞癌,具有较好的近期疗效及生存获益,明显优于单纯放疗。
Abstract:ObjectiveTo analyze the clinical efficacy and adverse reactions of precise radiotherapy concurrent cisplatin or cisplatin combined with paclitaxel liposome chemotherapy in patients with locally advanced esophageal squamous cell carcinoma.
MethodsThe retrospective data of 46 patients with locally advanced esophageal squamous cell carcinoma were collected. The patients were treated with precise radiotherapy concurrent with cisplatin-based chemotherapy. Twenty-six cases were delivered single agent cisplatin chemotherapy (RT+P group), 20 cases cisplatin combined with paclitaxel liposome chemotherapy (RT+TP group). The 1, 2, 3-year survival rates and the incidences of irradiation-induced esophagitis, pneumonia, gastrointestinal tract reaction and myelosuppression were assessed. The results were compared with those of 17 cases treated with radiotherapy alone (RT group).
ResultsNo grade Ⅳ-Ⅴ adverse reaction was observed in all the three groups. Only about 12%-15% patients in the three groups presented radiation pneumonia with low incidence and slight severity. There were no significant differences between the three groups (P=0.939). Mild adverse reaction of RT group was observed, of which grade Ⅰ-Ⅱ gastrointestinal tract reaction and grade Ⅲ myelosuppression were significantly lower than those in other groups. The response rates of RT+P and RT+TP groups were higher than that of RT group, however the difference was not significant (P=0.161). The 1, 2, 3-year survival rates and median survival times of RT+P and RT+TP groups were higher than those of RT group. The survival rate of RT+TP group was significantly better than that of RT group (P=0.019).
ConclusionThe better treatment effect and survival benefit could be obtained by precise radiotherapy concurrent with cisplatin combined with paclitaxel liposome chemotherapy for locally advanced esophageal squamous cell carcinoma, which was superior to radiotherapy alone remarkably.
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Key words:
- Esophageal cancer /
- Concurrent chemo-radiotherapy /
- Cisplatin /
- Paclitaxel liposome
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0 引言
食管癌是我国高发恶性肿瘤之一,90%以上为鳞癌,手术是治疗食管癌的主要手段[1],但对于局部晚期食管鳞癌,放疗占有重要地位。研究显示,术前放化疗可提高局部晚期食管癌的局部控制率,降低腹膜后淋巴结转移率[2]。而对于拒绝手术或不可手术的局部晚期食管癌患者,近年来同步放化疗的广泛应用,使疗效得到了提高,明显优于单纯放疗,在部分可切除患者群体中可达到与手术相当的疗效[3],但总的5年生存率仅为10%~20%[4],对于此类局部晚期食管癌患者同步放化疗方式的优化,值得进一步研究探讨。
