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不同治疗方式对卵巢上皮癌患者铂类药物耐药性的影响

黄裕, 李雨聪, 王冬, 周琦

黄裕, 李雨聪, 王冬, 周琦. 不同治疗方式对卵巢上皮癌患者铂类药物耐药性的影响[J]. 肿瘤防治研究, 2015, 42(11): 1139-1143. DOI: 10.3971/j.issn.1000-8578.2015.11.018
引用本文: 黄裕, 李雨聪, 王冬, 周琦. 不同治疗方式对卵巢上皮癌患者铂类药物耐药性的影响[J]. 肿瘤防治研究, 2015, 42(11): 1139-1143. DOI: 10.3971/j.issn.1000-8578.2015.11.018
Huang Yu, Li Yucong, Wang Dong, Zhou Qi. Platinum Resistance after Neoadjuvant Chemotherapy Interval Debulking Surgery Compared with Primary Debulking Surgery on Patients with Advanced Epithelial Ovarian Carcinoma[J]. Cancer Research on Prevention and Treatment, 2015, 42(11): 1139-1143. DOI: 10.3971/j.issn.1000-8578.2015.11.018
Citation: Huang Yu, Li Yucong, Wang Dong, Zhou Qi. Platinum Resistance after Neoadjuvant Chemotherapy Interval Debulking Surgery Compared with Primary Debulking Surgery on Patients with Advanced Epithelial Ovarian Carcinoma[J]. Cancer Research on Prevention and Treatment, 2015, 42(11): 1139-1143. DOI: 10.3971/j.issn.1000-8578.2015.11.018

不同治疗方式对卵巢上皮癌患者铂类药物耐药性的影响

基金项目: 重庆市科委应用开发计划项目(cstc2014yykfA110032)
详细信息
    作者简介:

    黄裕(1977-),女,硕士,副主任医师,主要从事妇科肿瘤的研究

  • 中图分类号: R737.31

Platinum Resistance after Neoadjuvant Chemotherapy Interval Debulking Surgery Compared with Primary Debulking Surgery on Patients with Advanced Epithelial Ovarian Carcinoma

  • 摘要: 目的 本研究回顾性分析比较初始肿瘤细胞减灭术(primary debulking surgery, PDS)辅以铂类药物的联合化疗和新辅助化疗后行间隔肿瘤细胞减灭术(neoadjuvant chemotherapy-intervaldebulking surgery, NACT-IDS)两种治疗方式对卵巢上皮癌患者铂类药物耐药性的影响。 方法 选择2007年1月至2013年12月符合研究要求的上皮性卵巢,输卵管和腹膜癌Ⅲ、Ⅳ期患者共87例,分为PDS(n=56)组和NACT-IDS(n=31)组,比较两组对铂类药物的敏感度,单因素及多因素Logistic回归分析各项基线资料与铂类药物耐药性的关系。 结果 以铂类药物为基础的初次治疗后,NACT-IDS组4例(7.1%)为铂耐药,PDS组也有4例(12.7%),耐药率比较两组差异有统计学意义(P<0.05)。采用多因素Logistic回归控制分析独立相关因素,NACT-IDS将增加产生铂类药物耐药的风险。手术残余病灶大小和临床分期仍是影响复发时间和铂耐药率的显著相关因素。 结论 晚期上皮性卵巢癌患者采取NACT-IDS治疗方式,与PDS治疗方式相比,有效化疗反应率相当,但更易出现铂类药物耐药。

     

    Abstract: Objective To retrospectively analyze the prognostic factors of platinum resistance in patients with advanced epithelial ovarian carcinoma treated with neoadjuvant chemotherapy followed by interval debulking surgery(NACT-IDS) or primary debulking surgery(PDS). Methods We divided 87 patients with stages Ⅲ and Ⅳ epithelial ovarian, tubal, and peritoneal carcinoma who underwent treatment from January, 2007 to December, 2013 into PDS(n=56) group and(n=31) NACT-IDS group, to compare the sensitivity to platinum drugs. Standard univariate analysis was performed, as was multivariable analysis with logistic regression, to analyze the relationship between baseline data and platinum resistance. Results After the initial platinum-based chemotherapy, 4(7.1%) cases in the NACT-IDS group were considered as platinum resistant disease, compared with 4(12.7%) in the PDS group(P<0.05). When univariate and multivariate logistic regression were used to control the factors independently associated with platinum resistance, NACT-IDS was significantly associated with an initial increased risk of platinum resistance. Residual lesion size and clinical staging were still the significant factors for the recurrence time and platinum resistance. Conclusion For advanced epithelial ovarian carcinoma patients treated with platinum-based chemotherapy,NACT-IDS has the similar chemotherapy efficiency to PDS, but increases the risk of platinum resistance.

