Options for first-line treatment of advanced NSCLC：what should the standard of care be
非小细胞肺癌2024版NCCN治疗指南中文版
非小细胞肺癌2024版NCCN治疗指南中文版肺癌治疗指南的主要内容包括：
1.根据患者所患肺癌深入研究，确定最佳治疗方案；
2.对患者进行全面的医疗诊断，更加细致地评估患者特殊情况；
3.考虑到患者的全面情况，尽可能多地提出治疗组合方案；
4.尊重患者的偏好和权利，提供更好的细化信息，以帮助患者确定最佳疗法；
5.尽可能使患者的治疗时间和治疗效果最佳，同时减少毒副作用的出现；
6.在患者治疗过程中，定期进行影像学检查，以更好地了解患者的病情变化；
7.根据病情变化，给予病情所需的抗癌治疗，特别是对肺癌晚期患者应该根据个体情况，进行合理的调整；
8.为患者提供支持性治疗，以缓解症状，改善质量和生活质量，从而增强患者心理承受能力；
9.加强门诊跟踪管理，定期复查，提前了解患者的病情变化，以期更有效地控制病情；
10.建立健全患者的长期护理机制。
晚期NSCLC优化治疗选择PPT46页
6、法律的基础有两个，而且只有两个……公平和实用。——伯克 7、有两种和平的暴力，那就是法律和礼节。——歌德
8、法律就是秩序，有好的法律才有好的秩序。——亚里士多德 9、上帝把法律和公平凑合在一起的，因为好人用不着它们，而坏人又不会因为它们而变得规矩起来。——德谟耶克斯
46、我们若已接受最坏的，就再没有什么损失。——卡耐基 47、书到用时方恨少、事非经过不知难。——陆游 48、书籍把我们引入最美好的社会，使我们认识各个时代的伟大智者。——史美尔斯 49、熟读唐诗三百首，不会作诗也会吟。——孙洙 50、谁和我一样用功，谁就会和我一样成功。——莫扎特
老年人潜在不恰当用药Beers标准2023年更新版要点介绍课程答题测试
老年人潜在不恰当用药Beers标准2023年更新版要点介绍课程答题测试1、以下错误的是（A）A.Beers标准最早在2001年提出B.PIM指的是潜在不适当用药C.本课程讨论的是Beers标准2023版D.老年人不适当处方筛查工具和处方遗漏筛查工具简称STOPP/START标准2、以下错误的是（D）A.老年患者应避免使用第一代抗组胺药。
B.第一代抗组胺药累积暴露量与老年患者跌倒、谵妄和痴呆的风险增加有关。
C.应避免阿司匹林用于老年患者心血管疾病的一级预防。
D.与直接口服抗凝剂(DOACs)相比，华法林发生大出血(特别是颅内出血)的风险更低。
3、以下错误的是（A）A.在用于VTE或非瓣膜性房颤的长期治疗时，利伐沙班在老年人中发生大出血和胃肠道出血的风险低于阿哌沙班和艾多沙班。
B.口服短效双嘧达莫可能引起直立性低血压，应避免用于老年患者。
C.多沙唑嗪、特拉唑嗪用于治疗老年人高血压,存在直立性低血压及相关危害的高风险，应避免作为降压药使用。
D.硝苯地平即释片具有潜在的低血压、诱发心肌缺血的风险，应避免用于老年患者。
4、以下错误的是（B）A.地高辛不应作为老年患者房颤和心衰的一线治疗。
B.“Z”类药物在老年人中可安全使用。
C.老年人对苯二氮䓬类药物的敏感性增加，对长效药物的代谢降低。
D.阿米替林、氯米帕明、多塞平(日剂量超过6 mg)、丙咪嗪和帕罗西汀具有高抗胆碱能和镇静作用，可引起直立性低血压，老年患者应避免使用。
5、以下错误的是（C）A.甲磺酸二氢麦角碱缺乏疗效，老年患者中均应避免使用。
B.老年患者中不要使用全身雌激素(例如口服片或经皮贴剂)。
对已经使用这种药物的老年妇女应进行处方精简。
C.甲地孕酮可降低老年人血栓事件和可能死亡的风险。
D.应避免将磺酰脲类作为老年患者一线或二线单药治疗或附加治疗。
如果使用磺酰脲类，请选择短效而不是长效药物。
6、以下错误的是（D）A.质子泵抑制剂(PPI)具有艰难梭菌感染、肺炎、胃肠道恶性肿瘤、骨丢失和骨折的风险。
NSCLC诊疗规范
1．多数早期肺癌患者无明显相关阳性体征。 2．出现原因不明、久治不愈的肺外征象，如杵状指(趾)、非游走性关节疼痛、男性乳腺增生、皮肤黝黑或皮肌炎、共济失调和静脉炎等。 3．临床表现高度可疑肺癌的患者，体检发现声带麻痹、上腔静脉梗阻综合征、Homer征、Pancoast综合征等提示局部侵犯及转移的可能。 4．临床表现高度可疑肺癌的患者，体检发现肝肿大伴有结节、皮下结节、锁骨上窝淋巴结肿大等提示远处转移的可能。
辅助检查
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MRI检查：MRI检查在胸部可选择性地用于以下情况：判定胸壁或纵隔是否受侵；显示肺上沟瘤与臂丛神经及血管的关系；区分肺门肿块与肺不张、阻塞性肺炎的界限；对禁忌注射碘造影剂的患者，是观察纵隔、肺门大血管受侵情况及淋巴结肿大的首选检查方法；对鉴别放疗后纤维化与肿瘤复发亦有一定价值。MRI特别适用于判定脑、脊髓有无转移，脑增强MRI应作为肺癌术前常规分期检查。MRI对骨髓腔转移敏感度和特异度均很高，可根据临床需求选用。
其他检查
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痰细胞学检查：是目前诊断肺癌简单方便的无创伤性诊断方法之一。 TFNA：可在CT或超声引导下进行胸内肿块或淋巴结的穿刺。 胸腔穿刺术：胸腔穿刺术可以获取胸腔积液，进行细胞学检查。 胸膜活检术：对于诊断不明的胸腔积液，胸膜活检可以提高阳性检出率。 浅表淋巴结及皮下转移结节活检术：对于伴有浅表淋巴结肿大及皮下转移结节者，应常规进行针吸或活检，以获得病理学诊断。
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无进展生存概率
OS: EGFR野生型
吉非替尼 (n=91) 卡铂/紫杉醇 (n=85)
如果该患者为EGFR野生型患者
First-SIGNAL研究： EGFR野生型患者一线使用EGFR-TKI的死亡风险增加20%，进展风险增加50%
厄洛替尼治疗晚期非小细胞肺癌的临床疗效及安全性观察
［９］ＸＵＥＹ，ＺＨＯＵＸ，ＸＵＥＬ，ｅｔａｌ．Ｔｈｅｒｏｌｅｏｆｐｒｅｔｒｅａｔｍｅｎｔｐｒｏｇｎｏｓｔｉｃｎｕｔｒｉｔｉｏｎａｌｉｎｄｅｘｉｎｅｓｏｐｈａｇｅａｌｃａｎｃｅｒ：Ａｍｅｔａ ａｎａｌｙｓｉｓ［Ｊ］．ＪＣｅｌｌＰｈｙｓｉｏｌ，２０１９，２３４（１１）：１９６５５ １９６６２．［１０］ＣＨＥＮＬ，ＺＨＡＮＧＱ，ＣＨＡＮＧＷ，ｅｔａｌ．Ｖｉｒａｌａｎｄｈｏｓｔｉｎｆｌａｍｍａｔｉｏｎ ｒｅｌａｔｅｄｆａｃｔｏｒｓｔｈａｔｃａｎｐｒｅｄｉｃｔｔｈｅｐｒｏｇｎｏｓｉｓｏｆｈｅｐａｔｏｃｅｌｌｕｌａｒｃａｒｃｉｎｏｍａ［Ｊ］．ＥｕｒＪＣａｎｃｅｒ，２０１２，４８（１３）：１９７７ １９８７．［１１］张春艳，刘明珠，侯宁，等．系统免疫炎症指数对放化疗老年食管癌患者预后的预测作用［Ｊ］．现代消化及介入诊疗，２０２１，２６（３）：３１４ ３１８．［１２］ＨＥＫ，ＳＩＬ，ＰＡＮＸ，ｅｔａｌ．Ｐｒｅｏｐｅｒａｔｉｖｅｓｙｓｔｅｍｉｃｉｍｍｕｎｅ ｉｎｆｌａｍｍａｔｉｏｎｉｎｄｅｘ（ｓｉｉ）ａｓａｓｕｐｅｒｉｏｒｐｒｅｄｉｃｔｏｒｏｆｌｏｎｇ ｔｅｒｍｓｕｒｖｉｖａｌｏｕｔ ｃｏｍｅｉｎｐａｔｉｅｎｔｓｗｉｔｈｓｔａｇｅｉ ｉｉｇａｓｔｒｉｃｃａｎｃｅｒａｆｔｅｒｒａｄｉｃａｌｓｕｒｇｅｒｙ［Ｊ］．ＦｒｏｎｔＯｎｃｏｌ，２０２２，１２：８２９６８９．［１３］ＺＨＡＮＧＨ，ＳＨＡＮＧＸ，ＲＥＮＰ，ｅｔａｌ．Ｔｈｅｐｒｅｄｉｃｔｉｖｅｖａｌｕｅｏｆａｐｒｅｏｐｅｒａｔｉｖｅｓｙｓｔｅｍｉｃｉｍｍｕｎｅ ｉｎｆｌａｍｍａｔｉｏｎｉｎｄｅｘａｎｄｐｒｏｇｎｏｓｔｉｃｎｕ ｔｒｉｔｉｏｎａｌｉｎｄｅｘｉｎｐａｔｉｅｎｔｓｗｉｔｈｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＪＣｅｌｌＰｈｙｓｉｏｌ，２０１９，２３４（２）：１７９４ １８０２．［１４］张艳华，李晓玲，李增宁．国内恶性肿瘤患者营养不良影响因素Ｍｅｔａ分析［Ｊ］．中国临床保健杂志，２０２０，２３（５）：６４９ ６５５．［１５］ＬＶＸ，ＨＡＮＳ，ＸＵＢ，ｅｔａｌ．Ｔｈｅｖａｌｕｅｏｆｃｏｍｐｌｅｔｅｂｌｏｏｄｃｏｕｎｔｆｏｒｔｈｅｐｒｏｇｎｏｓｉｓａｎａｌｙｓｉｓｏｆｐｒｅｏｐｅｒａｔｉｖｅｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＢＭＣＣａｎｃｅｒ，２０２１，２１（１）：１０７２．［１６］ＺＨＡＮＧＸ，ＧＡＲＩＡ，ＬＩＭ，ｅｔａｌ．Ｃｏｍｂｉｎｉｎｇｓｅｒｕｍｉｎｆｌａｍｍａｔｉｏｎｉｎｄｅｘｅｓａｔｂａｓｅｌｉｎｅａｎｄｐｏｓｔｔｒｅａｔｍｅｎｔｃｏｕｌｄｐｒｅｄｉｃｔｐａｔｈｏｌｏｇｉｃａｌｅｆｆｉｃａｃｙｔｏａｎｔｉ ＰＤ １ｃｏｍｂｉｎｅｄｗｉｔｈｎｅｏａｄｊｕｖａｎｔｃｈｅｍｏｔｈｅｒａｐｙｉｎｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＪＴｒａｎｓｌＭｅｄ，２０２２，２０（１）：６１．［１７］ＯＫＡＤＯＭＥＫ，ＢＡＢＡＹ，ＹＡＧＩＴ，ｅｔａｌ．Ｐｒｏｇｎｏｓｔｉｃｎｕｔｒｉｔｉｏｎａｌｉｎｄｅｘ，ｔｕｍｏｒ ｉｎｆｉｌｔｒａｔｉｎｇｌｙｍｐｈｏｃｙｔｅｓ，ａｎｄｐｒｏｇｎｏｓｉｓｉｎｐａｔｉｅｎｔｓｗｉｔｈｅｓｏｐｈａｇｅａｌｃａｎｃｅｒ［Ｊ］．ＡｎｎＳｕｒｇ，２０２０，２７１（４）：６９３ ７００．［１８］ＺＨＡＮＧＹ，ＤＩＮＧＨ，ＣＨＥＮＴ，ｅｔａｌ．ＯｕｔｃｏｍｅｓｏｆｅｎｄｏｓｃｏｐｉｃｓｕｂｍｕｃｏｓａｌｄｉｓｓｅｃｔｉｏｎｖｓｅｓｏｐｈａｇｅｃｔｏｍｙｆｏｒＴ１ｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａｉｎａｒｅａｌ ｗｏｒｌｄｃｏｈｏｒｔ［Ｊ］．ＣｌｉｎＧａｓｔｒｏｅｎｔｅｒｏｌＨｅｐａ ｔｏｌ，２０１９，１７（１）：７３ ８１．［１９］ＨＯＳＨＩＮＯＳ，ＴＡＫＥＵＣＨＩＭ，ＫＡＷＡＫＵＢＯＨ，ｅｔａｌ．Ｕｓｅｆｕｌｎｅｓｓｏｆｎｅｕｔｒｏｐｈｉｌｔｏｌｙｍｐｈｏｃｙｔｅｒａｔｉｏａｔｒｅｃｕｒｒｅｎｃｅｆｏｒｐｒｅｄｉｃｔｉｎｇｌｏｎｇ ｔｅｒｍｏｕｔｃｏｍｅｓｉｎｐａｔｉｅｎｔｓｗｉｔｈｒｅｃｕｒｒｅｎｔｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＡｎｎＳｕｒｇＯｎｃｏｌ，２０２１，２８（６）：３００１ ３００８．