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[摘要] 目的 对培美曲塞联合顺铂治疗晚期非小细胞肺癌(NSCLC)进行临床疗效和毒性评价。方法 45例经病理组织学和/或细胞学检查确诊NSCLC,均为初治患者,其中男性28例,女性17例;年龄31~76岁,中位年龄58岁,鳞癌12例,腺癌30例,腺鳞癌3例,TNM分期:ⅢA7例,ⅢB16例,Ⅳ22例,应用培美曲塞联合顺铂治疗,即培美曲塞500mg/m2,顺铂75mg/m2,21d为一周期,至少接受2个周期化疗。按照WHO标准评价临床疗效和毒性。结果 45例患者中,无完全缓解(CR)病例,部分缓解(PR)10例,稳定(SD)13例,进展(PD)22例,有效率(CR PR)22.22%,临床获益率(CR PR SD)51.11%,主要毒性反应为骨髓抑制,胃肠道反应。结论 培美曲塞联合顺铂治疗晚期NSCLC疗效可靠,毒性反应小,与国内外文献报道的缓解率及有效率类似。
[关键词] 培美曲塞;顺铂;晚期非小细胞肺癌;化疗
[中图分类号] R734.2 [文献标识码] A [文章编号] 1673-9701(2009)36-54-03
Pemetrexed Combined with Oxaliplatin in Treatment of Advanced Non-small Cell Lung Cancer:A Clinical Observation of 45 Cases
BI Shuting
Department of Respiratory,Nanjing Municipal Chest Hospital,Nanjing 210029,China
[Abstract]Objective To observe the clinical efficacy and adverse effects of pemetrexed combined with oxaliplatin to treat advanced non-small cell lung cancer. Methods Forty-five cases aged 31~76 years(a median age of 58 years)were newly diagnosed as advanced non-small cell lung cancer by histopathological and/or cytology,28 cases were male and 17 female,and in 45 cases,12 cases were squamous cell carcinoma,30 were adenocarcinoma and 3 were adenosquamous carcinoma. TNM staging showed 7 cases of ⅢA,16 cases of Ⅲ B and 22cases of Ⅳ. Pemetrexed 500mg/m2 and cisplatin 75mg/m2 were used for at least 2 cycles of chemotherapy with 21 days as a cycle. Based on WHO criteria,the clinical efficacy and toxicity were evaluated. Results In 45 patients,there were no cases of complete remission(CR),10 cases of partial remission(PR)13 cases of stablility(SD)and 22 cases of progress(PD). The effective rate(CR PR)was 22.22% and the clinical benefit rate(CR PR SD) was 51.11%,and the main side effects were myelosuppression and gastrointestinal tract reaction. Conclusion The combination of pemetrexed and oxaliplatin in the treatment of advanced non-small cell lung cancer has reliable efficacy and fewer side effects,showing similar remission rate and effective rate reported in the literature at home and abroad.
