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胃癌是一项全球性的临床难题,多发于东亚地区(尤其是韩国、蒙古、日本和中国),是世界恶性肿瘤第二大死亡原因。据估计,2012年全球新发胃癌病人约951 600例,而约723 100例病人将死于胃癌[1]。胃癌的生存时间与其疾病分期呈负相关,5年相对存活率从局限期的65.4%降至晚期的4.5%[2]。不幸的是,绝大多数胃癌病人在确诊时已经为晚期,失去手术机会[3]。尽管晚期胃癌的治疗手段在进步,但其中位生存时间仍小于1年[4]。目前,对晚期胃癌病人推荐行姑息化疗延长生存时间,但因胃癌容易发生继发性耐药,一线化疗后的疾病进展难以避免,而二线化疗方案仍无统一标准。
培美曲塞是一种多靶点抗肿瘤药物,其主要抑制胸苷酸合成酶(TS)、二氢叶酸还原酶(DHFR)和甘胺酰胺核苷甲酰基转移酶(GARFT)的活性,导致嘌呤和嘧啶合成障碍,影响肿瘤细胞的DNA及RNA合成[5]。培美曲塞联合顺铂方案已成为非小细胞肺癌的一线标准治疗,也有研究[6-8]证明此方案对晚期胃癌病人有一定疗效,且不良反应较低,但临床应用报道较少。本研究采用培美曲塞联合顺铂方案二线治疗未手术晚期胃癌病人,与最佳支持治疗的病人相比明显获益,现作报道。
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观察组中34例病人共完成85个化疗周期,平均为2.5个周期。34例可评价疗效,其中CR 1例,PR 8例,SD 10例。RR为26.5%,DCR为55.9%。
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观察组中常见的不良反应为乏力和恶心呕吐,多为1~2级,3~4级不良反应仅见白细胞减少,其中3级发生率为8.8%,4级为3.0%;病人均无肾功能异常、发热及化疗相关性死亡事件发生,不良反应发生情况见表 1。
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63例病人中失访2人,随访率96.8%。观察组和对照组中位PFS-1分别为4.0个月(95%CI:3.1~4.9个月)和4.0个月(95%CI:2.6~5.4个月)。2组之间PFS-1差异无统计学意义(χ2=1.037, P>0.05)。截至2016年1月31日,观察组中32例死亡,对照组中27例死亡。其中有1例死于肺栓塞,1例死于消化道出血,均为观察组病人。观察组和对照组中位OS分别为10.8个月(95%CI:7.5~14.1个月)和5.8个月(95%CI:2.6~9.0个月),2组比较差异有统计学意义(χ2=10.141, P<0.01)。
不良反应 毒性分级 0级 1级 2级 3级 4级 白细胞减少 5(14.7) 18(52.9) 7(20.6) 3(8.8) 1(3.0) 贫血 8(23.5) 20(58.8) 6(17.7) 0(0.0) 0(0.0) 血小板减少 17(50.0) 9(26.5) 8(23.5) 0(0.0) 0(0.0) 乏力 7(20.6) 18(52.9) 9(26.5) 0(0.0) 0(0.0) 恶心呕吐 12(35.3) 16(47.0) 6(17.7) 0(0.0) 0(0.0) 腹泻 28(82.4) 3(8.8) 3(8.8) 0(0.0) 0(0.0) 肝功能损害 25(73.5) 6(17.7) 3(8.8) 0(0.0) 0(0.0) 皮疹 31(91.2) 3(8.8) 0(0.0) 0(0.0) 0(0.0) 表 1 培美曲塞联合顺铂二线治疗晚期胃癌的不良反应[n;百分率(%)]
培美曲塞联合顺铂二线治疗未手术晚期胃癌病人的临床观察
Clinical observation of the second-line chemotherapy of pemetrexed combined with cisplatin in the treatment of unresectable advanced gastric cancer
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摘要:
目的评价培美曲塞联合顺铂二线治疗未手术晚期胃癌病人的疗效及不良反应,并比较是否采用二线化疗对生存时间的影响。 方法选取63例一线化疗失败的晚期未手术胃癌病人。34例同意化疗者作为观察组,给予培美曲塞联合顺铂方案二线治疗至少两个周期,计算有效率(RR)和疾病控制率(DCR),并评价不良反应。另29例拒绝化疗作为对照组,给予最佳支持治疗。随访无进展生存时间-2(PFS-2)和总生存时间(OS)。 结果观察组中,34例均可评价近期疗效,完全缓解1例,部分缓解8例,稳定10例,进展15例,RR为26.5%,DCR为55.9%。主要不良反应为1~2级的骨髓抑制、乏力和恶心呕吐。3~4级不良反应仅见白细胞减少,其中3级发生率为8.8%,4级为3.0%。病人均无发热、肾功能异常及化疗相关性死亡事件发生。观察组PFS-2为3.3个月。观察组及对照组OS分别为10.8个月(95%CI:7.5~14.1月)及5.8月(95%CI:2.6~9.0月),差异有统计学意义(P < 0.01)。 结论培美曲塞联合顺铂二线治疗晚期未手术胃癌的疗效较好,且不良反应轻、耐受性好。与最佳支持治疗相比,二线化疗能明显延长病人生存时间。 Abstract:ObjectiveTo evaluate the efficacy and adverse reaction of the second-line chemotherapy of pemetrexed combined with cisplatin(PemCis) in the treatment of unresectable advanced gastric cancer(AGC), and analyze the survival time of patients with second-line chemotherapy. MethodsSixty-three patients with unresectable AGC, who failed to the first-line chemotherapy, were divided into the observation group(34 cases treated with second-line chemotherapy of PemCis for two cycles at least) and control group(29 cases treated with best supportive care).The response rate(RR) and disease control rate(DCR) in observation group were calculated to evaluate the adverse reaction.The progression-free