［２０］ＫＡＭＡＥ，ＭＡＳＯＯＤＡ．Ｔｈｅｐｒｏｇｎｏｓｔｉｃｒｏｌｅｏｆｔｈｅｎｅｕｔｒｏｐｈｉｌｔｏｌｙｍｐｈｏｃｙｔｅｒａｔｉｏａｔｒｅｃｕｒｒｅｎｃｅｉｎｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉ ｎｏｍａ：ｃｈａｌｌｅｎｇｅｓａｎｄｆｕｔｕｒｅｄｉｒｅｃｔｉｏｎｓ［Ｊ］．ＡｎｎＳｕｒｇＯｎｃｏｌ，２０２１，２８（６）：２９３９ ２９４０．［２１］ＧＵＶＥＮＤＣ，ＳＡＨＩＮＴＫ，ＥＲＵＬＥ，ｅｔａｌ．Ｔｈｅａｓｓｏｃｉａｔｉｏｎｂｅｔｗｅｅｎｔｈｅｐａｎ ｉｍｍｕｎｅ ｉｎｆｌａｍｍａｔｉｏｎｖａｌｕｅａｎｄｃａｎｃｅｒｐｒｏｇｎｏｓｉｓ：ａｓｙｓ ｔｅｍａｔｉｃｒｅｖｉｅｗａｎｄｍｅｔａ ａｎａｌｙｓｉｓ［Ｊ］．Ｃａｎｃｅｒｓ（Ｂａｓｅｌ），２０２２，１４（１１）：２６７５．［２２］ＺＨＥＮＧＫ，ＬＩＵＸ，ＪＩＷ，ｅｔａｌ．Ｔｈｅｅｆｆｉｃａｃｙｏｆｄｉｆｆｅｒｅｎｔｉｎｆｌａｍｍａｔｏｒｙｍａｒｋｅｒｓｆｏｒｔｈｅｐｒｏｇｎｏｓｉｓｏｆｐａｔｉｅｎｔｓｗｉｔｈｍａｌｉｇｎａｎｔｔｕｍｏｒｓ［Ｊ］．ＪＩｎｆｌａｍｍＲｅｓ，２０２１，１４：５７６９ ５７８５．（收稿日期：２０２２ １１ １０）·临床研究·基金项目：安徽省高校协同创新项目（ＧＸＸＴ ２０２０ ０６２）；２０２０年度重大新药创制科技重大专项（２０２０ＺＸ０９２０１００４ ００７）作者简介：吴方雨，硕士研究生，Ｅｍａｉｌ：３２８６９４７９２４＠ｑｑ．ｃｏｍ通信作者：沈爱宗，主任药师，硕士研究生导师，Ｅｍａｉｌ：ｓｈｅｎａｉｚｏｎｇ＠ｕｓｔｃ．ｅｄｕ．ｃｎ厄洛替尼治疗晚期非小细胞肺癌的临床疗效及安全性观察吴方雨１，陈卫东１，夏盼盼１，张旭东１，沈爱宗１，２１．安徽中医药大学药学院，合肥２３００１２；２．中国科学技术大学附属第一医院（安徽省立医院）药剂科［摘要］ 目的 探讨厄洛替尼治疗晚期非小细胞肺癌（ＮＳＣＬＣ）的临床疗效和安全性。
alk阳性nsclc的一线治疗：克唑替尼还是标准化疗？
ALK阳性 NSCLC的一线治疗：克唑替尼，还是标准化疗？作者：pumcmonk---《新英格兰医学杂志》于12月4日在线发表了一篇关于非小细胞肺癌（NSCLC）的临床研究，是首个证实克唑替尼可用于ALK阳性NSCLC患者一线治疗的III期临床试验，进一步巩固了克唑替尼在NSCLC中的治疗地位。
克唑替尼是一种ALK抑制剂。
与标准的化疗方案相比，克唑替尼作为一线治疗在ALK阳性的晚期NSCLC患者中的疗效尚不清楚。
Solomon教授等人进行了一项开放式的III期临床研究来比较克唑替尼和化疗的疗效，共纳入343例未接受过全身治疗的ALK阳性的晚期非鳞癌NSCLC患者。
患者被随机分成两组，一组口服250mg克唑替尼每日2次，一组接受每3周一次、共6个周期的静脉化疗（500mg/m2培美曲塞联合顺铂75mg/m2或卡铂AUC=5、6mg/ml`min）。
接受化疗的患者出现疾病进展后，被允许接受克唑替尼治疗。
该研究的主要研究终点是无进展生存期（PFS），由独立的放射科医师进行评估。
研究显示，接受克唑替尼治疗的患者，其PFS显著长于接受化疗的患者（中位PFS分别为10.9个月和7.0个月；接受克唑替尼治疗患者的进展风险比为0.45,95%置信区间0.35-0.60，P）。
治疗的客观缓解率在接受克唑替尼的患者中为74%，而在接受化疗的患者中仅为45%（P）。
两组患者均未达到中位生存期（接受克唑替尼治疗患者的死亡风险比为0.82,95%置信区间0.54-1.26，P=0.36），其中接受克唑替尼治疗患者的1年生存率为84%，接受化疗患者的1年生存率为79%。
接受克唑替尼治疗后最常见的不良反应为视觉障碍、腹泻、恶心和水肿，接受化疗后最常见的不良反应为恶心、乏力、呕吐和厌食。
与化疗相比，克唑替尼可以减少肺癌相关的临床症状，改善患者的生活质量。
研究者认为，在初治的晚期ALK阳性非小细胞肺癌患者中，克唑替尼作为一线治疗要优于标准的培美曲塞+铂类方案化疗。
卡瑞利珠单抗联合化疗一线治疗晚期转移性非鳞状非小细胞肺癌疗效观察
2020年10月 第17卷 第19期非小细胞肺癌（NSCLC）是临床常见的肺部恶性肿瘤，高发于吸烟人群，临床致死率较高［1］。
多数早中期NSCLC患者并无明显临床症状，常被患者忽略，因此部分NSCLC患者确诊时病情已进入晚期，肿瘤病灶已经开始转移［2］，此时已错过手术切除病灶最佳时期。
临床多采用培美曲塞联合顺铂化疗方案治疗晚期/转移性NSCLC患者，临床发现即使能够延长生存期，但患者免疫功能下降严重，不利于治疗开展［3］。
程序性细胞死亡受体（PD-1）单抗药物治疗晚期NSCLC疗效已被广泛证实，可提高患者免疫功能［4］。
卡瑞利珠单抗属于新型PD-1单抗药物，本研究旨在观察卡瑞利珠单抗联合化疗一线治疗晚期/转移性非鳞状NSCLC的疗效，具示如下。
1 资料与方法1.1 一般资料选取2017年9月—2019年12月我院收治的88例晚期/转移性非鳞状NSCLC患者为研究对象，按照随机数字表法分成对照组（44例）与观察组（44例）。
对照组：男28例，女16例；年龄53～76岁，平均（62.82±6.84）岁；体力状况（ECOG）评分等级：1级14例，2级23例，3级7例。
观察组：男26例，女18例；年龄52～76岁，平均（62.45±6.77）岁；ECOG评分等级：1级15例，2级20例，3级9例。
两组ECOG评分等级等资料对比，差异无统计学意义（P＞0.05）。
本研究经我院医学伦理委员会审查批准。
卡瑞利珠单抗联合化疗一线治疗晚期/转移性非鳞状非小细胞肺癌疗效观察涂建仁，付华珍江西省肿瘤医院,南昌大学附属肿瘤医院，南昌 330029［摘要］目的：观察卡瑞利珠单抗联合化疗一线治疗晚期/转移性非鳞状非小细胞肺癌（NSCLC）的疗效。
方法：选取我院收治的88例晚期/转移性非鳞状NSCLC患者，按照随机数字表法分成对照组（44例）与观察组（44例）。
对照组给予常规化疗方案治疗，观察组在对照组基础上联合卡瑞利珠单抗治疗，连续化疗3个疗程后对比两组免疫因子及毒副反应情况。
Gemzar健择吉西他滨FDA说明书
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use Gemzar safely and effectively. See full prescribing information for Gemzar.GEMZAR (gemcitabine for injection) Powder, Lyophilized, For Solution For Intravenous UseInitial U.S. Approval: 1996---------------------------RECENT MAJOR CHANGES --------------------------Warnings and Precautions, Capillary Leak Syndrome (5.8) 05/2013----------------------------INDICATIONS AND USAGE ---------------------------Gemzar ® is a nucleoside metabolic inhibitor indicated:• in combination with carboplatin, for the treatment of advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy (1.1)• in combination with paclitaxel, for first-line treatment of metastatic breast cancer after failure of prior anthracycline-containing adjuvantchemotherapy, unless anthracyclines were clinically contraindicated(1.2)• in combination with cisplatin for the treatment of non-small cell lung cancer (1.3)• as a single agent for the treatment of pancreatic cancer (1.4)-----------------------DOSAGE AND ADMINISTRATION ----------------------Gemzar is for intravenous use only.• Ovarian Cancer: 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle (2.1)• Breast Cancer: 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21day cycle (2.2)• Non-Small Cell Lung Cancer: 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle or 1250 mg/m2 over 30 minutes on Days1 and 8 of each 21-day cycle (2.3)• Pancreatic Cancer: 1000 mg/m2 over 30 minutes once weekly for the first 7 weeks, then one week rest, then once weekly for 3 weeks of each 28-day cycle (2.4)----------------------DOSAGE FORMS AND STRENGTHS---------------------• 200 mg/single-use vial (3) • 1 g/single-use vial (3)-------------------------------CONTRAINDICATIONS------------------------------Patients with a known hypersensitivity to gemcitabine (4)------------------------WARNINGS AND PRECAUTIONS -----------------------• Schedule-dependent toxicity: Increased toxicity with infusion time greater than 60 minutes or dosing more frequently than once weekly.