Volume 42 Issue 5
Oct.  2018
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Comparison of toxicities and treatment outcome of weekly and triweekly cisplatin concurrent with intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma

  • Corresponding author: Xiaoshen Wang, ruijin702@163.com
  • Received Date: 2018-01-06
  • Objective To evaluate the rates of hematologic and mucosal toxicities and treatment outcome of a weekly cisplatin (QW) and triweekly cisplatin (Q3W) regimens concurrent with intensity-modulated radiotherapy (IMRT) for local regionally advanced nasopharyngeal carcinoma (NPC).MethodsA total of 148 patients with biopsy-proven NPC staged at Ⅲ to IVB were retrospectively enrolled from October 2009 to December 2013 in this study. Among all patients, 75 and 73 received QW and Q3W cisplatin chemotherapy regimens concurrent with IMRT, respectively. All patients received neoadjuvant chemotherapy. The χ2-test was used to compare clinical characteristics of the patients and hematologic and mucosal toxicities. Tumor response and survival rates were estimated through the Kaplan-Meier method with log-rank test.Results The mean total cycles of the cisplatin regimen was 3.64 in the QW group with 15 patients (20%) reaching five cycles and 1.86 in the Q3W group with 86% reaching two cycles. Grades 1, 2 leucopenia were 31% vs. 51% and 35% vs. 19%, respectively, in the QW and Q3W groups. The two groups showed significant differences in Grades 1 and 2 leucopenia (χ2=6.150, 4.500, both P < 0.05) but not for other hematological toxicities and mucositis (χ2=0.137, P=0.934). The complete remission rates at 6 months after radiotherapy for the QW and QW3 groups were 98.7% and 98.6%, respectively. The 5-year estimated overall survival, disease-free survival, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival rates of the QW and Q3W groups were 77.84% vs. 79.97% (χ2=3.78, P=0.059), 67.96% vs. 69.10% (χ2=1.25, P=0.27), 88.76% vs. 86.96% (χ2=0.43, P=0.56), 91.49% vs. 90.84% (χ2=0.18, P=0.67), and 77.86% vs. 78.90% (χ2=0.31, P=0.56), respectively, and were not significantly different between the two groups.ConclusionsHematological toxicities associated with the QW3 regimen concurrent with IMRT for locally advanced NPC were milder than those associated with the QW weekly regimen. Mucositis and treatment outcome did not significantly differ between the two groups. Patients showed better compliance with the Q3W regimen than with the QW regimen.
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  • [1] Al-Sarraf M, LeBlanc M, Giri PG, et al. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer:phase Ⅲ randomized Intergroup study 0099[J]. J Clin Oncol, 1998, 16 (4):1310-1317. DOI:10.1200/JCO.1998.16.4.1310.
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    [13] Ho KF, Swindell R, Brammer CV. Dose intensity comparison between weekly and 3-weekly Cisplatin delivered concurrently with radical radiotherapy for head and neck cancer:a retrospective comparison from New Cross Hospital, Wolverhampton, UK[J]. Acta Oncol, 2008, 47 (8):1513-1518. DOI:10.1080/02841860701846160.
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    [15] Loong HH, Ma BB, Leung SF, et al. Prognostic significance of the total dose of cisplatin administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma[J]. Radiother Oncol, 2012, 104 (3):300-304. DOI:10.1016/j.radonc.2011.12.022.
    [16] Meng DF, Sun R, Peng LX, et al. A comparison of weekly versus 3-weekly cisplatin during concurrent chemoradiotherapy for locoregionally advanced nasopharyngeal carcinoma using intensity modulated radiation therapy:a matched study[J]. J Cancer, 2018, 9 (1):92-99. DOI:10.7150/jca.21357.
    [17] Kong L, Hu C, Niu X, et al. Neoadjuvant chemotherapy followed by concurrent chemoradiation for locoregionally advanced nasopharyngeal carcinoma:interim results from 2 prospective phase 2 clinical trials[J]. Cancer, 2013, 119 (23):4111-4118. DOI:10.1002/cncr.28324.
    [18] Zhong YH, Dai J, Wang XY, et al. Phase Ⅱ trial of neoadjuvant docetaxel and cisplatin followed by intensity-modulated radiotherapy with concurrent cisplatin in locally advanced nasopharyngeal carcinoma[J]. Cancer Chemother Pharmacol, 2013, 71 (6):1577-1583. DOI:10.1007/s00280-013-2157-2.
    [19] Ou X, Zhou X, Shi Q, et al. Treatment outcomes and late toxicities of 869 patients with nasopharyngeal carcinoma treated with definitive intensity modulated radiation therapy:new insight into the value of total dose of cisplatin and radiation boost[J]. Oncotarget, 2015, 6 (35):38381-38397. DOI:10.18632/oncotarget.5420.
    [20] Sun X, Su S, Chen C, et al. Long-term outcomes of intensitymodulated radiotherapy for 868 patients with nasopharyngeal carcinoma:an analysis of survival and treatment toxicities[J]. Radiother Oncol, 2014, 110 (3):398-403. DOI:10.1016/j.radonc.2013.10.020.
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Comparison of toxicities and treatment outcome of weekly and triweekly cisplatin concurrent with intensity-modulated radiotherapy for locally advanced nasopharyngeal carcinoma

