酪氨酸激酶抑制剂维持治疗晚期非小细胞肺癌的临床研究
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摘要
目前肺癌已成为全世界发病率及死亡率最高的恶性肿瘤。近年研究表明对于术后复发、转移或不能手术切除的晚期肺癌，维持治疗是延长生存期的重要方法。多项大规模临床研究显示，对EGFR突变者应用表皮生长因子受体酪氨酸激酶抑制剂（Epidermal Growth Factor Receptor-TyrosineKinase Inhibitor，EGFR-TKI）维持治疗较支持治疗相比，无进展生存期（PFS）显著延长。但与单药化疗相比，在临床疗效、无进展生存期（PFS）、生存率等方面是否存在优势，副毒作用如何，国内外无相关报道。为对比EGFR突变的晚期NSCLC维持治疗中TKI与细胞毒药物疗效，本文对22例接受EGFR-TKI（治疗组）者及16例接受单药化疗（对照组）者就临床疗效、生存率、无进展生存期（PFS）及毒性反应进行回顾性分析。结果显示治疗组3例CR（13.6%），12例PR（54.5%），5例SD（22.7%），2例PD(9.1%)，RR68.2%，DCR90.9%；对照组2例CR（12.5%），6例PR（37.5%），5例SD（31.25%），3例PD（18.8%），RR50%，DCR81.3%。治疗组及对照组1年生存率81.8%（18/22）vs68.8%（11/16）；2年生存率63.3%（14/22）vs31.2%（5/16）。治疗组及对照组PFS分别为11.4个月和5.0个月。毒副作用：治疗组主要的不良反应为皮疹和腹泻。皮疹发生率为41%（9/22），其中31.8%（7/22）为Ⅰ～Ⅱ度，9%（2/22）为Ⅲ度；腹泻发生率为27.3%（6/22），其中Ⅰ度腹泻发生率为18.2%（4/22），Ⅱ度发生率为9.1%（2/22）；白细胞Ⅰ度减少发生率为4.5%（1/22），未见其他血液学毒性；食欲减退发生率为4.5%（1/22）。无恶心、呕吐及肝功能转氨酶增高。对照组主要的毒副作用为血液学毒性。轻度骨髓抑制，发生率为50%（8/16）：5例白细胞I度减少，发生率为31.3%（5/16）；2例白细胞II度减少，发生率为12.5%（2/16）；1例血小板I度减少，发生率为6.25%（1/16）；未见其他血液学毒性。3例I度恶心、呕吐，发生率为18.8%（3/16）；1例I度肝功能转氨酶升高，发生率为6.25%（1/16）。无皮疹、腹泻发生。两组均未出现肾毒性、神经毒性，无治疗相关死亡。本研究显示EGFR突变的晚期NSCLC维持治疗，EGFR-TKI与单药化疗相比在CR、PR、SD、PD、RR、DCR、1年生存率方面无统计学差异；PFS（11.4个月vs5.0个月）及2年生存率（63.3%vs31.2%）显著提高，具有统计学差异；EGFR-TKI毒副作用较轻，除血液学毒性（4.5%vs50%，P＜0.01）、皮疹（41%vs0%，P＜0.01）、腹泻（27.3%vs0%，P＜0.05）外与单药化疗无统计学差异，可保证维持治疗的持续性。
Background and purpose:
Lung cancer is currently the world 's highest incidence of malignancy, hasbecome the leading cause of cancer death. Because of insidious onset, nospecific symptoms, most of patients losing operation cure chance,5yearssurvival rate is5%～10%. Although cluding platinum of double medicinechemotherapy remains the first line to standard treatment regimens of advancednon small cell lung cancer (NSCLC), but reaching its effect platform. Inrecent years, epidermal growth factor receptor tyrosine kinase inhibitor（EGFR-TKI) in treating advanced NSCLC has achieved remarkable effect,has become the first-line therapy to EGFR mutation of advanced non small celllung cancer. For the EGFR mutation of advanced NSCLC maintenancetreatment, a number of large-scale clinical trials to support to use EGFR-TKIthan supportive therapy,because of PFS was significantly prolonged ofEGFR-TKI team. Becase of defferent mechanisms, lower toxicity and sideeffects, better tolerance,EGFR-TKI is the ideal drug for maintence. The thesisaims to retrospectively analyzed EGFR-TKI and chemotherapeutic drug’sinclinical effects, the progression free survival and toxicity in maintenancetherapy for EGFR mutation of advanced NSCLC.