(5.1)• Myelosuppression: Monitor for myelosuppression prior to each cycle and reduce or withhold dose for severe myelosuppression. (5.2, 5.7) • Pulmonary Toxicity and Respiratory Failure: Discontinue Gemzar immediately for unexplained new or worsening dyspnea or evidence of severe pulmonary toxicity. (5.3)• Hemolytic-Uremic Syndrome (HUS): Monitor renal function prior to initiation and during therapy. Discontinue Gemzar for HUS or severerenal impairment. (5.4)• Hepatic Toxicity: Monitor hepatic function prior to initiation and during therapy. Discontinue Gemzar for severe hepatic toxicity. (5.5)• Embryofetal Toxicity: Can cause fetal harm. Advise women of potential risk to the fetus. (5.6, 8.1)• Exacerbation of Radiation Therapy Toxicity: May cause severe and life-threatening toxicity when administered during or within 7 days ofradiation therapy. (5.7)• Capillary Leak Syndrome: Discontinue Gemzar. (5.8)-------------------------------ADVERSE REACTIONS ------------------------------The most common adverse reactions for the single agent (≥20%) arenausea/vomiting, anemia, hepatic transaminitis, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and peripheral edema (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or /medwatch.See 17 for PATIENT COUNSELING INFORMATIONRevised: 05/2013FULL PRESCRIBING INFORMATION: CONTENTS*1 I NDICATIONSANDUSAGE1.1 OvarianCancer1.2 BreastCancer1.3 Non-Small Cell Lung Cancer1.4 PancreaticCancer2 D OSAGEANDADMINISTRATION2.1 OvarianCancer2.2 BreastCancer2.3 Non-Small Cell Lung Cancer2.4 PancreaticCancer2.5 Dose Modifications for Non-Hematologic Adverse Reactions2.6 Preparation and Administration Precautions2.7 Preparation for Intravenous Infusion Administration3 DOSAGE FORMS AND STRENGTHS4 C ONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Schedule-dependent Toxicity5.2 Myelosuppression5.3 Pulmonary Toxicity and Respiratory Failure5.4 Hemolytic Uremic Syndrome5.5 HepaticToxicity5.6 EmbryofetalToxicity5.7 Exacerbation of Radiation Therapy Toxicity5.8 CapillaryLeakSyndrome6 A DVERSEREACTIONS6.1 Clinical Trials Experience6.2 Post-MarketingExperience7 D RUGINTERACTIONS8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 NursingMothers8.4 PediatricUse8.5 GeriatricUse8.6 RenalImpairment8.7 HepaticImpairment8.8 Gender10 OVERDOSAGE11 D ESCRIPTION12 C LINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics13 N ONCLINICAL TOXICOLOGY13.1 Carcinogenesis,Mutagenesis, Impairment of Fertility14 C LINICAL STUDIES14.1 OvarianCancer14.2 BreastCancer14.3 Non-Small Cell Lung Cancer (NSCLC)14.4 PancreaticCancer16 HOW SUPPLIED/STORAGE AND HANDLING16.1 HowSupplied16.2 Storage and Handling17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATION1 INDICATIONSANDUSAGE1.1 OvarianCancerGemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy.1.2 BreastCancerGemzar in combination with paclitaxel is indicated for the first-line treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing adjuvant chemotherapy, unless anthracyclines were clinically contraindicated.1.3 Non-Small Cell Lung CancerGemzar is indicated in combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic (Stage IV) non-small cell lung cancer.1.4 PancreaticCancerGemzar is indicated as first-line treatment for patients with locally advanced (nonresectable Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma of the pancreas. Gemzar is indicated for patients previously treated with 5-FU.2 DOSAGEANDADMINISTRATION2.1 OvarianCancerRecommended Dose and ScheduleThe recommended dose of Gemzar is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemzar administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.Dose ModificationsRecommended Gemzar dose modifications for myelosuppression are described Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Table 1: Dosage Reduction Guidelines for Gemzar for Myelosuppression on Day of Treatment in Ovarian CancerTreatment Day Absolute granulocyte count(x 106/L)Platelet count(x 106/L)% of full doseDay 1 ≥1500 and ≥100,000 100%<1500 or <100,000 Delay Treatment Cycle Day 8 ≥1500 and ≥100,000 1001000-1499 or 75,000-99,999 50<1000 or <75,000 