课件：晚期非小细胞肺癌一线化疗后的治疗策略.ppt

晚期非小细胞肺癌一线化疗后的治疗策略,安徽医科大学第一附属医院肿瘤内科 陈振东 ,什么叫晚期肺癌？ 一线化疗后可能有几种情况？ 一线化疗后的治疗有哪些选择？ ASCO：the treatment of stage 4 NCSLC,什么叫晚期肺癌？,不可手术的期 期,一线化疗后可能有几种情况？,进展 稳定、稍有缩小或难以精确测量 部分或完全缓解 发现了新病灶，但不能肯定为进展 目标病灶与非目标病灶的反应不同 化疗有效但因为医疗或非医疗的原因改变治疗,一线化疗后的治疗：不同的情况,维持治疗是指在完成标准的几个周期化疗且疾病得到控制后再接受的化疗。 理论基础：Goldie and Coldman假设，早期使用非交叉耐药的药物可以在耐药性产生前增加杀伤肿瘤细胞的效能。使治疗效果最优化，杀死更多的肿瘤细胞。 完全缓解、部分缓解或者疾病稳定的患者最有可能从维持治疗中获益。但同时也延长了治疗时间，且化疗的毒性反应可在体内蓄积，导致过度治疗。 一线化疗失败后的治疗严格意义上属于挽救治疗，但两者并没有本质区别。,一线化疗后的治疗有哪些选择？,放疗 中医药治疗及最佳支持治疗 化疗 分子靶向治疗 联合治疗,放疗,有下列情况者一般不做根治性放疗： 两肺或全身广泛转移 胸膜广泛转移有癌性胸腔积液 癌性空洞或肿瘤巨大 严重肺气肿 心包或心肌有癌瘤侵犯者 伴有感染，抗炎治疗不能控制 肝、肾功能严重受损，KPS60分者。 姑息放疗可能有价值（心理支持、老年人）,药物维持治疗,二线细胞毒药物，并非都是 单抗类靶向治疗药物 表皮生长因子受体酪氨酸蛋白激酶抑制剂 联合治疗,Pemetrexed,July 6, 2009 FDA has approved pemetrexed for the maintenance therapy of advanced or metastatic NSCLC. Pemetrexed is the first drug indicated as a maintenance therapy in this setting.,J M E N 研究，patients received either pemetrexed (n = 441) or placebo (n = 222), along with the best supportive care. Patients had advanced or metastatic (stage 3B or 4) NSCLC (both squamous and nonsquamous subtypes) that had not progressed after 4 cycles of initial platinum-based chemotherapy.,For all patients in the study, the pemetrexed treatment group had an overall survival of 13.4 months, compared with 10.6 months for the placebo group. For the nonsquamous subgroup, overall survival was 15.5 months for patients taking pemetrexed and 10.3 months for patients taking placebo (P = .002).,the trial was not designed to indicate whether maintenance therapy was superior to using pemetrexed at time of disease progression. dont think we have the answer as to when it is best to start pemetrexed. Should we start immediately after standard chemotherapy or later on?,多西紫杉醇,第一个被认可的二线治疗药物。 Fidias等，进展期NSCLC，4周期卡铂联合吉西他滨的诱导化疗后，对治疗有反应或者稳定的患者随机分成2组，一组立即接受多西他赛，另外一组于疾病进展时接受多西他赛作为挽救治疗(延迟组)。结果：立即组的总有效率高于延迟组(425 VS 99 )；中位生存时间，立即组为119个月，延迟组91个月，但无统计学意义；中位PFS，立即组为65个月显著高于延迟组28个月(P00001)，生活质量评估两组无显著性差异。,分子靶向药物：厄洛替尼,SATURN，889例一线化疗后疾病未进展的晚期NSCLC患者，随机分组后给予150 mg/d维持治疗或安慰剂，直至疾病进展。 维持治疗显著改善了患者的PFS，疾病进展风险显著降低了29%，其中EGFR免疫组化（IHC）阳性患者疾病进展风险降低31%。 无论年龄、种族、病理类型和吸烟史如何，均可从维持治疗中显著获益。 EGFR突变者疾病进展风险大幅度降低90%，野生型患者降低22%。,分子靶向药物：厄洛替尼,SATURN，维持治疗显著延迟了疼痛症状的出现，对其他各生活质量指标也无不利影响。在维持治疗组中发生率超过10%的不良反应仅有皮疹和腹泻，但达到34级的比例很低。 患者经一线化疗后仍有症状（如咯血、胸痛和胸闷等），维持治疗的价值最大。,分子靶向药物：吉非替尼,日本，WJTOG0203研究，一线化疗后疾病未进展的晚期NSCLC患者给予吉非替尼维持治疗或安慰剂，结果维持治疗组PFS有显著延长，但OS未见显著获益。但在亚组分析中，有腺癌和吸烟患者可从吉非替尼维持治疗中显著获得生存益处。,分子靶向药物与化疗效果比较,韩国李（Lee）： 313例从不吸烟、PS02分、具有足够器官功能的初治B/期肺腺癌患者，随机给予吉非替尼（250 mg，口服，每日1次）或GP方案化疗（吉西他滨1250 mg/m2，d1、d8；顺铂80 mg/m2，d1，每3周为1个周期，共3个周期）。主要终点为OS；次要终点为ORR、PFS期和毒性。初次疾病进展后，依照临床医师的推荐接受二线治疗。309例，其中女性占88.7%，期患者占90.0%，PS 2分者占9.1%。 结果：吉非替尼组ORR优于GP组（53.5%对42.0%），但无显著差异，而中位PFS（5.9个月）显著优于GP组（5.8个月，HR=0.737，P=0.0063）。,分子靶向药物与化疗合用,有待研究： EGFR突变患者应用时机 化疗与TKI的使用顺序 单药维持治疗 EGFR-TKI耐药的后续治疗 对野生型患者的作用 贝伐单抗、西妥昔单抗,J M E N 研究中安慰剂组在进展后仅有1 9 的患者使用了培美曲塞作为二线治疗。 S A T U R N 中安慰剂组只有1 6 的患者在进展后使用了厄洛替尼。,ASCO： the treatment of stage 4 NCSLC,November 24, 2009 Guidelines for using chemotherapy in have been updated by the ASCO. J Clin Oncol. Published online November 16, 2009.,2019/9/3,21,可编辑,cytotoxics in first-line treatment,The recommendations for using cytotoxics in first-line treatment have not changed, but there are several additional recommendations about the use of targeted agents.,cytotoxics in first-line treatment,For patients with a performance status of 0 or 1, a platinum-based 2-drug combination of cytotoxic drugs is recommended. For patients with a performance status of 2, single-agent chemotherapy is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. First-line chemotherapy should be stopped at disease progression, or after 4 cycles in patients not responding to