     

  • 调强放疗时代(intensity-modulated roditherapy,IMRT),鼻咽癌的局控率已超过95%[1-2],5年总生存率达到80%以上[2-3],远处转移是治疗失败的主要原因[1-3]。在保证高局控率的基础上,如何进一步降低远处转移率,提高远期生存率是当前面临的问题。诱导化疗作为一种新的辅助治疗方式目前广泛应用于临床,但对于它的作用,仍存在争议[4-7]。本研究回顾性分析了广西医科大学第一附属医院收治的224例局部中晚期鼻咽癌患者资料,比较诱导化疗+IMRT同期化疗与IMRT同期化疗的疗效,观察诱导化疗能否改善鼻咽癌的预后。

    2008年10月至2010年12月在本院初治并经病理确诊的局部中晚期鼻咽癌患者,确诊时无远处转移。治疗前全部行鼻咽部+颈部MRI检查确定临床分期为Ⅲ、ⅣA、ⅣB期(2010UICC分期);均接受IMRT+同期化疗,同期化疗采用单药顺铂方案,化疗周期数均≥2。所有患者均未接受辅助化疗。

    共224例患者符合上述入组标准,其中男165例、女59例,年龄14~68岁,中位年龄45岁。临床分期为Ⅲ、ⅣA、ⅣB期的病例数分别为91、115、18。按是否行诱导化疗分为诱导化疗+同期放化疗组118例(诱导组)与同期放化疗组106例(同期组)。两组病例一般资料具有可比性,见表 1

    表  1  224例局部中晚期鼻咽癌患者临床特征分布(例)
    Table  1  Characteristics of 224 patients with locoregionally advanced nasopharyngeal carcinoma (n)
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    全组病例均接受调强放疗。靶区勾画按照国际辐射单位与测量委员会(ICRU)相关规定执行。处方剂量:GTVnx 68~74 Gy,GTVnd 66~70 Gy,CTV1 60­~64 Gy,CTV2 50~56 Gy,每天1次,每周5次,共30~33次,照射时间为6~7周。危及器官限量参照RTOG相关规定。

    诱导化疗方案为TP(多西他赛75 mg/m2,第1天,顺铂80~100 mg/m2,第1~3天)或PF(氟尿嘧啶750 mg/m2,第1~5天,顺铂80~100 mg/m2,第1~3天)方案,以21天为1周期,均化疗2周期。同期放化疗在诱导化疗结束后3周开始。同期化疗采用单药顺铂三周方案(80~100 mg/m2,第1~3天,>90%的病例)或每周方案(40 mg/m2,第1天),三周方案化疗周期数≥2,每周方案化疗周期数≥4。

    近期疗效评价包括对诱导化疗疗效的评价(在诱导化疗结束时)以及对两组病例近期疗效的比较(在同期放化疗结束后3月),评价标准参考RECIST1.1。不良反应的评价标准参考NCI-CTC 3.0。按照RTOG标准评价放射损伤。计算5年OS、DFS、DMFS、RFS。

    随访时间为治疗后2年内,每3月复查一次,第3~5年每6月复查一次。复查项目包括鼻咽部+颈部MRI或CT、间接/直接鼻咽镜、胸片/胸部CT、腹部彩超、骨ECT、实验室检查等。

    采用SPSS19.0软件进行统计分析,两组间一般资料比较使用χ2 检验,不良反应比较使用秩和检验,用Kaplan-Meier法计算生存率,用Log rank检验比较生存曲线。P<0.05为差异有统计学意义。

    诱导化疗完成时,诱导组中12例达CR(10.2%),84例达PR(71.2%),22例为SD(18.6%),有效率为81.4%。同期放化疗结束后3月,诱导组中100例达CR(84.7%),18例为PR(15.3%);同期组中85例达CR(80.2%),21例为PR(19.8%)。两组有效率均为100%。两组近期疗效比较差异无统计学意义(P=0.369)。

    随访截止2015年12月,5年随访率为92.1%。全组5年OS、DFS、DMFS、RFS分别为83.0%、83.1%、87.1%、93.7%。诱导组与同期组的5年OS、DFS、DMFS、RFS对比,差异均无统计学意义。T3-4N0-1期患者中,诱导组(54例)与同期组(57例)相比,各项生存指标差异无统计学意义。将T1-4N2-3期患者中的诱导组(64例)与同期组(49例)进行比较,各项生存指标也均相近,差异无统计学意义。诱导方案TP(59例)与PF(59例)对比,各项生存指标的差异也无统计学意义,见表 2

    表  2  224例局部中晚期鼻咽癌不同治疗模式的远期疗效比较及亚组分析
    Table  2  Summary of long-term survival and subset analyses in 224 patients with locoregionally advanced NPC between NACT+CCRT and CCRT group
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    无5级急性不良反应(死亡)发生。诱导组相比同期组明显增加了白细胞减少、中性粒细胞减少、血小板减少、血红蛋白减少、恶心、呕吐等不良反应,差异有统计学意义,见表 3