survival time-2(PFS-2) and overall survival(OS) in two groups were followed up. ResultsThe short-term efficacy in observation group was evaluated, the complete remission in 1 case, partial remission in 8 cases, stability in 10 cases and progress in 15 cases were identified, and the RR and DCR were 26.5%, and 55.9%, respectively.The major side effects in observation group were grade 1-2 bone marrow suppression, fatigue, nausea and vomiting, the eucopenia was grade 3-4 toxic reaction, and the incidence rate of grade 3 and 4 were 8.8% and 3.0%, respectively.No fever, renal dysfunction or chemotherapy-related death in all patients was identified.The PFS-2 of the observation group was 3.3 months.The OS in observation group and control group were 10.8 months(95%CI:7.5 to 14.1 months) and 5.8 months(95%CI:2.6 to 9.0 months), respectively, and the difference of which was statistically significant(P < 0.01). ConclusionsThe second-line treatment with PemCis for unresectable AGC has good effect and tolerance, which can significantly prolong the survival time of patients compared with supportive care. -
Key words:
- gastric neoplasms /
- pemetrexed /
- overall survival /
- chemotherapy
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表 1 培美曲塞联合顺铂二线治疗晚期胃癌的不良反应[n;百分率(%)]
不良反应 毒性分级 0级 1级 2级 3级 4级 白细胞减少 5(14.7) 18(52.9) 7(20.6) 3(8.8) 1(3.0) 贫血 8(23.5) 20(58.8) 6(17.7) 0(0.0) 0(0.0) 血小板减少 17(50.0) 9(26.5) 8(23.5) 0(0.0) 0(0.0) 乏力 7(20.6) 18(52.9) 9(26.5) 0(0.0) 0(0.0) 恶心呕吐 12(35.3) 16(47.0) 6(17.7) 0(0.0) 0(0.0) 腹泻 28(82.4) 3(8.8) 3(8.8) 0(0.0) 0(0.0) 肝功能损害 25(73.5) 6(17.7) 3(8.8) 0(0.0) 0(0.0) 皮疹 31(91.2) 3(8.8) 0(0.0) 0(0.0) 0(0.0) -
[1] TORRE LA, BRAY F, SIEGEL RL, et al.Global cancer statistics, 2012[J].CA Cancer J Clin, 2015, 65(2):87. doi: 10.3322/caac.21262 [2] HOWLADER N, NOONE AM, KRAPCHO M, et al.SEER Cancer Statistics Review, 1975-2012[Z].National Cancer Institute, Bethesda, MD, 2015.http://seer.cancer.gov/csr/1975_2012/.Accessed April 23, 2015. [3] WAGNER AD, UNVERZAGT S, GROTHE W, et al.Chemotherapy for advanced gastric cancer[J].Cochrane Database Syst Rev, 2010, 3:CD004064. [4] GASTRIC GROUP, OBA K, PAOLETTI X, et al.Role of chemotherapy for advanced/recurrent gastric cancer:an individual-patient-data meta-analysis[J].Eur J Cancer, 2013, 49(7):1565. doi: 10.1016/j.ejca.2012.12.016 [5] SHIH C, CHEN VJ, GOSSETT LS, et al.LY231514, a pyrrolo[2, 3-d]pyrimidine-based antifolate that inhibits multiple folate-requiring enzymes[J].Cancer Res, 1997, 57(6):1116. [6] BAJETTA E, CELIO L, BUZZONI R, et al.Phase Ⅱ study of pemetrexed disodium(Alimta) administered with oral folic acid in patients with advanced gastric cancer[J].Ann Oncol, 2003, 14(10):1543. doi: 10.1093/annonc/mdg406 [7] KIM YH, CHUNG HC, KANG WK, et al.Pemetrexed and cisplatin in patients with advanced gastric cancer:a Korean cancer study group multicenter phase Ⅱ study[J].Cancer Chemother Pharmacol, 2008, 62(2):263. doi: 10.1007/s00280-007-0600-y [8] CHEN JS, CHAO Y, BANG YJ, et al.A phase Ⅰ/Ⅱ and pharmacogenomic