[Key words] Pemetrexed;Cisplatin;Advanced non-small cell lung cancer;Chemotherapy
肺癌的发病率和死亡率在过去的一个世纪快速上升,至20 世纪末已经成为世界范围内最重要的人群死因之一。肺癌是我国第三大恶性肿瘤,发病率也日益上升,目前已居城市中常见恶性肿瘤的首位。到2010 年我国肺癌患者将达到60 万。肺癌的新发病例中,非小细胞肺癌(NSCLC)约占85%,其中大部分为局部晚期(Ⅲ期)或转移性(Ⅳ期)肺癌。除了极少部分Ⅲ期患者可以通过综合治疗手段获得治愈以外,大部分晚期患者的治疗目的是延长生存期和提高生活质量,化疗在其中起到了重要作用。培美曲塞(pemetrexed,PEM)是一种新型的多靶点抗叶酸制剂,作用于叶酸依赖性代谢途径中的多个酶,包括胸苷酸合成酶(TS),二氢叶酸还原酶(DHFR)和甘氨酰胺核苷甲酰基转移酶(GARFT)等,从而抑制肿瘤细胞的生长。由于其耐受性较好,不良反应小,与铂类药物联合应用治疗晚期非小细胞肺癌(NSCLC)目前受到推崇[1-3]。从2006年6月起,我们观察了培美曲塞、顺铂方案联合治疗晚期初治非小细胞肺癌患者45例,现报道如下。
1资料与方法
1.1一般资料
选取我院2006 年6月~2009 年6月经病理组织学和/或细胞学检查确诊的晚期非小细胞肺癌患者45例,其中纤支镜确诊16例,经皮肺穿刺确诊13例,锁骨上淋巴结活检9例,痰细胞学确诊4例,胸腔镜下胸膜活检确诊3例,Karnofsky 评分≥60 分,预计生存时间3个月以上,可评估近期疗效;肝肾功能及血常规均正常;均有可测量病灶。其中,ⅢA期7例,ⅢB期16例,Ⅳ期22例;年龄31~76 岁,中位年龄58岁;其中男性28例,女性17例;腺癌30例,鳞癌12例,腺鳞癌3例;均化疗2个周期以上。
1.2 给药方法
用药前1 周开始补充维生素B12、叶酸;给药前1d、当天及用药后1d给予地塞米松口服。培美曲塞(美国礼来公司,力比泰Alimta)500mg/m2,10min静脉注射,顺铂75mg/m2,21d为1个周期。每用药2 个周期后进行评价疗效。
1.3疗效和毒性反应评价
疗效评价按世界卫生组织(WHO)1981年统一评价标准,判定为完全缓解(CR),部分缓解(PR),稳定(SD)和进展(PD),近期有效率为(CR PR)/总例数×100%,临床获益率为(CR PR SD)/总例数×100%。毒性反应按WHO化疗药物急性与亚急性毒性表现和分度标准进行观察和判断,分为0～Ⅳ度。
2 结果
2.1 疗效
45例患者均按计划完成了相应的治疗,共化疗112个周期,无中途退出及治疗相关死亡发生。PR 10例,SD 13例,PD 22例。近期有效率22.22%,临床获益率51.11%,见表1。
3讨论
培美曲塞是一种新型的抗代谢药物,结构上含有核心为吡咯嘧啶基团的抗叶酸制剂,表现为多靶点抗叶酸代谢,能够抑制几种与嘌呤和嘧啶分泌相关的叶酸依赖性酶,抑制细胞复制,从而抑制肿瘤的生长。已表现出对多种肿瘤的抗癌活性,包括大肠癌、乳腺癌、肺癌、胰腺癌、间皮瘤及胃癌等[4]。但值得注意的是,PEM 组骨髓抑制的发生率和严重程度明显低于现在较为流行的一线化疗药物如多西他赛、吉西他滨等。该药已被美国FDA批准二线治疗NSCLC[5],随着培美曲塞广泛用于临床,其疗效较好,较低的累积毒性及副反应得到了广泛的应用。有鉴于此,FDA于2008年9月30日又正式批准增加培美曲塞的适应证,允许其与顺铂联用作为局部恶化和转移并伴有非鳞状组织学特性的非小细胞肺癌(NSCLC)的一线治疗方案。而PEM 与铂类药物联合治疗晚期NSCLC的Ⅱ期临床研究[6-7]表明,PEM/铂类联合方案的疗效与其他常用的含铂两药方案相似,而毒性反应的发生率则明显较低[8]。本组治疗45 例晚期患者,近期有效率22.22%,临床获益率51.11%,与报道[9-10]结果相近。
培美曲塞主要毒副作用为Ⅲ～Ⅳ度白细胞减少、皮疹、贫血以及肝功能异常,血小板减少少见。补充叶酸和维生素能够降低骨髓毒性的发生率,口服地塞米松可预防皮疹的发生。本组病人均予以地塞米松口服及补充叶酸和维生素,未有皮疹发生,Ⅲ～Ⅳ度白细胞下降也极为罕见。Ⅱ度白细胞下降和Ⅰ～Ⅱ度的非血液学毒性,经升白细胞治疗等对症处理后可好转。顺铂的主要副作用表现为胃肠道反应、脱发等,经镇吐等对症处理可改善。部分患者还存在有静脉炎,可能与药物浓度及给药速度有关,选深静脉、增大稀释比例和迅速冲洗静脉可减少其发生率。综上所述,PEM/铂类联合化疗方案使用未见严重的毒副反应及治疗相关死亡,而且以上毒性大多能在下一周期化疗前恢复。
总之,培美曲塞与顺铂联合治疗晚期非小细胞肺癌可获较高疗效,且毒性低,耐受性、安全性好,是目前拥有较为理想近期疗效的方案,值得在临床中加以应用。但该方案出现时间并不长,其中远期疗效还有待进一步大规模随访、统计并加以总结。
[参考文献]
[1] Gridelli C,Kaukel E,Gregorc V,et al. Single-agent pemetrexed or sequential pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in elderly patients or patients ineligible for platinum-based chemotherapy:amulticenter,randomized,phase II trial[J]. J Thorac Oncol,2007,2:221-229.