    Corresponding author: Xiaoshen Wang, ruijin702@163.com
  • 1. Department of Radiation Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei 230000, China
  • 2. Department of Radiation Oncology, Tumor Hospital of Fudan University, Shanghai 200000, China

Abstract: Objective To evaluate the rates of hematologic and mucosal toxicities and treatment outcome of a weekly cisplatin (QW) and triweekly cisplatin (Q3W) regimens concurrent with intensity-modulated radiotherapy (IMRT) for local regionally advanced nasopharyngeal carcinoma (NPC).MethodsA total of 148 patients with biopsy-proven NPC staged at Ⅲ to IVB were retrospectively enrolled from October 2009 to December 2013 in this study. Among all patients, 75 and 73 received QW and Q3W cisplatin chemotherapy regimens concurrent with IMRT, respectively. All patients received neoadjuvant chemotherapy. The χ2-test was used to compare clinical characteristics of the patients and hematologic and mucosal toxicities. Tumor response and survival rates were estimated through the Kaplan-Meier method with log-rank test.Results The mean total cycles of the cisplatin regimen was 3.64 in the QW group with 15 patients (20%) reaching five cycles and 1.86 in the Q3W group with 86% reaching two cycles. Grades 1, 2 leucopenia were 31% vs. 51% and 35% vs. 19%, respectively, in the QW and Q3W groups. The two groups showed significant differences in Grades 1 and 2 leucopenia (χ2=6.150, 4.500, both P < 0.05) but not for other hematological toxicities and mucositis (χ2=0.137, P=0.934). The complete remission rates at 6 months after radiotherapy for the QW and QW3 groups were 98.7% and 98.6%, respectively. The 5-year estimated overall survival, disease-free survival, local recurrence-free survival, regional recurrence-free survival, and distant metastasis-free survival rates of the QW and Q3W groups were 77.84% vs. 79.97% (χ2=3.78, P=0.059), 67.96% vs. 69.10% (χ2=1.25, P=0.27), 88.76% vs. 86.96% (χ2=0.43, P=0.56), 91.49% vs. 90.84% (χ2=0.18, P=0.67), and 77.86% vs. 78.90% (χ2=0.31, P=0.56), respectively, and were not significantly different between the two groups.ConclusionsHematological toxicities associated with the QW3 regimen concurrent with IMRT for locally advanced NPC were milder than those associated with the QW weekly regimen. Mucositis and treatment outcome did not significantly differ between the two groups. Patients showed better compliance with the Q3W regimen than with the QW regimen.

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  • 鼻咽癌是临床常见的头颈部恶性肿瘤之一,高发于我国的华南地区、部分东南亚国家。随着鼻咽癌Intergroup 0099临床试验及后续研究论文的发表,同步放化疗方案被证实优于单纯放疗方案,是目前公认的局部晚期鼻咽癌的标准治疗方案[1-3]。尽管如此,局部晚期鼻咽癌治疗疗效并不理想,仍存在较高的远处转移率。Meta分析证实,在同步放化疗前应用5-氟尿嘧啶联合顺铂诱导化疗方案(PF方案)可以减少远处转移,延长生存时间[4],在PF方案基础上加入紫杉醇显著提高了总生存期(overall survival,OS)、局部及远处转移控制率[5]。相关研究结果发现,紫杉醇联合顺铂诱导化疗后行同期放化疗的序贯治疗方案是较为有效的治疗方案[6]

    一项包括了17 346例病例的Meta分析证实顺铂是最有效的头颈部鳞癌同步化疗药物之一[4],放疗联合顺铂单药同期化疗是局部晚期鼻咽癌的标准治疗手段,2005年以前,主要采用每3周高剂量顺铂方案同期放疗,直至Chan等[2]研究发现每周顺铂方案同期放疗患者耐受性良好,与单纯放疗相比具有生存获益。但哪种方案的不良反应更小、疗效更好尚缺乏系统的研究。笔者通过回顾性分析来评价两种顺铂方案的血液学不良反应及疗效。

