11

IV期NSCLC的治疗

40%的新诊断非小细胞肺癌(NSCLC)患者为 IV期肿瘤。治疗目的是延长生存时间与控制疾病相关症状。治疗选择包括细胞毒性药物化疗和靶向药物。影响治疗选择的因素包括合并症、身体状况评分(PS)、肿瘤的组织学和分子遗传学特征。放疗和手术常用于缓解某些患者的症状。

IV期NSCLC的标准治疗选择

IV期NSCLC​的标准治疗选择包括:

在身体状况评分良好的IV期肿瘤患者中开展的随机对照临床试验发现含顺铂化疗改善患者生存并可缓解疾病相关症状[5]。[ 证据等级:1iiA]紫杉醇与卡铂化疗联合贝伐单抗可能有助于使组织学非鳞状细胞、身体状况评分良好、无咯血或其他出血性疾病病史且近期亦无心血管事件的患者获益。以EGFR酪氨酸激酶抑制剂取代一线或二线化疗可能有助于使携带EGFR突变的肿瘤患者,尤其是东亚患者、从未吸烟者与腺癌患者获益。多西他赛、培美曲塞或埃罗替尼也改善身体状况评分良好患者的生存[5]。[ 证据等级:1iiA​]尚不明确化疗对身体状况评分较差患者的作用。

细胞毒性药物联合化疗(一线)

多项随机临床试验与荟萃分析曾深入评估过用于治疗晚期NSCLC患者的化疗药类型与剂量。

一些随机临床试验评估过不同的药物联合顺铂或卡铂对初治晚期NSCLC患者的作用。基于这些试验的荟萃分析,可得到下列结论:

添加靶向药物的某些三药联合治疗可能改善生存。

EGFR抑制剂可能使某些携带EGFR突变的患者获益。

4周期铂类联合化疗后行维持化疗可能延长无进展生存时间(PFS)。

铂类联合长春瑞滨、紫杉醇、多西他赛、吉西他滨、伊立替康与培美曲塞联合化疗改善生存率的效果相似,但毒性反应的类别和发生率各异,进行患者个体化治疗方案选择时需考虑这些因素。腺癌患者可能受益于培美曲塞。

顺铂与卡铂改善预后的效果相似,但毒性反应不同。一些(而非所有)临床试验与荟萃分析发现顺铂可能更优,尽管顺铂的毒性反应如恶心、呕吐等的发生率也较高。

非铂类联合化疗与含铂类化疗相比无更多优势,一些研究甚至认为其劣于后者。

常见化疗药的三药联合化疗与两药联合化疗相比并不进一步提高生存率,毒性却更大。

证据(联合化疗):

在有效的联合化疗中,除了培美曲塞治疗肺腺癌之外,无法明确地推荐其他药物剂量及方案。

证据(药物及剂量方案):

化疗联合贝伐单抗或西妥昔单抗

证据(化疗联合贝伐单抗或西妥昔单抗):

EGFR酪氨酸激酶抑制剂(一线)

某些患者可能获益于EGFR酪氨酸激酶抑制剂单药治疗。在未行过化疗的携带EGFR突变的NSCLC患者中开展的随机对照临床试验显示EGFR抑制剂与联合化疗相比,提高PFS,但不提高OS,毒性反应优于联合化疗。

证据(EGFR酪氨酸激酶抑制剂):

上述试验证实,吉非替尼或厄洛替尼等EGFR酪氨酸激酶抑制剂治疗初治东亚非吸烟或少量吸烟肺腺癌患者的效果优于含铂类联合化疗。这些结果可能也适用于非亚洲人群。

一线化疗后的维持治疗

在NSCLC中被广泛研究的一种治疗策略为对化疗有初始反应后的维持治疗。曾被研究过的维持治疗包括:

继续初始联合化疗方案。

继续单药化疗。

使用新药作为“维持治疗”。

很多随机临床试验评估了继续沿用一线联合细胞毒性化疗药超过3-4程的效果。

证据(一线化疗后的维持治疗):

这些数据均提示,继续有效化疗至4程以上或立即换用其他化疗可能延长PFS但并不影响OS。但增加细胞毒性化疗疗程后,PFS延长的同时伴随不良事件发生率升高,且患者生活质量改善情况不一。对病情稳定、对一线治疗有反应的患者,当前证据并不支持在疾病进展前继续使用细胞毒性化疗,或在疾病进展前开始其他化疗。这些试验均提示一线细胞毒性联合化疗应在疾病进展时或治疗后不缓解的患者用到4程后停用,总疗程数应不超过6程[42][43][45][46]

证据(一线含铂类联合化疗后应用培美曲塞):

证据(含铂类双药化疗后厄洛替尼维持治疗):

放疗

气管、食管或支气管压迫。

疼痛。

声带麻痹。

咯血。

上腔静脉综合征。 

有时可用经支气管镜激光治疗和(或)近距离放射治疗缓解近端梗阻性病变[1]