[2] Scagliotti GV,Parikh P,von Pawel J,et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer[J]. J Clin Oncol,2008,26(21):3543-3551.
[3] Grnberg BH,Bremnes RM,Fltten O,et al. Phase III study by the Norwegian lung cancer study group:pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cance[J]. J Clin Oncol. 2009,27(19):3217-3224.
[4] Calver H. MAT,a novel multitargeted antifolate,from precliniccl to phaseⅠ and beyond:summary and conclusions[J]. Semin Oncol,1999,26(2):1052-1108.
[5] Rollins KD, Lindley C1Pemetrexed: a multitargeted arrtifolate[J]. Clin Ther,2005,27(9):1343.
[6] Scagliotti GV,Kortsik C,Dark GG,et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non- small cell lung cancer:a multicenter,randomized,phase Ⅱ trial[J]. Clin Cancer Res,2005,11(2 Pt 1):690-696.
[7] Zinner RG, Fossella FV, Gladish GW, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced non-small cell lung cance[J]. Cancer,2005,104(11):2449 -2456.
[8] Scagliotti GV,Park K,Patil S,et al. Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemona?ve patients with advanced non-small cell lung cancer:a risk -benefit analysis of a large phase Ⅲ study[J]. Eur J Cancer,2009, 45(13):2298-2303.
[9] Manegold C,GatzemeierU,von Pawel J,et al. Front-line treatment of advanced non-small-cell lung cancer with MTA(LY231514,pemetrexed disodium,ALIMTA)and cisplatin:a multicenter phase II trial[J]. Ann Oncol,2000,11(4):4352-4440.
[10] Sculier JP, Moro-Sibilot D. First-and second-line therapy for advanced nonsmall cell lung cancer[J]. Eur Respir J, 2009,33(4):915-930.
(收稿日期:2009-09-24)
[关键词] 培美曲塞;顺铂;晚期非小细胞肺癌;化疗
[中图分类号] R734.2 [文献标识码] A [文章编号] 1673-9701(2009)36-54-03
Pemetrexed Combined with Oxaliplatin in Treatment of Advanced Non-small Cell Lung Cancer:A Clinical Observation of 45 Cases
BI Shuting
Department of Respiratory,Nanjing Municipal Chest Hospital,Nanjing 210029,China
[Abstract]Objective To observe the clinical efficacy and adverse effects of pemetrexed combined with oxaliplatin to treat advanced non-small cell lung cancer. Methods Forty-five cases aged 31~76 years(a median age of 58 years)were newly diagnosed as advanced non-small cell lung cancer by histopathological and/or cytology,28 cases were male and 17 female,and in 45 cases,12 cases were squamous cell carcinoma,30 were adenocarcinoma and 3 were adenosquamous carcinoma. TNM staging showed 7 cases of ⅢA,16 cases of Ⅲ B and 22cases of Ⅳ. Pemetrexed 500mg/m2 and cisplatin 75mg/m2 were used for at least 2 cycles of chemotherapy with 21 days as a cycle. Based on WHO criteria,the clinical efficacy and toxicity were evaluated. Results In 45 patients,there were no cases of complete remission(CR),10 cases of partial remission(PR)13 cases of stablility(SD)and 22 cases of progress(PD). The effective rate(CR PR)was 22.22% and the clinical benefit rate(CR PR SD) was 51.11%,and the main side effects were myelosuppression and gastrointestinal tract reaction. Conclusion The combination of pemetrexed and oxaliplatin in the treatment of advanced non-small cell lung cancer has reliable efficacy and fewer side effects,showing similar remission rate and effective rate reported in the literature at home and abroad.