既往同步放化疗多采用传统顺铂/5-Fu方案,随着紫杉醇等新型药物的临床应用,局部晚期食管癌的疗效有得到提升的可能,但对于不同放化疗方案的肿瘤治疗效果,以及伴随的不良反应报道尚不一致[5]。寻找安全、有效的同步放化疗方案,提高局部晚期食管鳞癌的疗效,是目前临床研究热点。因此,本研究对46例局部晚期食管鳞癌患者的精确放疗同步含顺铂方案化疗的临床疗效及不良反应进行回顾性分析,对适用于临床的优选同步放化疗方案进行探讨,现将结果报道如下。
1 资料与方法
1.1 临床资料
收集2011年3月至2015年3月期间于南京医科大学附属苏州医院诊治的局部晚期食管癌患者共63例。所有病例均经胃镜活检病理诊断证实为鳞癌,临床分期为ⅡB~ⅢC期的初治患者。其中男43例、女20例,年龄43~76岁,中位年龄60岁,Karnofsky评分60分以上。本研究纳入的患者均接受精确放疗,包括三维适形放疗(3DCRT)或调强放疗(IMRT)。放疗期间,26例患者接受每周同步单药顺铂方案(RT+P组),20例患者接受同步紫杉醇脂质体联合顺铂方案化疗(RT+TP组)。另有17例患者因个人原因拒绝化疗,充分告知后仅行单纯放疗(RT组)。患者一般临床资料见表 1。
表 1 63例局部晚期食管鳞癌患者一般临床资料Table 1 Clinical characteristics of 63 patients with locally advanced esophageal squamous cell carcinoma1.2 治疗方法
1.2.1 精确放疗方法
患者取仰卧位,真空体膜固定体位,双上肢上举(颈段食管癌患者双上肢置于体侧),双手抱肘置于前额。CT模拟定位,扫描范围:(1)胸段食管癌,自环甲膜扫描至L2下缘;(2)颈段食管癌,自下颌角扫描至隆突分叉水平。CT扫描影像传至治疗计划系统进行靶区勾画及计划设计。所有患者均采用均一条件进行放射治疗,具体要求如下:肿瘤大体靶区(GTV)为食管原发肿瘤及转移淋巴结。临床靶区(CTV)为GTV外扩1 cm形成。计划靶区(PTV):食管原发肿瘤CTV上下外扩2 cm、转移淋巴结CTV即为PTV。采用直线加速器,6MV-X线精确放疗。3DCRT:先给予PTV 50 Gy/25次/5周,然后根据肿瘤退缩情况缩野加量至60 Gy。IMRT:PTV 54 Gy、CTV 60 Gy,于30次/6周同时完成。3DCRT采用正向设计方法,IMRT计划采用逆向设计方法。以PTV作为处方剂量点,> 97%PTV应接受到100%处方剂量。正常组织限量:双肺V20≤25%,肺Dmean≤13 Gy,心脏V30≤40%、V40≤30%,脊髓Dmax≤40 Gy。
1.2.2 同步化疗方法
同步化疗方案包括两种情况:单药P方案或TP两药方案。单药P方案为顺铂30 mg/m2,d1。TP方案为紫杉醇脂质体135 mg/m2,d1、顺铂30 mg/(m2·d),d1~3。均在放疗第1天开始化疗。单药P方案为每周化疗一次,放疗期间最多完成6次化疗;联合方案在放疗第29天进行第二次化疗,在放疗期间共完成2次化疗。
1.3 观察指标及随访
急性不良反应:观察各组放射性食管炎、放射性肺炎、胃肠道反应、骨髓抑制的发生率。不良反应评价参照EROTC-RTOG分级标准。近期疗效:近期疗效评价采用韩春等[6]提出的食管钡餐造影结合CT检查的评价方法,分为完全缓解(CR),部分缓解(PR),无缓解或病情进展(NR),有效率=CR+PR。生存率:观察三组患者中位生存时间和1、2、3年总生存率。随访:放化疗后,两年内每3月随访1次,第3年起每6月随访1次,末次随访时间为2016年3月。
1.4 统计学方法
采用SPSS11.0统计软件进行统计分析。Kaplan-Meier法计算生存率,Log rank检验差异性,其余数据用χ2检验,P<0.05为差异有统计学意义。
2 结果
2.1 三组患者急性不良反应比较
三组患者中,放射性食管炎、放射性肺炎、消化道反应及骨髓抑制等急性不良反应以Ⅰ~Ⅱ级为主,未发生Ⅲ级以上严重不良反应。其中,所有患者均出现放射性食管炎,而放射性肺炎的发生率则较低,在16%以下。三组患者急性不良反应比较见表 2。
表 2 三组患者急性不良反应比较(例)Table 2 Comparison of acute adverse reactions between three groups (n)2.2 三组患者近期疗效比较
三组患者均有较好的近期疗效,其中RT+P组及RT+TP组的CR率在30%以上,总有效率达85%,但三组间差异无统计学意义(P>0.05)。三组患者近期疗效比较见表 3。
表 3 三组患者近期疗效比较(例)Table 3 Comparison of short-term effects between three groups (n)2.3 三组患者生存情况比较
RT、RT+P及RT+TP组的中位生存时间分别为16、24、29月,1年生存率分别为60.8%、76.9%、85%,2年生存率分别为35.5%、47.8%、55%,3年生存率分别为17.7%、29.4%、44%。三组患者生存情况比较差异有统计学意义(χ2=6.404, P=0.041),组间两两比较,RT+TP组的生存明显好于RT组(χ2=5.465, P=0.019),而RT组与RT+P组相似(χ2=2.023, P=0.154),RT+P组与RT+TP组之间差异无统计学意义(χ2=2.042, P=0.153)。三组患者的生存曲线见图 1。
3 讨论
同步放化疗是局部晚期食管癌的主要治疗手段[7],疗效明显优于单纯放疗[8-10]。国内外常用的同步化疗方案主要以氟尿嘧啶类和铂类为基础,如顺铂联合5-Fu方案以及紫杉类(紫杉醇或多西紫杉醇)加铂类方案[11]。RTOG8501临床研究已证实5-Fu联合顺铂的同步放化疗方案优于单纯放疗[12],然而由于5-Fu给药时间长,使用不方便,且不良反应较大,在临床实践中常会采用一些新颖的化疗方案如紫杉醇脂质体。