虽然EBRT常用于缓解治疗,但何时使用分割方案尚无共识。不同的多次分割方案缓解症状的效果似乎相似[52][53][54][55][56][57],但NCIC临床试验分组试验( NCT00003685)结果表明相较于大分割或标准方案,单次分割治疗缓解症状的效果不佳[2]。[ 证据等级:1iiC]有研究发现身体状况评分较佳的患者行大剂量EBRT后生存率略增加[4][58]。[ 证据等级:1iiA]对于密切观察中的无症状患者,治疗通常适当推迟到肿瘤进展产生症状或体征时再进行。

证据(放疗):

处于临床评估阶段的治疗选择

处于临床评估阶段的治疗选择包括:

目前开展的临床试验

现招募 IV期非小细胞肺癌​患者的美国临床试验请参见美国NCI癌症临床试验列表,可根据部位、药物、干预或其他标准进行筛选。

NCI网站提供关于临床试验的基本信息。 

参考文献

1. Miller JI Jr, Phillips TW: Neodymium:YAG laser and brachytherapy in the management of inoperable bronchogenic carcinoma. Ann Thorac Surg 50 (2): 190-5; discussion 195-6, 1990.[PUBMED Abstract]

2. Bezjak A, Dixon P, Brundage M, et al.: Randomized phase III trial of single versus fractionated thoracic radiation in the palliation of patients with lung cancer (NCIC CTG SC.15). Int J Radiat Oncol Biol Phys 54 (3): 719-28, 2002.[PUBMED Abstract]

3. Macbeth F, Toy E, Coles B, et al.: Palliative radiotherapy regimens for non-small cell lung cancer. Cochrane Database Syst Rev (3): CD002143, 2001.[PUBMED Abstract]

4. Sundstrøm S, Bremnes R, Aasebø U, et al.: Hypofractionated palliative radiotherapy (17 Gy per two fractions) in advanced non-small-cell lung carcinoma is comparable to standard fractionation for symptom control and survival: a national phase III trial. J Clin Oncol 22 (5): 801-10, 2004.[PUBMED Abstract]

5. Weick JK, Crowley J, Natale RB, et al.: A randomized trial of five cisplatin-containing treatments in patients with metastatic non-small-cell lung cancer: a Southwest Oncology Group study. J Clin Oncol 9 (7): 1157-62, 1991.[PUBMED Abstract]

6. Delbaldo C, Michiels S, Rolland E, et al.: Second or third additional chemotherapy drug for non-small cell lung cancer in patients with advanced disease. Cochrane Database Syst Rev (4): CD004569, 2007.[PUBMED Abstract]

7. Ardizzoni A, Boni L, Tiseo M, et al.: Cisplatin- versus carboplatin-based chemotherapy in first-line treatment of advanced non-small-cell lung cancer: an individual patient data meta-analysis. J Natl Cancer Inst 99 (11): 847-57, 2007.[PUBMED Abstract]

8. Jiang J, Liang X, Zhou X, et al.: A meta-analysis of randomized controlled trials comparing carboplatin-based to cisplatin-based chemotherapy in advanced non-small cell lung cancer. Lung Cancer 57 (3): 348-58, 2007.[PUBMED Abstract]

9. Hotta K, Matsuo K, Ueoka H, et al.: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22 (19): 3852-9, 2004.[PUBMED Abstract]

10. D'Addario G, Pintilie M, Leighl NB, et al.: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23 (13): 2926-36, 2005.[PUBMED Abstract]

11. Rajeswaran A, Trojan A, Burnand B, et al.: Efficacy and side effects of cisplatin- and carboplatin-based doublet chemotherapeutic regimens versus non-platinum-based doublet chemotherapeutic regimens as first line treatment of metastatic non-small cell lung carcinoma: a systematic review of randomized controlled trials. Lung Cancer 59 (1): 1-11, 2008.[PUBMED Abstract]

12. Pujol JL, Barlesi F, Daurès JP: Should chemotherapy combinations for advanced non-small cell lung cancer be platinum-based? A meta-analysis of phase III randomized trials. Lung Cancer 51 (3): 335-45, 2006.[PUBMED Abstract]

13. Douillard JY, Laporte S, Fossella F, et al.: Comparison of docetaxel- and vinca alkaloid-based chemotherapy in the first-line treatment of advanced non-small cell lung cancer: a meta-analysis of seven randomized clinical trials. J Thorac Oncol 2 (10): 939-46, 2007.[PUBMED Abstract]

14. Belani CP, Ramalingam S, Perry MC, et al.: Randomized, phase III study of weekly paclitaxel in combination with carboplatin versus standard every-3-weeks administration of carboplatin and paclitaxel for patients with previously untreated advanced non-small-cell lung cancer. J Clin Oncol 26 (3): 468-73, 2008.[PUBMED Abstract]

15. Schuette W, Blankenburg T, Guschall W, et al.: Multicenter randomized trial for stage IIIB/IV non-small-cell lung cancer using every-3-week versus weekly paclitaxel/carboplatin. Clin Lung Cancer 7 (5): 338-43, 2006.[PUBMED Abstract]

16. Scagliotti GV, Parikh P, von Pawel J, et al.: Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26 (21): 3543-51, 2008.[PUBMED Abstract]

17. Langer CJ, Vangel M, Schiller J, et al.: Age-specific subanalysis of ECOG 1594: fit elderly patients (70-80 YRS) with NSCLC do as well as younger pts (<70). [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-2571, 2003.