Hold Table 2: Gemzar Dose Modification for Myelosuppression in Previous Cycle In Ovarian Cancer Occurrence MyelosuppressionDuringTreatment Cycle Dose ModificationInitial Occurrence Absolute granulocyte count less than 500 x 106/L formore than 5 daysAbsolute granulocyte count less than 100 x 106/L formore than 3 daysFebrile neutropeniaPlatelets less than 25,000x106/LCycle delay of more than one week due to toxicity Permanently reduce Gemzar to 800 mg/m2 on Days 1 and 8Subsequent Occurrence If any of the above toxicities occur after the initial dosereductionPermanently reduce Gemzar dose to 800 mg/m2on Day 1 only2.2 BreastCancerRecommended Dose and ScheduleThe recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before Gemzar administration.Dose ModificationsRecommended dose modifications for Gemzar for myelosuppression are described in Table 3 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Table 3: Recommended Dose Reductions for Gemzar for Myelosuppression on Day of Treatment in Breast Cancer Treatment Day Absolute granulocyte count Platelet count % of full dose3 Day 1 ≥1500 and ≥100,000 100%Day 8 less than 1500≥12001000-1199orandorless than 100,000>75,00050,000-75,000Hold100%75% 700-999<700andor≥50,000<50,00050%Hold2.3 Non-Small Cell Lung CancerRecommended Dose and ScheduleEvery 4-week scheduleThe recommended dose of Gemzar is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination withcisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar.Every 3-week scheduleThe recommended dose of Gemzar is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination withcisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemzar.Dose ModificationsRecommended dose modifications for Gemzar myelosuppression are described in Table 4 [see Warnings and Precautions(5.2)]. Refer to Dosage and Administration (2.5) for Gemzar recommendations for non-hematologic adverse reactions.2.4 PancreaticCancerRecommended Dose and ScheduleThe recommended dose of Gemzar is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule• Weeks 1-8: weekly dosing for the first 7 weeks followed by one week rest.• After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.Dose ModificationsRecommended dose modifications for Gemzar for myelosuppression are described in Table 4 [see Warnings and Precautions(5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differentialand platelet count. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 4.Table 4: Recommended Dose Reductions for Gemzar for Myelosuppression in Pancreatic Cancer and Non-Small Cell LungCancer(x 106/L) (x 106/L)500-999 Or50,000-99,99975<500 Or <50,000 Hold2.5 Dose Modifications for Non-Hematologic Adverse ReactionsPermanently discontinue Gemzar for any of the following• Unexplained dyspnea or other evidence of severe pulmonary toxicity• Severe hepatic toxicity• Hemolytic-UremicSyndrome• Capillary Leak SyndromeWithhold Gemzar or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.2.6 Preparation and Administration PrecautionsExercise caution and wear gloves when preparing Gemzar solutions. Immediately wash the skin thoroughly or rinse themucosa with copious amounts of water if Gemzar contacts the skin or mucus membranes. Death has occurred in animal studies dueto dermal absorption. For further guidance on handling Gemzar go to “OSHA Hazardous Drugs” (refer to antineoplastic weblinksincluding OSHA Technical Manual) at OSHA. /SLTC/hazardousdrugs/index.html2.7 Preparation for Intravenous Infusion AdministrationReconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial. These dilutions each yield a Gemzar concentration of 38 mg/mL.Complete withdrawal of the vial contents will provide 200 mg or 1 g of Gemzar. Prior to administration the appropriate amount ofdrug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL.Reconstituted Gemzar is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemzar solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.3 DOSAGE FORMS AND STRENGTHSGemzar (gemcitabine for injection USP) is a white to off-white lyophilized powder available in sterile single-use vials containing 200 mg or 1 g gemcitabine.4 CONTRAINDICATIONSGemzar is contraindicated in patients with a known hypersensitivity to gemcitabine.ANDPRECAUTIONS5 WARNINGSToxicity5.1 Schedule-dependentIn clinical trials evaluating the maximum tolerated dose of Gemzar, prolongation of the infusion time beyond 60 minutes or