    表  3  224例局部中晚期鼻咽癌患者不同治疗模式的不良反应分布与比较
    Table  3  Treatment-related toxicities in 224 patients with locoregionally advanced NPC between NACT+CCRT and CCRT group
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    全组224例病例中,治疗失败的有37例;其中单纯复发者9例(24.3%),单纯远处转移者24例(64.9%),复发合并远处转移者4例(10.8%)。死亡病例38例,其中16例(42.1%)死于单纯转移,4例(10.5%)死于复发合并转移,6例(15.8%)死于单纯复发,1例死于脑梗(2.6%),11例(28.9%)死亡原因不明。

    多项研究报道,治疗失败的局部中晚期鼻咽癌患者中发生远处转移的比例超过70%,是治疗失败的主要原因[8-9]。调强技术的应用,使鼻咽癌的局控率已超过95%[1-2];进一步提高局控率空间已不大,通过减少远处转移从而提高远期生存率成为共识。多项研究指出在同期放化疗基础上加入辅助化疗未带来生存获益[10-11]。而对于诱导化疗的疗效,各家报道不一。如Sun的研究报道诱导化疗可以提高DMFS[4],Song的荟萃分析结果也提示诱导化疗可显著提高PFS及DMFS[5]。然而Founmilas[6]的研究及Liang[7]的荟萃分析却指出诱导化疗并未改善预后。但这些研究纳入的大多数是常规放疗病例,调强放疗的病例不多,且只报道了2年或3年短期生存情况。在调强放疗时代,诱导化疗是否能改善局部中晚期鼻咽癌的远期预后,相关的报道不多。

    本研究显示在IMRT同期化疗的基础上加入诱导化疗并未明显提高5年OS、DFS、DMFS、RFS,这与近期的两个研究结果相同[9, 12]。治疗失败的病例中75.7%发生远处转移,死亡病例中至少52.6%的死因为远处转移,远处转移是治疗失败及死亡的主要原因。诱导化疗未带来远期生存获益的原因,笔者思考可能有以下几点:第一,以调强放疗为基础的同期放化疗使鼻咽癌的疗效较常规放疗时代已有显著提升,5年的OS已超过80%[2](本研究中全组病例5年OS为83%),进一步提高的难度较大。第二,本研究显示诱导化疗明显增加了血液系统及消化道等方面不良反应,这与之前的研究[9, 12]结果相似。而近来有报道,放化疗引起的不良反应是影响预后的不利因素[13]。诱导化疗虽增加了治疗强度,但导致了更严重的不良反应,而严重的不良反应可能抵消强化治疗带来的生存获益,制约生存率的进一步提高。第三,诱导化疗作为一种全身性的辅助治疗,理论上可在短期内缩小瘤体,提高肿瘤局控率;也可以消灭远处微转移病灶,降低远处转移率,从而提高远期生存率。本研究对以局部复发失败为主的T分期晚(T3-4N0-1)患者进行亚组分析显示,诱导组与同期组在各项生存指标的差异上虽都未达统计学意义,但都有明显差距,局控率(RFS)的提高较明显,OS更是接近达到统计学意义(P=0.054)。然而在以远处转移失败为主的N分期晚(N2-3)的患者中,两组在各项生存指标上均较接近,诱导化疗未表现出降低远处转移率的趋势。这表明诱导化疗的作用可能主要是在提高局控率方面,而对于减少远处转移作用不大。诱导化疗没有带来生存获益的原因是未能有效降低远处转移率。然而最近Du的大宗回顾性研究[14]指出诱导化疗对含有多个(≥2个)高危因素的患者有生存获益,能明显提高DMFS及PFS。这些高危因素包括:分期N2-3,EB病毒DNA>4 000拷贝每毫升,血清白蛋白≤46 g/L,血小板>300×109/L。因此,诱导化疗是否只对某些高危患者有生存获益?

    此外,本研究中的诱导化疗方案为PF和TP。但近来有报道TPF(多西他赛+顺铂+氟尿嘧啶)方案诱导化疗联合IMRT同期化疗治疗局部晚期鼻咽癌取得了不错的疗效[15]。Huang[16]的研究更是指出TPF方案优于PF方案。马俊[17]的Ⅲ期前瞻性研究也报道TPF方案诱导化疗可显著提高局部晚期鼻咽癌2年的无瘤生存率及无转移生存率,但该研究5年的远期随访结果尚未发布。另Zheng[18]的研究报道,GP(吉西他滨+顺铂)方案用于治疗局部晚期鼻咽癌优于TP、PF。因此本研究未获得阳性结果的原因是否与TP、PF方案化疗强度较弱有关?TPF或GP方案是否为治疗局部中晚期鼻咽癌的更好选择?仍有待Ⅲ期大宗前瞻性研究远期随访结果明确。

    综上所述,与IMRT同期化疗相比,诱导化疗加IMRT同期化疗未明显提高局部中晚期鼻咽癌患者的远期生存率,且血液系统、消化道等不良反应明显增加。诱导化疗在局部中晚期鼻咽癌治疗中的作用有待继续观察。识别高危人群或寻找更有效的化疗方案可能是未来的研究方向。

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出版历程
  • 收稿日期:  2014-12-30
  • 修回日期:  2015-04-06
  • 刊出日期:  2015-11-24

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