1.   资料与方法

    1.1.   研究对象

  • 选取2009年10月至2013年12月间在复旦大学肿瘤医院收治的鼻咽癌患者,纳入标准:年龄18~70岁;经病理学结果明确诊断;初次治疗;根据第7版美国癌症分期联合委员会(American Joint Committee on Cancer)分期为Ⅲ~ⅣB期;治疗方案为同步放化疗联合诱导化疗。排除标准:未按照诱导化疗序贯同步放化疗方案进行;同步化疗期间未遵医嘱行血液学、黏膜不良反应评估。本回顾性分析共纳入了148例患者,其中男性125例,女性23例,中位年龄48岁。顺铂单周组75例,年龄范围19~68岁,中位年龄50岁;顺铂三周组73例,年龄范围23~75岁,中位年龄48岁。患者分期等详细资料见表 1,两组间差异均无统计学意义。

    项目 顺铂单周组(n=75) 顺铂三周组(n=73) χ2 P
    年龄(岁) 1.028 0.311
      ≤50 39 44
       > 50 36 29
    性别 0.372 0.542
      女性 13 10
      男性 62 63
    肿瘤分期(T) 0.691 0.875
      T1 19 16
      T2 22 24
      T3 13 15
      T4 21 18
    淋巴结分期(N) 5.052 0.160
      N0 4 2
      N1 26 21
      N2 28 40
      N3 17 10
    肿瘤分期 2.847 0.099
      Ⅲ 38 47
      IVA/B 37 26

    Table 1.  Clinical characteristics of 148 patients nasonharyngel carcinama

  • 1.2.   化疗方案

  • 诱导化疗方案:多西他赛(江苏恒瑞医药股份有限公司生产)75 mg/m2,第1天,持续静脉滴注>1 h;顺铂(江苏豪森药业有限公司生产)75 mg/m2,第1天,持续静脉滴注>1 h;21 d为1个疗程,共2个疗程。在多西他赛给药前1天开始服用地塞米松(天津力生制药股份有限公司生产)8 mg,每天2次,连续3 d预处理防止过敏反应。同步化疗方案:顺铂3周组为顺铂40 mg/m2,1~2 d,静脉滴注,自放疗第1天开始,每3周重复1次;顺铂单周组为顺铂35 mg/m2,1 d,静脉滴注,自放疗第1天开始,每周重复1次。化疗过程中如出现Ⅲ、Ⅳ度的血液学不良反应或3~4级黏膜反应,为避免影响放疗,暂停化疗直至相关不良反应恢复。

  • 1.3.   放疗方案

  • 所有患者均接受调强放射治疗。采用头颈肩面罩固定,5 mm CT薄层扫描,通过局域网传输至治疗计划系统。靶区勾画在每层CT图像上进行,大体肿瘤体积(gross tumor volume,GTV)包括原发肿瘤和肿大的淋巴结,临床靶体积(clinical target volume,CTV)包括鼻咽、咽后淋巴结、斜坡、颅底、翼窝、咽旁间隙、后组筛窦以及后1/3鼻腔和上颌窦,并勾画需保护的正常组织。计划靶区(planning target volume, PTV)PTVg和PTVc分别为GTV、CTV外扩0.5 cm边界并加以修正。PTVg单次照射剂量为2.2 Gy/次,总剂量为66.0~70.4 Gy,分30~32次进行;高危及低危PTVc总剂量分别为60及54 Gy,分30~32次进行。按照放射治疗协作组0225研究(Radiation Therapy Oncology Group 0225)中的正常组织限量对计划进行评估[7]

  • 1.4.   随访方法

  • 治疗期间每周检查血常规及黏膜反应,并根据世界卫生组织抗癌药急性及亚急性不良反应分度标准[8]及RTOG急性放射损伤分级标准[9]进行记录。肿瘤近期疗效根据实体肿瘤疗效评估标准在新辅助化疗和放疗结束后3个月进行评估。治疗结束后2年内,每3个月复查1次,2~5年间隔6个月复查1次,以后则每年1次。复查时常规检查胸片、腹部彩超和鼻咽部MRI、鼻咽镜,有临床症状者行头颅CT或MRI检查及全身骨骼发射型计算机断层扫描(emission computed tomography, ECT)。所有患者均进行了随访,末次随访是以电话随访为主,其次是门诊随访。患者中无失访。