treatment. Two-drug cytotoxic combinations should be administered for no more than 6 cycles.,cytotoxics in first-line treatment,Platinum compounds are preferred over nonplatinum compounds because they are superior in response rate and marginally superior in overall survival, the authors explain. The choice of either cisplatin (Platinol) or carboplatin (Paraplatin) is acceptable because neither is consistently superior, they note; cisplatin might have better efficacy but carboplatin might have less toxicity.,targeted agents in first-line treatment,New in the update are recommendations on the use of targeted agents in first-line treatment, as follows:,targeted agents in first-line treatment,The addition of bevacizumab (Avastin) to carboplatin/paclitaxel is recommended, except in patients with certain characteristics (i.e., those with squamous cell carcinoma histology, brain metastases, clinically significant hemoptysis, inadequate organ function, a performance status greater than 1, therapeutic anticoagulation, clinically significant cardiovascular disease, or medically uncontrolled hypertension).,targeted agents in first-line treatment,The addition of cetuximab (Erbitux) to cisplatin/vinorelbine can be considered in patients with tumors testing positive for epidermal growth-factor receptor (EGFR), as measured by immunohistochemistry.,targeted agents in first-line treatment,First-line gefitinib (Iressa) use can be recommended for patients with activating EGFR mutations. However, if EGFR mutation status is negative or unknown, cytotoxic chemotherapy is preferred. Erlotinib (Tarceva) or gefitinib should not be used in first-line therapy in combination with cytotoxics in unselected stage 4 NSCLC patients.,Second- and Third-Line Treatment,There has been a change in the drugs recommended for use in second-line therapy. Previously, only docetaxel (Taxotere) was recommended for use after progression on platinum-based first-line therapy, and gefitinib was recommended after a failure of both platinum-based therapies and docetaxel. Now the guidelines state that docetaxel, gefitinib, erlotinib, and pemetrexed are acceptable as second-line therapies.,Second- and Third-Line Treatment,The guideline committee notes that pemetrexed was recently approved by the US Food and Drug Administration for maintenance therapy in NSCLC, but this is based on recently presented data that were “outside the scope“ of the comprehensive data review undertaken.,Second- and Third-Line Treatment,Third-line therapy with erlotinib can be recommended for patients with a performance status of 0 to 3 who have progressed on or after second-line therapy and who have not previously received erlotinib or gefitinib. There is not enough evidence to make a recommendation for or against using a cytotoxic drug as a third-line therapy,Second- and Third-Line Treatment,There is insufficient evidence to recommend the routine use of molecular markers to select systemic treatment in patients with metastatic NSCLC.,Drug Estimated Cost for 2 Cycles of Therapy ($),Bevacizumab 14,040 Carboplatin 146 Cetuximab 18,981 Cisplatin 68 Docetaxel 5,060 Erlotinib 9,114,Gefitinib 4,255 Gemcitabine 6,914 Irinotecan 527 Paclitaxel 201 Pemetrexed 9,682 Vinorelbine 257,Drug Estimated Cost for Therapy,Most of the cancer agents ( 90%) approved by the FDA) in the past 4 years cost more than $20,000 for a 12-week course of therapy, 1.2-month survival benefit with cetuximab plus a platinum-based chemotherapy compared with chemotherapy alone was hailed as the “new standard“ for NSCLC. cetuximab for NSCLC, which costs $80,000 for an 18-week course.,Drug Estimated Cost for Therapy,bevacizumab for metastatic breast cancer provides progression-free su