[Key words] Pemetrexed;Cisplatin;Advanced non-small cell lung cancer;Chemotherapy
肺癌的发病率和死亡率在过去的一个世纪快速上升,至20 世纪末已经成为世界范围内最重要的人群死因之一。肺癌是我国第三大恶性肿瘤,发病率也日益上升,目前已居城市中常见恶性肿瘤的首位。到2010 年我国肺癌患者将达到60 万。肺癌的新发病例中,非小细胞肺癌(NSCLC)约占85%,其中大部分为局部晚期(Ⅲ期)或转移性(Ⅳ期)肺癌。除了极少部分Ⅲ期患者可以通过综合治疗手段获得治愈以外,大部分晚期患者的治疗目的是延长生存期和提高生活质量,化疗在其中起到了重要作用。培美曲塞(pemetrexed,PEM)是一种新型的多靶点抗叶酸制剂,作用于叶酸依赖性代谢途径中的多个酶,包括胸苷酸合成酶(TS),二氢叶酸还原酶(DHFR)和甘氨酰胺核苷甲酰基转移酶(GARFT)等,从而抑制肿瘤细胞的生长。由于其耐受性较好,不良反应小,与铂类药物联合应用治疗晚期非小细胞肺癌(NSCLC)目前受到推崇[1-3]。从2006年6月起,我们观察了培美曲塞、顺铂方案联合治疗晚期初治非小细胞肺癌患者45例,现报道如下。
1资料与方法
1.1一般资料
选取我院2006 年6月~2009 年6月经病理组织学和/或细胞学检查确诊的晚期非小细胞肺癌患者45例,其中纤支镜确诊16例,经皮肺穿刺确诊13例,锁骨上淋巴结活检9例,痰细胞学确诊4例,胸腔镜下胸膜活检确诊3例,Karnofsky 评分≥60 分,预计生存时间3个月以上,可评估近期疗效;肝肾功能及血常规均正常;均有可测量病灶。其中,ⅢA期7例,ⅢB期16例,Ⅳ期22例;年龄31~76 岁,中位年龄58岁;其中男性28例,女性17例;腺癌30例,鳞癌12例,腺鳞癌3例;均化疗2个周期以上。
1.2 给药方法
用药前1 周开始补充维生素B12、叶酸;给药前1d、当天及用药后1d给予地塞米松口服。培美曲塞(美国礼来公司,力比泰Alimta)500mg/m2,10min静脉注射,顺铂75mg/m2,21d为1个周期。每用药2 个周期后进行评价疗效。
1.3疗效和毒性反应评价
疗效评价按世界卫生组织(WHO)1981年统一评价标准,判定为完全缓解(CR),部分缓解(PR),稳定(SD)和进展(PD),近期有效率为(CR PR)/总例数×100%,临床获益率为(CR PR SD)/总例数×100%。毒性反应按WHO化疗药物急性与亚急性毒性表现和分度标准进行观察和判断,分为0～Ⅳ度。
2 结果
2.1 疗效
45例患者均按计划完成了相应的治疗,共化疗112个周期,无中途退出及治疗相关死亡发生。PR 10例,SD 13例,PD 22例。近期有效率22.22%,临床获益率51.11%,见表1。
3讨论
培美曲塞是一种新型的抗代谢药物,结构上含有核心为吡咯嘧啶基团的抗叶酸制剂,表现为多靶点抗叶酸代谢,能够抑制几种与嘌呤和嘧啶分泌相关的叶酸依赖性酶,抑制细胞复制,从而抑制肿瘤的生长。已表现出对多种肿瘤的抗癌活性,包括大肠癌、乳腺癌、肺癌、胰腺癌、间皮瘤及胃癌等[4]。但值得注意的是,PEM 组骨髓抑制的发生率和严重程度明显低于现在较为流行的一线化疗药物如多西他赛、吉西他滨等。该药已被美国FDA批准二线治疗NSCLC[5],随着培美曲塞广泛用于临床,其疗效较好,较低的累积毒性及副反应得到了广泛的应用。有鉴于此,FDA于2008年9月30日又正式批准增加培美曲塞的适应证,允许其与顺铂联用作为局部恶化和转移并伴有非鳞状组织学特性的非小细胞肺癌(NSCLC)的一线治疗方案。而PEM 与铂类药物联合治疗晚期NSCLC的Ⅱ期临床研究[6-7]表明,PEM/铂类联合方案的疗效与其他常用的含铂两药方案相似,而毒性反应的发生率则明显较低[8]。本组治疗45 例晚期患者,近期有效率22.22%,临床获益率51.11%,与报道[9-10]结果相近。
培美曲塞主要毒副作用为Ⅲ～Ⅳ度白细胞减少、皮疹、贫血以及肝功能异常,血小板减少少见。补充叶酸和维生素能够降低骨髓毒性的发生率,口服地塞米松可预防皮疹的发生。本组病人均予以地塞米松口服及补充叶酸和维生素,未有皮疹发生,Ⅲ～Ⅳ度白细胞下降也极为罕见。Ⅱ度白细胞下降和Ⅰ～Ⅱ度的非血液学毒性,经升白细胞治疗等对症处理后可好转。顺铂的主要副作用表现为胃肠道反应、脱发等,经镇吐等对症处理可改善。部分患者还存在有静脉炎,可能与药物浓度及给药速度有关,选深静脉、增大稀释比例和迅速冲洗静脉可减少其发生率。综上所述,PEM/铂类联合化疗方案使用未见严重的毒副反应及治疗相关死亡,而且以上毒性大多能在下一周期化疗前恢复。