more frequent than weekly dosing resulted in an increased incidence of clinically significant hypotension, severe flu-like symptoms, myelosuppression, and asthenia. The half-life of Gemzar is influenced by the length of the infusion [see Clinical Pharmacology (12.3)].5.2 MyelosuppressionMyelosuppression manifested by neutropenia, thrombocytopenia, and anemia occurs with Gemzar as a single agent and the risks are increased when Gemzar is combined with other cytotoxic drugs. In clinical trials, Grade 3-4 neutropenia, anemia, and thrombocytopenia occurred in 25%, 8%, and 5%, respectively of patients receiving single-agent. The frequencies of Grade 3-4 neutropenia, anemia, and thrombocytopenia varied from 48% to 71%, 8 to 28%, and 5 to 55%, respectively, in patients receiving Gemzar in combination with another drug.5.3 Pulmonary Toxicity and Respiratory FailurePulmonary toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported. In some cases, these pulmonary events can lead to fatal respiratory failure despite discontinuation of therapy. The onset of pulmonary symptoms may occur up to 2 weeks after the last dose of Gemzar. Discontinue Gemzar in patients who develop unexplained dyspnea, with or without bronchospasm, or have any evidence of pulmonary toxicity [see Adverse Reactions (6.1 and 6.2)].SyndromeUremic5.4 HemolyticHemolytic Uremic Syndrome to include fatalities from renal failure or the requirement for dialysis can occur in patients treated with Gemzar. In clinical trials, HUS was reported in 6 of 2429 patients (0.25%). Most fatal cases of renal failure were due to HUS [see Adverse Reactions (6.1 and 6.2)]. Assess renal function prior to initiation of Gemzar and periodically during treatment. Consider the diagnosis of HUS in patients who develops anemia with evidence of microangiopathic hemolysis, elevation of bilirubin or LDH, or reticulocytosis; severe thrombocytopenia; or evidence of renal failure (elevation of serum creatinine or BUN) [see Dosage and Administration (2.5) and Use In Specific Populations (8.6)]. Permanently discontinue Gemzar in patients with HUS or severe renal impairment. Renal failure may not be reversible even with discontinuation of therapy. Renal failure may not be reversible even with discontinuation of therapy.Toxicity5.5 HepaticDrug-induced liver injury, including liver failure and death, has been reported in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs [see Adverse Reactions (6.1 and 6.2)]. Administration of Gemzar in patients with concurrent liver metastases or a pre-existing medical history or hepatitis, alcoholism, or liver cirrhosis can lead to exacerbation of the underlying hepatic insufficiency [see Use in Specific Populations (8.7)]. Assess hepatic function prior to initiation of Gemzar and periodically during treatment. Discontinue Gemzar in patients that develop severe liver injury.5.6 EmbryofetalToxicityGemzar can cause fetal harm when administered to a pregnant woman, based on its mechanism of action. Gemcitabine was teratogenic, embryotoxic, and fetotoxic in mice and rabbits. If this drug is used during pregnancy, or if a woman becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to a fetus. [see Use In Specific Populations (8.1)]5.7 Exacerbation of Radiation Therapy ToxicityGemzar is not indicated for use in combination with radiation therapy.Concurrent (given together or ≤7 days apart) — Life-threatening mucositis, especially esophagitis and pneumonitis occurred in a trial in which Gemzar was administered at a dose of 1000 mg/m2 to patients with non-small cell lung cancer for up to 6 consecutive weeks concurrently with thoracic radiation.Non-concurrent (given >7 days apart) — Excessive toxicity has not been observed when Gemzar is administered more than 7 days before or after radiation. Radiation recall has been reported in patients who receive Gemzar after prior radiation.5.8 Capillary Leak SyndromeCapillary leak syndrome (CLS) with severe consequences has been reported in patients receiving Gemzar as a single agent or in combination with other chemotherapeutic agents. Discontinue Gemzar if CLS develops during therapy.REACTIONS6 ADVERSEThe following serious adverse reactions are discussed in greater detail in another section of the label[see Warnings and Precautions (5.1)]Toxicity• Schedule-Dependent[see Warnings and Precautions (5.2)]• Myelosuppression• Pulmonary Toxicity and Respiratory