靶向药物西妥昔单抗联合伊立替康治疗胃癌的基础与临床研究
摘要
背景：晚期胃癌患者的治疗效果很差,急需新的治疗方法以改善这类患者的预后。西妥昔单抗是抗EGFR(表皮生长因子受体)的单克隆抗体,临床前研究显示西妥昔单抗能增强伊立替康在肠癌中的抗肿瘤作用,但其机制并不十分明了。本研究将观察西妥昔单抗联合伊立替康在胃癌细胞中是否具有协同作用,并进一步阐明两药协同作用的分子机制。
方法：我们以表达EGFR的SGC-7901和MKN-45人胃癌细胞株为研究对象,检测了西妥昔单抗和伊立替康单药或两药联合作用后对细胞增殖,细胞凋亡,细胞周期,细胞衰老,以及p53、p16和EGFR信号传导通路相关蛋白表达水平的影响。
结果：在胃癌细胞中,西妥昔单抗单药无明显的抗细胞增殖、诱导细胞凋亡、细胞周期阻滞和细胞衰老的能力；但可增强伊立替康抑制细胞增殖、诱导细胞凋亡和G2/M期阻滞的作用。伊立替康可引起EGFR通路的上调,包括上调磷酸化EGFR、MAPK和AKT的表达,下调P27Kip1的表达,在MKN-45细胞中上调CyclinD1的表达。而这些作用在联合西妥昔单抗后可得到抑制。两药均能抑制磷酸化mTOR的表达,而对p53、p16、PTEN和HIF-1α的表达水平无影响。
结论：西妥昔单抗可通过抑制伊立替康引起的EGFR通路上调增强伊立替康在胃癌细胞中的抗肿瘤作用。
背景：大多数胃癌在诊断时已是晚期,全身化疗是晚期胃癌治疗的主要方法,而传统细胞毒药物的治疗效果并不理想。我们之前的临床前研究表明在胃癌细胞中,西妥昔单抗联合伊立替康具有协同抗肿瘤作用。因此,我们进一步开展了此项前瞻性多中心Ⅱ期临床研究,探索西妥昔单抗联合FOLFIRI方案在一线治疗失败的局部晚期或转移性胃癌患者中的疗效和安全性,并进行相关分子标记物的研究。
方法：本研究主要的入组标准为年龄18-70岁,经病理组织学证实的转移性或局部复发晚期胃腺癌一线化疗失败者,有可测量的病灶,ECOGPS评分≤1分。入组患者均接受西妥昔单抗联合FOLFIRI方案治疗(西妥昔单抗首次400mg/m2,后每周250mg/m2；伊立替康180mg/m2,d2；亚叶酸钙200mg/m2,d2；5-氟尿嘧啶400mg/m2推注,后2.4g/m246小时持续静脉推注,d2)。该方案将持续使用直至疾病进展或出现不可耐受的不良反应或患者主动要求退出研究。研究的首要终点是至疾病进展时间(TTP),次要终点是缓解率(RR),总生存(OS)和不良事件。同时检测患者肿瘤标本K-Ras基因突变情况,磷酸化EGFR和磷酸化AKT表达情况,并观察其与疗效和预后的相关性。
结果：总共入组了61例患者,在54例能评价疗效的患者中总缓解率为33.3%。在所有61例患者中,中位TTP为4.6个月(95%可信区间：3.5个月-5.7个月),中位OS为8.6个月(95%可信区间：7.3个月-9.9个月)。该方案安全性良好,未发生治疗相关性死亡,主要的毒性为骨髓抑制(Ⅲ/Ⅳ度粒细胞减少的发生率为52.5%,贫血的发生率为29.5%,血小板下降的发生率为8.2%)。Ⅲ/Ⅳ度非血液学毒性主要包括腹泻(6.6%),皮疹(9.8%)等。磷酸化EGFR表达阴性与阳性患者的缓解率分别为32.4%和28.6%(P=0.791)；中位TTP分别为5.3个月和4.3个月(P=0.503)；中位OS分别为7.8个月和9.1个月(P=0.520)。磷酸化AKT表达阴性与阳性患者的缓解率分别为29.6%和33.3%(P=0.776)；中位TTP分别为5.2个月和4.0个月(P=0.497)；中位OS分别为8.1个月和9.1个月(P=0.394)。在40例取得肿瘤标本进行K-Ras基因第2外显子检测的患者中,无一例发现突变。
结论：在晚期胃癌患者的二线治疗中西妥昔单抗联合FOLFIRI是一个安全有效的方案。本研究中肿瘤组织K-Ras基因突变,磷酸化EGFR和磷酸化AKT表达不能作为疗效和预后的预测物。
Background:Treatment effects of advanced gastric cancer (AGC) are unsatisfactory, and the prognosis of patients suffering from AGC is poor. Thus, novel therapeutic approaches are much needed. The EGFR monoclonal antibody cetuximab inhibits the growth of several human cancer cells but has been tested rarely for the treatment of GC. The synergy between EGFR inhibition and DNA-damaging agents, such as irinotecan, has been reported, but the mechanisms are still not fully clarified. Consequently, we hypothesized cetuximab/irinotecan combination should enhance the antitumor activity of irinotecan in GC cells.
Methods:The in vitro antiproliferative, proapoptotic, cell cycle arrest effects and induction of senescence were examined in SGC-7901 and MKN-45 human GC cell lines. The effects of cetuximab or irinotecan as single agents or the combination on p53, p16 and EGFR signaling pathways were also studied.