  • 1.5.   统计学分析

  • 采用SPSS 19.0软件进行统计学分析。对分组资料比较行χ2检验;对相关生存率行Kaplan-Meier法计算并行log-rank检验。P<0.05表示差异有统计学意义。

2.   结果

    2.1.   血液学不良反应

  • 所有患者均完成了预定的放疗方案,中途并未因严重的血液学不良反应而中止放疗。根据世界卫生组织血液学不良反应反应分度标准分度,单周组对比三周组放疗过程中出现的Ⅲ度血液学不良反应分别为白细胞减少(7例vs.3例)、血小板降低(2例vs.0例),两组中均未发现Ⅲ度贫血。本研究中顺铂三周组白细胞减少较顺铂单周组不明显,其中Ⅰ度白细胞减少的患者分别为23例(31%)和37例(51%),Ⅱ度白细胞减少分别为26例(35%)和14例(19%),两组白细胞减少的患者比例的差异有统计学意义(χ2=8.343,P=0.037),贫血级血小板减少的患者比例的差异无统计学意义(χ2=0.195,P=0.946)(表 2)。

    血液学不良反应 顺铂单周组(n=75) 顺铂三周组(n=73) χ2 P
    白细胞减少 8.343 0.037
    0度 19(25%) 19(26%) 0.009 1.000
    Ⅰ度 23(31%) 37(51%) 6.150 0.019
    Ⅱ度 26(35%) 14(19%) 4.500 0.042
    Ⅲ度 7(9%) 3(4%) 1.602 0.327
    Ⅳ度 0(0%) 0(0%) - -
    贫血 0.195 0.946
    0度 29(39%) 29(40%) 0.017 1.000
    Ⅰ度 36(48%) 36(49%) 0.026 1.000
    Ⅱ度 10(13%) 8(11%) 0.195 0.803
    Ⅲ度 0(0%) 0(0%) - -
    Ⅳ度 0(0%) 0(0%) - -
    血小板 6.320 0.070
    0度 53(71%) 55(75%) 0.410 0.581
    Ⅰ度 10(13%) 15(21%) 1.372 0.277
    Ⅱ度 10(13%) 3(4%) 3.928 0.078
    Ⅲ度 2(3%) 0(0%) 2.027 0.497
    Ⅳ度 0(0%) 0(0%) - -
    注:表中,-:无此项数据据。

    Table 2.  The comparison of nasopharyngeal carcinoma patients' hematologic toxicities between the weekly cisplatin group and the 3-weekly cisplatin group

  • 2.2.   黏膜反应

  • 顺铂单周组放疗期间出现1、2、3级黏膜反应的患者分别为10例(13%)、44例(59%)、21例(28%);顺铂三周组出现1、2、3级黏膜反应的患者分别为9例(12%)、45例(62%)、19例(26%),两组患者均未出现4级黏膜反应,差异无统计学意义(χ2=0.137, P=0.944)。

  • 2.3.   同步化疗的依从性

  • 同步化疗期间顺铂单周组的平均化疗疗程为3.64个周期,仅15例(20%)患者治疗完成了5个周期;顺铂三周组平均化疗疗程为1.86个周期,63例(86%)患者完成了2个周期。顺铂单周及顺铂三周组的平均总剂量分别为128 mg/m2和141 mg/m2

  • 2.4.   疗效结果

  • 放疗结束后6个月顺铂单周组总体有效率为100%(完全缓解率为98.7%);三周组总体有效率为100%(完全缓解率为98.6%),两组各有1例淋巴结残留接受手术。中位随访49.2个月(1.0~72个月),单周组及三周组的5年生存率分别为77.84%和79.97%,三周组略高于单周组,但两组差异无统计学意义(χ2=3.78,P=0.059)。单周顺铂组5年无病生存率、无局部复发生存率、无区域复发生存率以及无远处转移生存率分别为67.96%、88.76%、91.49%和77.86%,三周顺铂组为69.10%、86.96%、90.84%和78.90%,两组间差异均无统计学意义(χ2=0.18~3.78,P>0.05)(表 3)。

    组别 生存率 无病生存率 无局部复发生存率 无区域复发生存率 无远处转移生存率
    顺铂单周组 77.84 67.96 88.76 91.49 77.86
    顺铂三周组 79.97 69.10 86.96 90.84 78.90
    χ2 3.78 1.25 0.43 0.18 0.31
    P 0.059 0.27 0.56 0.67 0.56

    Table 3.  The comparison of survivals between the the weekly cisplatin group and the 3-weekly cisplatin group(%)