18. Langer CJ, Manola J, Bernardo P, et al.: Cisplatin-based therapy for elderly patients with advanced non-small-cell lung cancer: implications of Eastern Cooperative Oncology Group 5592, a randomized trial. J Natl Cancer Inst 94 (3): 173-81, 2002.[PUBMED Abstract]

19. Ries LA: Influence of extent of disease, histology, and demographic factors on lung cancer survival in the SEER population-based data. Semin Surg Oncol 10 (1): 21-30, 1994 Jan-Feb.[PUBMED Abstract]

20. Ramsey SD, Howlader N, Etzioni RD, et al.: Chemotherapy use, outcomes, and costs for older persons with advanced non-small-cell lung cancer: evidence from surveillance, epidemiology and end results-Medicare. J Clin Oncol 22 (24): 4971-8, 2004.[PUBMED Abstract]

21. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91 (1): 66-72, 1999.[PUBMED Abstract]

22. Takeda K, Kudoh S, Nakagawa K, et al.: Randomized phase III study of docetaxel (D) versus vinorelbine (V) for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): Results of a West Japan Thoracic Oncology Group trial (WJTOG9904). [Abstract] J Clin Oncol 23 (Suppl 16): A-7009, 2005.

23. Schiller JH, Harrington D, Belani CP, et al.: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 346 (2): 92-8, 2002.[PUBMED Abstract]

24. Belani CP, Fossella F: Elderly subgroup analysis of a randomized phase III study of docetaxel plus platinum combinations versus vinorelbine plus cisplatin for first-line treatment of advanced nonsmall cell lung carcinoma (TAX 326). Cancer 104 (12): 2766-74, 2005.[PUBMED Abstract]

25. Lilenbaum RC, Herndon JE 2nd, List MA, et al.: Single-agent versus combination chemotherapy in advanced non-small-cell lung cancer: the cancer and leukemia group B (study 9730). J Clin Oncol 23 (1): 190-6, 2005.[PUBMED Abstract]

26. Hensing TA, Peterman AH, Schell MJ, et al.: The impact of age on toxicity, response rate, quality of life, and survival in patients with advanced, Stage IIIB or IV nonsmall cell lung carcinoma treated with carboplatin and paclitaxel. Cancer 98 (4): 779-88, 2003.[PUBMED Abstract]

27. Sweeney CJ, Zhu J, Sandler AB, et al.: Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma . Cancer 92 (10): 2639-47, 2001.[PUBMED Abstract]

28. Tester WJ, Stephenson P, Langer CJ, et al.: ECOG 1599: randomized phase II study of paclitaxel/carboplatin or gemcitabine/cisplatin in performance status (PS) 2 patients with advanced non-small cell lung cancer (NSCLC). [Abstract] J Clin Oncol 22 (Suppl 14): A-7055, 630s, 2004.

29. Vansteenkiste JF, Vandebroek JE, Nackaerts KL, et al.: Clinical-benefit response in advanced non-small-cell lung cancer: A multicentre prospective randomised phase III study of single agent gemcitabine versus cisplatin-vindesine. Ann Oncol 12 (9): 1221-30, 2001.[PUBMED Abstract]

30. Hickish TF, Smith IE, O'Brien ME, et al.: Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends to the elderly and those with poor prognostic factors. Br J Cancer 78 (1): 28-33, 1998.[PUBMED Abstract]

31. Sandler A, Gray R, Perry MC, et al.: Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355 (24): 2542-50, 2006.[PUBMED Abstract]

32. Reck M, von Pawel J, Zatloukal P, et al.: Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. J Clin Oncol 27 (8): 1227-34, 2009.[PUBMED Abstract]

33. Lynch TJ, Patel T, Dreisbach L, et al.: Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 28 (6): 911-7, 2010.[PUBMED Abstract]

34. Pirker R, Pereira JR, Szczesna A, et al.: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 373 (9674): 1525-31, 2009.[PUBMED Abstract]

35. Khambata-Ford S, Harbison CT, Hart LL, et al.: Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 28 (6): 918-27, 2010.[PUBMED Abstract]

36. Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361 (10): 947-57, 2009.[PUBMED Abstract]

37. Maemondo M, Inoue A, Kobayashi K, et al.: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362 (25): 2380-8, 2010.[PUBMED Abstract]

38. Mitsudomi T, Morita S, Yatabe Y, et al.: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol 11 (2): 121-8, 2010.[PUBMED Abstract]

39. Zhou C, Wu YL, Chen G, et al.: Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutat 非小细胞肺癌的治疗–专业版 (PDQ®)