Results:Cetuximab alone did not show any anti-proliferative or pro-apoptotic effect on GC cells but cetuximab combined with irinotecan synergistically inhibits GC cells proliferation and induces apoptosis and G2/M arrest. Irinotecan is capable of inducing phosphorylation of EGFR, MAPK and AKT and decreasing the expression of P27Kip1, which could be all abrogated by its combination with cetuximab.
Conclusions:Cetuximab enhances the activities of irinotecan on human gastric cancer cells. Given the lack of curative options for patients with advanced gastric cancer, combination therapy with cetuximab and irinotecan, a novel therapeutic approach, warrants further study.
Background:This multicenter, non-randomized phaseⅡstudy was launched to evaluate the efficacy and safety of cetuximab in combination with modified FOLFIRI as second-line treatment for advanced gastric cancer patients and to identify potential predictive biomarkers.
Methods:Inclusion criteria were:18-70 years, ECOG PS≤1, histologically confirmed adenocarcinoma of stomach and failure to first-line therapy. Cetuximab was given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. On day 2 of each 14-day period, patients received irinotecan at a dose of 180 mg/m2; CF at a dose of 200 mg/m2; and 5-Fu as a bolus of 400 mg/m2 and then 2400 mg/m2 by continuous infusion for 46 hours. Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal of consent. The primary endpoint was time to progression (TTP). Secondary endpoints included response rate (RR), overall survival (OS) and adverse events. Activating mutations in exon 2 of the K-ras gene and expression of phosphorylated EGFR and AKT in tumor samples and their association with efficacy and prognosis were also analysed.
Results:Sixty-one patients were enrolled:34 males (56%),27 females (44%); median age was 52 years (range 26-69).54 patients were evaluable for response and the response rate was 33.3%. In the intention-to-treat analysis, the median TTP was 4.6 months (95% CI:3.5-5.7 months), the median OS was 8.6 months (95% CI:7.3-9.9 months). The major grade 3-4 toxicities were 52.5% neutropenia,29.5% anemia, 8.2% thrombocytopenia,6.6% diarrhea and 9.8% skin reactions. The expression of phosphorylated EGFR and AKT in tumor samples were not associated with RR, TTP or OS. No patient exhibited K-ras mutations.
Conclusions:The combination of cetuximab and FOLFIRI was well-tolerated and appears to be active as second-line treatment for advanced gastric cancer patients. The mutation of the K-ras gene, expression of phosphorylated EGFR and AKT in tumor samples can not predict the outcome.