总之,培美曲塞与顺铂联合治疗晚期非小细胞肺癌可获较高疗效,且毒性低,耐受性、安全性好,是目前拥有较为理想近期疗效的方案,值得在临床中加以应用。但该方案出现时间并不长,其中远期疗效还有待进一步大规模随访、统计并加以总结。
[参考文献]
[1] Gridelli C,Kaukel E,Gregorc V,et al. Single-agent pemetrexed or sequential pemetrexed/gemcitabine as front-line treatment of advanced non-small cell lung cancer in elderly patients or patients ineligible for platinum-based chemotherapy:amulticenter,randomized,phase II trial[J]. J Thorac Oncol,2007,2:221-229.
[2] Scagliotti GV,Parikh P,von Pawel J,et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer[J]. J Clin Oncol,2008,26(21):3543-3551.
[3] Grnberg BH,Bremnes RM,Fltten O,et al. Phase III study by the Norwegian lung cancer study group:pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cance[J]. J Clin Oncol. 2009,27(19):3217-3224.
[4] Calver H. MAT,a novel multitargeted antifolate,from precliniccl to phaseⅠ and beyond:summary and conclusions[J]. Semin Oncol,1999,26(2):1052-1108.
[5] Rollins KD, Lindley C1Pemetrexed: a multitargeted arrtifolate[J]. Clin Ther,2005,27(9):1343.
[6] Scagliotti GV,Kortsik C,Dark GG,et al. Pemetrexed combined with oxaliplatin or carboplatin as first-line treatment in advanced non- small cell lung cancer:a multicenter,randomized,phase Ⅱ trial[J]. Clin Cancer Res,2005,11(2 Pt 1):690-696.
[7] Zinner RG, Fossella FV, Gladish GW, et al. Phase II study of pemetrexed in combination with carboplatin in the first-line treatment of advanced non-small cell lung cance[J]. Cancer,2005,104(11):2449 -2456.
[8] Scagliotti GV,Park K,Patil S,et al. Survival without toxicity for cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemona?ve patients with advanced non-small cell lung cancer:a risk -benefit analysis of a large phase Ⅲ study[J]. Eur J Cancer,2009, 45(13):2298-2303.
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(收稿日期:2009-09-24)