Failure [see Warnings and Precautions (5.3)]• Hemolytic Uremic Syndrome [see Warnings and Precautions (5.4)][see Warnings and Precautions (5.5)]Toxicity• H epatic[see Warnings and Precautions (5.6), Use in Specific Populations (8.1), and Nonclinical • E mbryo-fetalToxicityToxicology (13.1)]• Exacerbation of Radiation Toxicity [see Warnings and Precautions (5.7)]• Capillary Leak Syndrome [see Warnings and Precautions (5.8)]6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Single-Agent Use:The data described below reflect exposure to Gemzar as a single agent administered at doses between 800 mg/m2 to 1250mg/m2 over 30 minutes intravenously, once weekly, in 979 patients with a variety of malignancies. The most common (≥20%) adverse reactions of single-agent Gemzar are nausea/vomiting, anemia, increased ALT, increased AST, neutropenia, increased alkaline phosphatase, proteinuria, fever, hematuria, rash, thrombocytopenia, dyspnea, and edema. The most common (≥5%) Grade 3 or 4 adverse reactions were neutropenia, nausea/vomiting; increased ALT, increase alkaline phosphatase, anemia, increased AST, and thrombocytopenia. Approximately 10% of the 979 patients discontinued Gemzar due to adverse reactions. Adverse reactions resulting in discontinuation of Gemzar in 2% of 979 patients were cardiovascular adverse events (myocardial infarction, cerebrovascular accident, arrhythmia, and hypertension) and adverse reactions resulting in discontinuation of Gemzar in less than 1% of the 979 patients were anemia, thrombocytopenia, hepatic dysfunction, renal dysfunction, nausea/vomiting, fever, rash, dyspnea, hemorrhage, infection, stomatitis, somnolence, flu-like syndrome, and edema.Table 5 presents the incidence of adverse reactions reported in 979 patients with various malignancies receiving single-agent Gemzar across 5 clinical trials. Table 5 includes all clinical adverse reactions, reported in at least 10% of patients. A listing of clinically significant adverse reactions is provided following the table.Table 5: Selected Per-Patient Incidence of Adverse Events in Patients Receiving Single-Agent Gemzar aAll Patients bAll Grades Grade 3 Grade 4 Laboratory cHematologicAnemia 68 7 1Neutropenia 63 19 6Thrombocytopenia 24 4 1HepaticIncreased ALT 68 8 2Increased AST 67 6 2Increased Alkaline Phosphatase 55 7 2Hyperbilirubinemia 13 2 <1RenalProteinuria 45 <1 0Hematuria 35 <1 0Increased BUN 16 0 0Increased Creatinine 8 <1 0Non-laboratory dNausea and Vomiting 69 13 1Fever 41 2 0Rash 30 <1 0Dyspnea 23 3 <1Diarrhea 19 1 0Hemorrhage 17 <1 <1Infection 16 1 <1Alopecia 15 <1 0Stomatitis 11 <1 0Somnolence 11 <1 <1Paresthesias 10 <1 06c aGrade based on criteria from the World Health Organization (WHO). bN=699-974; all patients with laboratory or non-laboratory data. Regardless of causality.d For approximately 60% of patients, non-laboratory adverse events were graded only if assessed to be possibly drug-related. • Transfusion requirements — Red blood cell transfusions (19%); platelet transfusions (<1%) • Fever — Fever occurred in the absence of clinical infection and frequently in combination with other flu-like symptoms. • Pulmonary — Dyspnea unrelated to underlying disease and sometimes accompanied by bronchospasm.• Edema — Edema (13%), peripheral edema (20%), and generalized edema (<1%); <1% of patients. discontinued Gemzardue to edema.• Flu-like Symptoms — Characterized by fever, asthenia, anorexia, headache, cough, chills, myalgia, asthenia insomnia,rhinitis, sweating, and/or malaise (19%); <1% of patients discontinued Gemzar due to flu-like symptoms• Infection — Sepsis (<1%)• E xtravasation — Injection-site reactions (4%)•Allergic — Bronchospasm (<2%); anaphylactoid reactions [see Contraindications (4)]. Non-Small Cell Lung Cancer:Table 6 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higherincidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=262) administered in 28-daycycles as compared to cisplatin alone (n=260) in patients receiving first-line treatment for locally advanced or metastatic non-smallcell lung cancer (NSCLC) [see Clinical Studies (14.3)]. Patients randomized to Gemzar plus cisplatin received a median of 4 cycles of treatment and those randomized to cisplatinreceived a median of 2 cycles of treatment. In this trial, the requirement for dose adjustments (>90% versus 16%), discontinuation oftreatment for adverse reactions (15% versus 8%), and