方法：我们以表达EGFR的SGC-7901和MKN-45人胃癌细胞株为研究对象,检测了西妥昔单抗和伊立替康单药或两药联合作用后对细胞增殖,细胞凋亡,细胞周期,细胞衰老,以及p53、p16和EGFR信号传导通路相关蛋白表达水平的影响。
结果：在胃癌细胞中,西妥昔单抗单药无明显的抗细胞增殖、诱导细胞凋亡、细胞周期阻滞和细胞衰老的能力；但可增强伊立替康抑制细胞增殖、诱导细胞凋亡和G2/M期阻滞的作用。伊立替康可引起EGFR通路的上调,包括上调磷酸化EGFR、MAPK和AKT的表达,下调P27Kip1的表达,在MKN-45细胞中上调CyclinD1的表达。而这些作用在联合西妥昔单抗后可得到抑制。两药均能抑制磷酸化mTOR的表达,而对p53、p16、PTEN和HIF-1α的表达水平无影响。
结论：西妥昔单抗可通过抑制伊立替康引起的EGFR通路上调增强伊立替康在胃癌细胞中的抗肿瘤作用。
背景：大多数胃癌在诊断时已是晚期,全身化疗是晚期胃癌治疗的主要方法,而传统细胞毒药物的治疗效果并不理想。我们之前的临床前研究表明在胃癌细胞中,西妥昔单抗联合伊立替康具有协同抗肿瘤作用。因此,我们进一步开展了此项前瞻性多中心Ⅱ期临床研究,探索西妥昔单抗联合FOLFIRI方案在一线治疗失败的局部晚期或转移性胃癌患者中的疗效和安全性,并进行相关分子标记物的研究。
方法：本研究主要的入组标准为年龄18-70岁,经病理组织学证实的转移性或局部复发晚期胃腺癌一线化疗失败者,有可测量的病灶,ECOGPS评分≤1分。入组患者均接受西妥昔单抗联合FOLFIRI方案治疗(西妥昔单抗首次400mg/m2,后每周250mg/m2；伊立替康180mg/m2,d2；亚叶酸钙200mg/m2,d2；5-氟尿嘧啶400mg/m2推注,后2.4g/m246小时持续静脉推注,d2)。该方案将持续使用直至疾病进展或出现不可耐受的不良反应或患者主动要求退出研究。研究的首要终点是至疾病进展时间(TTP),次要终点是缓解率(RR),总生存(OS)和不良事件。同时检测患者肿瘤标本K-Ras基因突变情况,磷酸化EGFR和磷酸化AKT表达情况,并观察其与疗效和预后的相关性。
结果：总共入组了61例患者,在54例能评价疗效的患者中总缓解率为33.3%。在所有61例患者中,中位TTP为4.6个月(95%可信区间：3.5个月-5.7个月),中位OS为8.6个月(95%可信区间：7.3个月-9.9个月)。该方案安全性良好,未发生治疗相关性死亡,主要的毒性为骨髓抑制(Ⅲ/Ⅳ度粒细胞减少的发生率为52.5%,贫血的发生率为29.5%,血小板下降的发生率为8.2%)。Ⅲ/Ⅳ度非血液学毒性主要包括腹泻(6.6%),皮疹(9.8%)等。磷酸化EGFR表达阴性与阳性患者的缓解率分别为32.4%和28.6%(P=0.791)；中位TTP分别为5.3个月和4.3个月(P=0.503)；中位OS分别为7.8个月和9.1个月(P=0.520)。磷酸化AKT表达阴性与阳性患者的缓解率分别为29.6%和33.3%(P=0.776)；中位TTP分别为5.2个月和4.0个月(P=0.497)；中位OS分别为8.1个月和9.1个月(P=0.394)。在40例取得肿瘤标本进行K-Ras基因第2外显子检测的患者中,无一例发现突变。
结论：在晚期胃癌患者的二线治疗中西妥昔单抗联合FOLFIRI是一个安全有效的方案。本研究中肿瘤组织K-Ras基因突变,磷酸化EGFR和磷酸化AKT表达不能作为疗效和预后的预测物。
Background:Treatment effects of advanced gastric cancer (AGC) are unsatisfactory, and the prognosis of patients suffering from AGC is poor. Thus, novel therapeutic approaches are much needed. The EGFR monoclonal antibody cetuximab inhibits the growth of several human cancer cells but has been tested rarely for the treatment of GC. The synergy between EGFR inhibition and DNA-damaging agents, such as irinotecan, has been reported, but the mechanisms are still not fully clarified. Consequently, we hypothesized cetuximab/irinotecan combination should enhance the antitumor activity of irinotecan in GC cells.