Method：
We studied38patients in advanced non small cell lung cancer, diagnosedbetween Janunary2008and March2012at China-Japan Union Hospital OfJilin University, including5males,33females, the median age was58years old.Adenocarcinoma in35cases, adenosquanosus carcinoma in2cases, squamous carcinoma in1cases. EGFR positive. According to the seventh edition LungCancer TNM staging system for cliniccal stage,IIIB stage are6cases, IV stageare32cases. The lesion could be estimated through the chest CT. All patientswith Karnofsky score≥80. Estamating the survival period over3months. Allpatients had no obvious pulmonary emphysema and respiratory failure.22patients were divided into therapeutic group and16patients were divided intocomparison group.Therapeutic group cluded5cases of erlotinib therapy,150mgeveryday,2h postprandia loral.17cases of gefitinib250mg every day, oral.Comparison group16case received single agent chemotherapy, including8cases of pemetrexed,4cases of gemcitabine,4cases of docetaxel. Usage:pemetrexed500mg/m2, on day1, every21days as a cycle, folic acid tablets400ug/d were taken from a week before pemetrexed was administered until21days after pemetrexed last used. A week before pemetrexed, VitB121000ugwas given by intramuscular injection and repeatd every three cycles.Theprevious day, the same day and the second day, dexamethasone was given4mgevery time,two times one day. Gemcitabine1000mg/m2by intravenousinfusion on the first and eighth day, every21days as a cycle. Docetaxel75/m2by intravenous infusion on the first day,every21days as a cycle, the previousday and the second day dexamethasone was given10mg, the same day30minutes before chemotherapy10mg dexamethasone was intravenous infusion.Estimateing the chest lesion by chest CT for every month. We quantified theseand used Х2to test the count data of clinical indicators, the progression freesurvival rate by log-rank test, SPSS17.0statistics software to drawKaplan-Meier disease progression free survival.
Result：
Efficacy: The therapeutic group: complete response(CR) is3(13.6%),partial response(PR) is12(54.5%), stable disease(SD) is5(22.7%),progressivedisease(PD) is2(9.1%),response rate(RR) is68.2%, disease control rate(DCR) is90.9%.The comparison group: complete response(CR) is2(12.5%), partialresponse(PR) is6(37.5%), stable disease(SD) is5(31.25%), progressivedisease(PD) is3(18.8%), response rate(RR) is50%, disease control rate(DCR)is81.3%. One years survival rate of81.8%(18/22) vs68.8%(11/16), two yearssurvival rate of63.3%(14/22) vs31.2%(5/16).The therapeutic group andcomparison group of PFS were respectively11.4months and5.0months. Twogroups of PFS, two years survival rate were significant statistically.CR,PR,SD,PD,RR,DCR,one year survival rates were not significant statistically.Side effects: the therapeutic group: the main side effect was rash and diarrhea.The rash rate was41%(9/22), Ⅰ～Ⅱgrade account for31.8%(7/22), Ⅲgradeaccount for9%(2/22). Diarrhea rate was27.3%(6/22)：Ⅰgrade diarrhea accountfor18.2%(4/22)，Ⅱgrade account for9.1%（2/22）.Ⅰgrade leucocyte reductionaccount for4.5%(1/22), no other hematological toxicity. Anorexia incidencewas4.5%(1/22), no nausea, vomiting. The comparisom group:the main sideeffects were hematologic toxicity. Mild bone marrow suppression rate was50%(8/16)：I grade leukocyte reduction31.3%（5/16），Ⅱgrade account for12.5%(2/16), Ⅰgrade thrombocytopenia account for6.25%(1/16), no otherhematological toxicity.Ⅰgrade nausea, vomiting account for18.8%(3/16).Ⅰgrade liver transaminase elevation account for6.25%(1/16), no Ⅱ～Ⅳgrade transaminase elevation. The two groups had no nephrotoxicity,neurotoxicity, no treatment related deaths.
Conclusion:
1. In the maintenance treatment of advanced non-small cell lung cancerwith EGFR positive, PFS and Two Years Survival Rate have significantstatistically difference.(PFS11.4months vs5.0months,P＜0.01. Two YearsSurvival Rate63.3%vs31.2%, P＜0.05)
2.The EGFR-TKI side effects was mild, so guarantee the sustained treatment of persistent.
3.EGFR-TKI can be used for maintenance therapy in advanced NSCLCwith EGFR positive.
Background and purpose:
Lung cancer is currently the world 's highest incidence of malignancy, hasbecome the leading cause of cancer death. Because of insidious onset, nospecific symptoms, most of patients losing operation cure chance,5yearssurvival rate is5%～10%. Although cluding platinum of double medicinechemotherapy remains the first line to standard treatment regimens of advancednon small cell lung cancer (NSCLC), but reaching its effect platform. Inrecent years, epidermal growth factor receptor tyrosine kinase inhibitor（EGFR-TKI) in treating advanced NSCLC has achieved remarkable effect,has become the first-line therapy to EGFR mutation of advanced non small celllung cancer. For the EGFR mutation of advanced NSCLC maintenancetreatment, a number of large-scale clinical trials to support to use EGFR-TKIthan supportive therapy,because of PFS was significantly prolonged ofEGFR-TKI team. Becase of defferent mechanisms, lower toxicity and sideeffects, better tolerance,EGFR-TKI is the ideal drug for maintence. The thesisaims to retrospectively analyzed EGFR-TKI and chemotherapeutic drug’sinclinical effects, the progression free survival and toxicity in maintenancetherapy for EGFR mutation of advanced NSCLC.