the proportion of patients hospitalized (36% versus 23%) were all higher forpatients receiving Gemzar plus cisplatin arm compared to those receiving cisplatin alone. The incidence of febrile neutropenia (9/262 versus 2/260), sepsis (4% versus 1%), Grade 3 cardiac dysrhythmias (3% versus <1%) were all higher in the Gemzar plus cisplatin arm compared to the cisplatin alone arm. The two-drug combination was more myelosuppressive with 4 (1.5%) possibly treatment-related deaths, including 3 resulting from myelosuppression with infection and one case of renal failure associated with pancytopeniaand infection. No deaths due to treatment were reported on the cisplatin arm.Table 6: Per-Patient Incidence of Selected Adverse Reactions from Randomized Trial of Gemzar plus Cisplatin versus Single-Agent Cisplatin in Patients with NSCLC Occurring at Higher Incidence in Gemzar-Treated Patients[Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3-4)]aGemzar plus Cisplatin b Cisplatin c All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4Laboratory dHematologic Anemia 89 22 3 67 6 1RBC Transfusion e39 13 Neutropenia 79 22 35 20 3 1 Thrombocytopenia 85 25 25 13 3 1Platelet Transfusions e21 <1 Lymphopenia 75 25 18 51 12 5 Hepatic Increased Transaminases 22 2 1 10 1 0 Increased Alkaline Phosphatase19 1 0 13 0 0 RenalProteinuria 23 0 0 18 0 0 Hematuria 15 0 0 13 0 0 Elevated creatinine 38 4 <1 31 2 <1 Other Laboratory Hyperglycemia 30 4 0 23 3 0 Hypomagnesemia 30 4 3 17 2 0 Hypocalcemia 18 2 0 7 0 <1Non-laboratory fNausea 93 25 2 87 20 <1 Vomiting 78 11 12 71 10 9 Alopecia 53 1 0 33 0 0 Neuro Motor 35 12 0 15 3 0 Diarrhea 24 2 2 13 0 0c Neuro Sensory InfectionFeverNeuro Cortical Neuro MoodLocalNeuro Headache Stomatitis Hemorrhage HypotensionRash 23181616161514141412111331111211812591067547311111a National Cancer Institute Common Toxicity Criteria (CTC) for severity grading.b N=217-253; all Gemzar plus cisplatin patients with laboratory or non-laboratory data Gemzar at 1000 mg/m2 on Days 1, 8, and 15and cisplatin at 100 mg/m2 on Day 1 every 28 days.N=213-248; all cisplatin patients with laboratory or non-laboratory data. Cisplatin at 100 mg/m2 on Day 1 every 28 days.d Regardless of causality.e Percent of patients receiving transfusions. Percent transfusions are not CTC-graded events.f Non-laboratory events were graded only if assessed to be possibly drug-related.Table 7 presents the incidence of selected adverse reactions, occurring in ≥10% of Gemzar-treated patients and at a higher incidence in the Gemzar plus cisplatin arm, reported in a randomized trial of Gemzar plus cisplatin (n=69) administered in 21-daycycles as compared to etoposide plus cisplatin alone (n=66) in patients receiving first-line treatment for locally advanced or metastaticnon-small cell lung cancer (NSCLC) [see Clinical Studies (14.3)]. A listing of clinically significant adverse reactions is provided following the table.Patients in the Gemzar cisplatin (GC) arm received a median of 5 cycles and those in the etoposide/cisplatin (EC) armreceived a median of 4 cycles. The majority of patients receiving more than one cycle of treatment required dose adjustments; 81% inthe (GC) arm and 68% in the (EC) arm. The incidence of hospitalizations for treatment-related adverse events was 22% (GC) and 27%in the (EC) arm. The proportion of discontinuation of treatment for treatment-related adverse reactions was higher for patients in the (GC) arm (14% versus 8%). The proportion of patients hospitalized for febrile neutropenia was lower in the (GC) arm (7% versus 12%). There was one death attributed to treatment, a patient with febrile neutropenia and renal failure, which occurred in theGemzar/cisplatin arm.Table 7: Per-Patient Incidence of Selected Adverse Reactions in Randomized Trial of Gemzar plus Cisplatin versus Etoposideplus Cisplatin in Patients with NSCLC aGemzar plus Cisplatin b Etoposide plus Cisplatin cAll Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory dHematologicAnemia 88 22 0 77 13 2RBC Transfusions e 29 --21 --Neutropenia 88 36 28 87 20 56Thrombocytopenia 81 39 16 45 8 5Platelet Transfusions e 3 --8 --HepaticIncreased ALT 6 0 0 12 0 0Increased AST 3 0 0 11 0 0Increased AlkalinePhosphatase16 0 0 11 0 0 Bilirubin 0 0 0 0 0 0RenalProteinuria 12 0 0 5 0 0Hematuria 22 0 0 10 0 0BUN 6 0 0 4 0 0Creatinine 2 0 0 2 0 0Non-laboratory f,gNausea and Vomiting 96 35 4 86 19 7Fever 6 0 0 3 0 0Rash 10 0 0 3 0 0Dyspnea 1 0 1 3 0 0Diarrhea 14 1 1 13 0 2。