3.   讨论
  • 目前,鼻咽癌Ⅲ期临床试验研究结果表明,同期放化疗作为局部晚期鼻咽癌的标准治疗方案,较单纯放疗显著延长了患者的OS[1-2, 10]及无进展生存时间[1, 10-11]。顺铂为头颈部肿瘤最有效的同期化疗药物之一[3]。在本研究中,所有局部晚期鼻咽癌患者均接受了诱导化疗后同期放化疗的序贯治疗方案。

    顺铂单周及三周治疗方案均证实为是有效的,但目前针对序贯治疗方案中顺铂单周及顺铂三周方案对比的临床研究较少。为比较两种同步化疗方案的优劣,协助临床选择最优的治疗策略,笔者回顾性分析了148例局部晚期鼻咽癌患者,所有患者均采用序贯治疗方案。放疗期间顺铂三周组白细胞减少较顺铂单周组不明显,三周组白细胞减少以0~Ⅰ度为主,为77%,两组白细胞减少差异有统计学意义。两组贫血级血小板减少发生率类似,未见明显差异。本研究中Ⅲ、Ⅳ度血液学不良反应发生率低于15%,与既往的研究结果类似[11-13],但低于Al-Sarraf等[1]及Hui等[6]报道的数据,可能的原因包括本研究中同期顺铂的剂量较低,同步的顺铂治疗周期较Al-Sarraf等[1]研究报道的少,且所有患者均采用了调强放疗模式。本研究放疗过程中两组的黏膜反应差异无统计学意义。

    在鼻咽癌-9901及鼻咽癌-9902临床试验的联合分析中,Lee等[14]发现同步放化疗阶段顺铂的总剂量及治疗周期对局部区域控制及生存率有显著影响,研究认为两周期高剂量顺铂同步放疗足够,第3周期的高剂量顺铂常在放疗后,增加了不良反应而疗效未相应增加,建议将三周期的同步高剂量顺铂改为两周期。之后Loong等[15]进行了一项类似研究,发现同步化疗过程中低剂量顺铂的周期数为重要的疗效预后因子。基于以上研究认为同期放化疗过程中的依从性与疗效密切相关。本研究中顺铂三周组86%的患者完成了2个周期的同步顺铂方案,而顺铂单周组仅20%的患者完成了5个周期的同步化疗,顺铂三周组治疗依从性明显优于单周顺铂组,考虑可能的原因为:①顺铂三周组血液学不良反应较单周顺铂组轻微;②单周化疗间隔时间短,患者恢复时间短;③顺铂为高致吐化疗药物,单周方案患者恶心呕吐频率较高,导致患者营养不良;④所有患者均为门诊放疗,缺乏及时对症处理可能导致单周组患者依从性较差。两组黏膜反应类似,对同期化疗依从性影响较小。在Chan等[2]进行的研究中完成4、5、6个周期低剂量顺铂方案的比例分别为78%、60%和44%。Meng等[16]报道91.1%的患者完成了至少5个周期单周顺铂同步化疗方案,95.6%的患者完成了2个周期顺铂三周同步化疗方案,4.4%的患者完成了3个周期三周方案;单周及三周组顺铂的平均总剂量分别为171.0 mg/m2和168.2 mg/m2。本研究单周及三周方案同期顺铂治疗周期数均明显低于上述研究,其中可能的原因为同期放化疗前进行了诱导化疗,患者对同步化疗的耐受性降低。

    本研究结果发现单周及三周组放化疗结束后总体有效率分别为100%(完全缓解率为98.7%)和100%(完全缓解率为98.8%),与既往结果类似[17-18]。中位随访49.2个月(1.0-72月),单周及三周组的5年生存率分别为77.84%和79.97%,与既往研究结果类似[19-20],三周组5年生存率较单周组好,但差异无统计学意义,其原因是否可能和病例数较少有关,后续可以通过增加样本量继续随访两组之间的差异。两组之间相关生存率(5年无病生存率、无局部复发生存率、无区域复发生存率、无远处转移生存率)未发现有差异。分析两组之间同步顺铂剂量的差异可能尚不足以影响生存。

    综上所述,局部晚期鼻咽癌在接受两周期诱导化疗后顺铂三周同期联合放疗方案在血液学不良反应优于顺铂单周方案,两组在黏膜相关不良反应以及疗效未见显著统计学差异,顺铂三周高剂量组较顺铂单周组具有较好的治疗依从性。目前我们科室局部晚期鼻咽癌的治疗策略为诱导化疗后行三周高剂量顺铂同步放化疗。由于回顾性研究的局限性,期待进一步的鼻咽癌Ⅲ期临床研究比较单周及三周同期顺铂方案之间的差异。

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