Methods:The in vitro antiproliferative, proapoptotic, cell cycle arrest effects and induction of senescence were examined in SGC-7901 and MKN-45 human GC cell lines. The effects of cetuximab or irinotecan as single agents or the combination on p53, p16 and EGFR signaling pathways were also studied.
Results:Cetuximab alone did not show any anti-proliferative or pro-apoptotic effect on GC cells but cetuximab combined with irinotecan synergistically inhibits GC cells proliferation and induces apoptosis and G2/M arrest. Irinotecan is capable of inducing phosphorylation of EGFR, MAPK and AKT and decreasing the expression of P27Kip1, which could be all abrogated by its combination with cetuximab.
Conclusions:Cetuximab enhances the activities of irinotecan on human gastric cancer cells. Given the lack of curative options for patients with advanced gastric cancer, combination therapy with cetuximab and irinotecan, a novel therapeutic approach, warrants further study.
Background:This multicenter, non-randomized phaseⅡstudy was launched to evaluate the efficacy and safety of cetuximab in combination with modified FOLFIRI as second-line treatment for advanced gastric cancer patients and to identify potential predictive biomarkers.
Methods:Inclusion criteria were:18-70 years, ECOG PS≤1, histologically confirmed adenocarcinoma of stomach and failure to first-line therapy. Cetuximab was given at an initial dose of 400 mg/m2, followed by weekly infusions of 250 mg/m2. On day 2 of each 14-day period, patients received irinotecan at a dose of 180 mg/m2; CF at a dose of 200 mg/m2; and 5-Fu as a bolus of 400 mg/m2 and then 2400 mg/m2 by continuous infusion for 46 hours. Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal of consent. The primary endpoint was time to progression (TTP). Secondary endpoints included response rate (RR), overall survival (OS) and adverse events. Activating mutations in exon 2 of the K-ras gene and expression of phosphorylated EGFR and AKT in tumor samples and their association with efficacy and prognosis were also analysed.
Results:Sixty-one patients were enrolled:34 males (56%),27 females (44%); median age was 52 years (range 26-69).54 patients were evaluable for response and the response rate was 33.3%. In the intention-to-treat analysis, the median TTP was 4.6 months (95% CI:3.5-5.7 months), the median OS was 8.6 months (95% CI:7.3-9.9 months). The major grade 3-4 toxicities were 52.5% neutropenia,29.5% anemia, 8.2% thrombocytopenia,6.6% diarrhea and 9.8% skin reactions. The expression of phosphorylated EGFR and AKT in tumor samples were not associated with RR, TTP or OS. No patient exhibited K-ras mutations.
Conclusions:The combination of cetuximab and FOLFIRI was well-tolerated and appears to be active as second-line treatment for advanced gastric cancer patients. The mutation of the K-ras gene, expression of phosphorylated EGFR and AKT in tumor samples can not predict the outcome.
引文
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[1]Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics,2002[J]. CA Cancer J Clin,2005,55:74-108.
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[3]Rivera F, Vega-Villegas ME, Lopez-Brea MF. Chemotherapy of advanced gastric cancer[J]. Cancer Treat Rev,2007,33:315-24.
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