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Vall d’Hebron University Hospital, Barcelona, Spain Lineberger Comprehensive Cancer Center, University of North Carolina, USA
2National
C, et al. JAMA 2004;292:470–84 Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology. Non-small cell lung cancer, version 1 2007. Available at: /professionals/physician_gls/PDF/nscl.pdf
1.0 0.8 Survival (%) 0.6 0.4 0.2 0 0 5 10 15 Months 20 25 30
Cisplatin/paclitaxel Cisplatin/gemcitabine Cisplatin/docetaxel Carboplatin/paclitaxel
Schiller JH, et al. N Engl J Med 2002;346:92–8
12%
9% 3% 10% 12%
Single agents Tarceva Other
Source: Tandem/Synovate US Oncology Monitor (MAT Q4 2006)
Phase III trial of Avastin in NSCLC (E4599): trial design
Treatment of advanced NSCLC in the USA
• NCCN guidelines recommend chemotherapy for advanced/recurrent NSCLC • Platinum combinations are superior to best supportive care • No specific new agent-platinum combination is clearly superior • First-line therapy: cisplatin or carboplatin in combination with – paclitaxel – docetaxel – gemcitabine – vinorelbine – irinotecan – etoposide – vinblastine
First-line treatment of advanced NSCLC in thitaxel (CP) Carboplatin/docetaxel
38%
Carboplatin/gemcitabine Cisplatin/docetaxel Other platinum-based
1Delbaldo
Treatment options for advanced NSCLC: pre-2006 (stage IIIB with pleural effusion/stage IV)
Suitable for chemotherapy? Yes Platinum doublet chemotherapy/ third-generation non-platinum doublet Single-agent chemotherapy (elderly) No (PS 3–4) Best supportive care
307,000 (22) 92,700 (13) 1 900,000 1 290,000
266,000 (30) 90,330 (31)
*1995 data; †2006 data; ‡In European women, breast cancer, colorectal cancer and stomach cancer were ranked 1–3, respectively; in the USA, the top two most common sites of cancer in women are breast and colorectal cancer
Previously untreated stage IIIB/IV non-squamous NSCLC (n=878) CP × 6 (n=444) Avastin (15mg/kg) every 3 weeks + CP × 6 (n=434) PD*
Avastin every 3 weeks until progression
Options for first-line treatment of advanced NSCLC: what should the standard of care be?
The lung cancer epidemic in Europe* and the USA†
Men Europe New cancer cases (million) Lung cancer, n (%) Rank incidence Cancer deaths, n Lung cancer, n (%) 1.4 USA 0.7 Women Europe 1.2 70,000 (6) 4‡ 700,000 64,000 (9) USA 0.7 81,770 (12) 3‡ 270,000 72,130 (26)
Response rate and survival with singleagent, doublet and triplet chemotherapy regimens
p value No. of No. of comparisons patients Response rate 2 vs 1 agent 3 vs 2 agents 1-year survival† 2 vs 1 agent 3 vs 2 agents Median survival‡ 2 vs 1 agent 3 vs 2 agents 33 34 13 10 30 30 7,175 4,814 4,125 2,249 6,022 4,550 Ratio (95% CI)* 0.42 (0.37–0.47) 0.66 (0.58–0.75) 0.80 (0.70–0.91) 1.01 (0.85–1.21) 0.83 (0.79–0.89) 1.00 (0.94–1.06) Treatment effect <0.001 <0.001 <0.001 0.88 <0.001 0.97 Heterogeneity <0.001 0.06 0.03 0.59 <0.001 0.04 Absolute benefit (%) 13 8 5 0 NA§ NA§
PD
• Primary endpoint: overall survival • Avastin 15mg/kg i.v. every 3 weeks • Carboplatin i.v. to AUC 6mg/mL and paclitaxel 200mg/m2 i.v. every 3 weeks • Patients in the Avastin plus CP arm received single-agent Avastin until disease progression
*No cross over permitted Sandler A, et al. N Engl J Med 2006;355:2542–50
Phase III trial of Avastin in NSCLC (E4599): eligibility criteria
• Histologically or cytologically confirmed, measurable or nonmeasurable, non-squamous NSCLC • Disease must be advanced (stage IIIB with malignant pleural effusion, stage IV or recurrent disease) • Adequate haematologic, hepatic and renal function • ECOG PS 0 or 1 • No central nervous system (CNS) metastases • No anticoagulation • No history of gross haemoptysis (≥½ teaspoon)
Bray F, et al. Eur J Cancer 2002;38:99–166 Jemal A, et al. CA Cancer J Clin 2006;56:106–30
E1594: randomised trial comparing modern platinum-based chemotherapy regimens
NCCN clinical practice guidelines in oncology. Non-small cell lung cancer, version 1 2007. Available at: /professionals/physician_gls/PDF/nscl.pdf
First line
OR
Second line
Tarceva monotherapy or chemotherapy (docetaxel or pemetrexed)
Third line
Tarceva monotherapy or best supportive care
Best supportive care
*Ratio is either an odds ratio or median ratio †The two odds ratios were significantly different (p<0.001) ‡The two odds ratios were significantly different (p=0.04) §Data not possible to calculate