紫杉醇是细胞周期特异性药物,具有显著的放疗增敏作用,其机制目前认为与紫杉醇延长放疗敏感的G2/M期、诱导凋亡促进乏氧细胞再氧合、抑制肿瘤再增殖有关。1994年Ajani等[13]首先报道了单药紫杉醇治疗晚期食管癌50例的疗效,结果显示,有效率约32%,中位生存期17周,从而确立了紫杉醇在食管癌治疗中的作用。黄镜等[14]报道紫杉醇联合顺铂治疗食管癌有效率高达59.3%,中位生存期9.7月。紫杉醇脂质体是用卵磷脂等将紫杉醇包裹,进入人体后主要被单核-吞噬细胞内皮系统吞噬,激活体内的自身免疫功能,在肝、脾、肺和骨髓等组织器官中累积,减慢紫杉醇的清除速度,延长紫杉醇的作用时间。近年研究还显示脂质体包被的紫杉醇能改变肿瘤微循环,有抗血管生成的作用[15]。紫杉醇脂质体与紫杉醇相比,可能具有更好的抗肿瘤活性,且无致敏性,具有更高的安全性。
近5年我院经治的局部晚期食管鳞癌患者中,绝大多数遵循指南给予根治性同步放化疗。单纯放疗仅应用于个人意愿拒绝化疗,或存在化疗禁忌证、不能耐受同步治疗的患者。本研究纳入的63例患者中,46例(73%)采用放疗同步联合含顺铂的两种不同方案化疗,即单药顺铂、紫杉醇脂质体联合顺铂;17例(27%)仅接受了单纯放疗。两个同步放化疗组均取得了较好的近期治疗疗效,约高出单纯放疗组10%,但差异无统计学意义(P=0.161)。这可能与单中心所观察的病例数受限、随访时间相对较短有关。与RTOG8501的结果相似,我们同样发现接受同步放化疗的患者其肿瘤退缩及局部控制方面优于仅接受单纯放疗者。值得注意的是,本研究的双药联合组在顺铂用药量及照射野范围设计强度上均较RTOG8501低,但本组同步放化疗患者的治疗完成率优于RTOG8501(100% vs. 68%)。三组患者观察期内均未出现Ⅳ~Ⅴ级不良反应,提示患者对于治疗均具有较好的耐受性。放射性食管炎是最常发生的不良反应,所有患者均出现不同程度的食管炎,但各组间差异无统计学意义(P=0.314)。三组仅12%~15%病例出现Ⅰ~Ⅱ级放射性肺炎,发生率低、程度轻,三组组间差异无统计学意义(P=0.939)。单纯放疗组的不良反应相对较轻,其中Ⅰ~Ⅱ级胃肠道反应发生率(P=0.009)及Ⅲ级骨髓抑制的发生率(P=0.014)均明显低于同步放化疗组。同步放化疗各组之间的不良反应情况无显著差别。在所有治疗方法中,单纯放疗的胃肠道反应及骨髓抑制轻,显示出良好的耐受性,可选择性应用于年龄偏大或者一般状况较弱的患者,然而单纯放疗组的生存时间差于同步放化疗组,RT、RT+P及RT+TP组的中位生存时间分别为16、24、29月。本组资料因回顾性分析的限制不能对治疗相关的混杂因素进行严格控制,难以完全排除初始治疗前患者其他未精确描述的化疗禁忌证、治疗耐受性不理想或经济原因等因素的干扰。但目前多数研究已证实同步放化疗可提高远期生存率[16],本研究结果与此类似。生存分析表明,RT+TP组的1、2、3年生存率显著高于RT组(P=0.019)。本研究中,RT+P组的生存率数值上高于RT组、低于联合化疗组,但差异均不显著。究其原因,可能跟同步单药顺铂化疗的周期完成数有关:最终8例(30.77%)完成3周期化疗、10例(38.46%)完成4周期化疗、6例(23.77%)完成5周期化疗,仅2例(7.69%)完成6周期化疗。接受单药顺铂化疗的26例患者中,发生Ⅲ级放射性食管炎及胃肠道反应比例分别为30.77%、26.92%,均高于其他各组。这可能与顺铂药物自身有较大的消化道不良反应及其同步时呈现的细胞放射增敏作用有关。同时,对于接受6周期单药P同期化疗的患者而言,其顺铂的药物总量即高于同期双药组;治疗期间不良反应的程度可明显影响治疗的完成率。但与既往文献[17]相比,本研究中接受同步放化疗患者在血液学及消化道的早期不良反应发生率并不劣于以往的结果。本研究中精确放疗大多采用3DCRT技术,仅12例(14.81%)采用IMRT,病例数太少,故未对3DCRT及IMRT的优劣进行探讨。有研究[18-19]认为,3DCRT常规分割60 Gy的照射方式更适合国人。李雪等[20]研究显示,大于70岁的老年食管癌也同样能较好地耐受根治性同步放化疗,且可取得与较年轻患者相似疗效,60 Gy为最适宜的放疗剂量,较小于60 Gy明显提高生存。本研究结果与此相似,今后可以扩大样本量,进行前瞻性临床试验给予深入研究。
综上所述,精确放疗同步顺铂联合紫杉醇脂质体化疗治疗局部晚期食管鳞癌,具有较好的近期疗效及生存获益,明显优于单纯放疗。与联合单药顺铂方案比较,放疗联合紫杉醇脂质体方案生存获益占优势,不良反应相似,值得临床进一步研究后推广应用。
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表 1 63例局部晚期食管鳞癌患者一般临床资料
Table 1 Clinical characteristics of 63 patients with locally advanced esophageal squamous cell carcinoma
表 2 三组患者急性不良反应比较(例)
Table 2 Comparison of acute adverse reactions between three groups (n)
表 3 三组患者近期疗效比较(例)
Table 3 Comparison of short-term effects between three groups (n)
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