Method：
We studied38patients in advanced non small cell lung cancer, diagnosedbetween Janunary2008and March2012at China-Japan Union Hospital OfJilin University, including5males,33females, the median age was58years old.Adenocarcinoma in35cases, adenosquanosus carcinoma in2cases, squamous carcinoma in1cases. EGFR positive. According to the seventh edition LungCancer TNM staging system for cliniccal stage,IIIB stage are6cases, IV stageare32cases. The lesion could be estimated through the chest CT. All patientswith Karnofsky score≥80. Estamating the survival period over3months. Allpatients had no obvious pulmonary emphysema and respiratory failure.22patients were divided into therapeutic group and16patients were divided intocomparison group.Therapeutic group cluded5cases of erlotinib therapy,150mgeveryday,2h postprandia loral.17cases of gefitinib250mg every day, oral.Comparison group16case received single agent chemotherapy, including8cases of pemetrexed,4cases of gemcitabine,4cases of docetaxel. Usage:pemetrexed500mg/m2, on day1, every21days as a cycle, folic acid tablets400ug/d were taken from a week before pemetrexed was administered until21days after pemetrexed last used. A week before pemetrexed, VitB121000ugwas given by intramuscular injection and repeatd every three cycles.Theprevious day, the same day and the second day, dexamethasone was given4mgevery time,two times one day. Gemcitabine1000mg/m2by intravenousinfusion on the first and eighth day, every21days as a cycle. Docetaxel75/m2by intravenous infusion on the first day,every21days as a cycle, the previousday and the second day dexamethasone was given10mg, the same day30minutes before chemotherapy10mg dexamethasone was intravenous infusion.Estimateing the chest lesion by chest CT for every month. We quantified theseand used Х2to test the count data of clinical indicators, the progression freesurvival rate by log-rank test, SPSS17.0statistics software to drawKaplan-Meier disease progression free survival.
Result：
Efficacy: The therapeutic group: complete response(CR) is3(13.6%),partial response(PR) is12(54.5%), stable disease(SD) is5(22.7%),progressivedisease(PD) is2(9.1%),response rate(RR) is68.2%, disease control rate(DCR) is90.9%.The comparison group: complete response(CR) is2(12.5%), partialresponse(PR) is6(37.5%), stable disease(SD) is5(31.25%), progressivedisease(PD) is3(18.8%), response rate(RR) is50%, disease control rate(DCR)is81.3%. One years survival rate of81.8%(18/22) vs68.8%(11/16), two yearssurvival rate of63.3%(14/22) vs31.2%(5/16).The therapeutic group andcomparison group of PFS were respectively11.4months and5.0months. Twogroups of PFS, two years survival rate were significant statistically.CR,PR,SD,PD,RR,DCR,one year survival rates were not significant statistically.Side effects: the therapeutic group: the main side effect was rash and diarrhea.The rash rate was41%(9/22), Ⅰ～Ⅱgrade account for31.8%(7/22), Ⅲgradeaccount for9%(2/22). Diarrhea rate was27.3%(6/22)：Ⅰgrade diarrhea accountfor18.2%(4/22)，Ⅱgrade account for9.1%（2/22）.Ⅰgrade leucocyte reductionaccount for4.5%(1/22), no other hematological toxicity. Anorexia incidencewas4.5%(1/22), no nausea, vomiting. The comparisom group:the main sideeffects were hematologic toxicity. Mild bone marrow suppression rate was50%(8/16)：I grade leukocyte reduction31.3%（5/16），Ⅱgrade account for12.5%(2/16), Ⅰgrade thrombocytopenia account for6.25%(1/16), no otherhematological toxicity.Ⅰgrade nausea, vomiting account for18.8%(3/16).Ⅰgrade liver transaminase elevation account for6.25%(1/16), no Ⅱ～Ⅳgrade transaminase elevation. The two groups had no nephrotoxicity,neurotoxicity, no treatment related deaths.
Conclusion:
1. In the maintenance treatment of advanced non-small cell lung cancerwith EGFR positive, PFS and Two Years Survival Rate have significantstatistically difference.(PFS11.4months vs5.0months,P＜0.01. Two YearsSurvival Rate63.3%vs31.2%, P＜0.05)
2.The EGFR-TKI side effects was mild, so guarantee the sustained treatment of persistent.
3.EGFR-TKI can be used for maintenance therapy in advanced NSCLCwith EGFR positive.
引文
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