study of pemetrexed and cisplatin in patients with unresectable, advanced gastric carcinoma[J].Anticancer Drugs, 2010, 21(8):777. doi: 10.1097/CAD.0b013e32833cfbca [9] VAN CUTSEM E, BONI C, TABERNERO J, et al.Docetaxel plus oxaliplatin with or without fluorouracil or capecitabine in metastatic or locally recurrent gastric cancer:a randomized phase Ⅱstudy[J].Ann Oncol, 2015, 26(1):149. doi: 10.1093/annonc/mdu496 [10] AL-BATRAN SE, HARTMANN JT, PROBST S, et al.Phase Ⅲ trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin:a study of the Arbeitsgemeinschaft Internistische Onkologie[J].J Clin Oncol, 2008, 26(9):1435. doi: 10.1200/JCO.2007.13.9378 [11] KIM GM, JEUNG HC, RHA SY, et al.A randomized phase Ⅱ trial of S-1-oxaliplatin versus capecitabine-oxaliplatin in advanced gastric cancer[J].Eur J Cancer, 2012, 48(4):518. [12] National Comprehensive Cancer Network.NCCN Clinical Practice Guidelines in Oncology: Gastric Cancer, Version 3, 2015[R].http://www.nccn.org/professionals/physician_gls/pdf/gastric.pdf. [13] HESS LM, MICHAEL D, MYTELKA DS, et al.Chemotherapy treatment patterns, costs, and outcomes of patients with gastric cancer in the United States:a retrospective analysis of electronic medical record(EMR) and administrative claims data[J].Gastric Cancer, 2016, 19(2):607. doi: 10.1007/s10120-015-0486-z [14] KIM HS, KIM HJ, KIM SY, et al.Second-line chemotherapy versus supportive cancer treatment in advanced gastric cancer:a meta-analysis[J].Ann Oncol, 2013, 24(11):2850. doi: 10.1093/annonc/mdt351 [15] KANAGAVEL D, FEDYANIN M, TRYAKIN A, et al.Second-line treatment of metastatic gastric cancer:current options and future directions[J].World J Gastroenterol, 2015, 21(41):11621. doi: 10.3748/wjg.v21.i41.11621 [16] CELIO L, STERNBERG CN, LABIANCA R, et al.Pemetrexed in combination with oxaliplatin as a first-line therapy for advanced gastric cancer:a multi-institutional phase Ⅱ study[J].Ann Oncol, 2009, 20(6):1062. doi: 10.1093/annonc/mdn766 [17] ZHANG DS, JIN Y, LUO HY, et al.Pemetrexed for previously treated patients with metastatic gastric cancer:a prospective phase Ⅱ study[J].Br J Cancer, 2015, 112(2):266. doi: 10.1038/bjc.2014.607 [18] THUSS-PATIENCE PC, KRETZSCHMAR A, BICHEV D, et al.Survival advantage for irinotecan versus best supportive care as second-line chemotherapy in gastric cancer--a randomised phase Ⅲ study of the Arbeitsgemeinschaft Internistische Onkologie(AIO)[J].Eur J Cancer, 2011, 47(15):2306. doi: 10.1016/j.ejca.2011.06.002 [19] KANG JH, LEE SI, LIM DH, et al.Salvage chemotherapy for pretreated gastric cancer:a randomized phase Ⅲ trial comparing chemotherapy plus best supportive care with best supportive care alone[J].J Clin Oncol, 2012, 30(13):1513. doi: 10.1200/JCO.2011.39.4585 [20] FORD HE, MARSHALL A, BRIDGEWATER JA, et al.Docetaxel versus active symptom control for refractory oesophagogastric adenocarcinoma(COUGAR-02):an open-label, phase 3 randomised controlled trial[J].Lancet Oncol, 2014, 15(1):78. doi: 10.1016/S1470-2045(13)70549-7