小细胞肺癌是一种侵袭性非常强的肿瘤,其主要治疗方案是细胞毒化疗,尽管有较高的初始治疗缓解率,但大部分患者在一线治疗后会出现复发或进展。目前只有较少的证据证明二线治疗能给复发或晚期小细胞肺癌患者带来生存获益,指南推荐药物较多,但临床多依据经验制定方案。本研究回顾性分析小细胞肺癌患者不同二线治疗方案的疗效和安全性,以指导临床医生更客观地选择小细胞肺癌二线治疗方案。
回顾性分析了309例接受二线治疗的小细胞肺癌患者,其中157例患者进展后仅予最佳支持治疗,其余152例患者进行了二线化疗。采用
接受二线化疗的患者较二线仅接受最佳支持治疗的患者生存获益明显,两组患者自一线治疗开始的OS分别为11.5个月和6.0个月(
二线化疗可以给一线治疗失败的小细胞肺癌患者带来生存获益;不同二线化疗方案患者的近期缓解和无进展生存相似;耐药/难治型患者二线化疗采用含TPT的方案可能会给患者带来更好的总生存获益。
Small-cell lung cancer (SCLC) is an aggressive disease for which the mainstay of treatment is cytotoxic chemotherapy. Despite good initial responses most patients will relapse or progress after the first-line therapy. The evidence of a benefit from second-line chemotherapy is limited in patients with relapsed/advanced SCLC. Some drugs are recommended by guidelines, but more regimens are formulated based on experience in clinical. So we conducted this retrospective study in order to compare the efficacy and safety of different second-line treatment regimens.
We totally analyzed 309 patients received second-line treatment in our retrospective study. 157 patients received best supportive care (BSC), and the rest 152 patients received second-line chemotherapy. The
Patients administered second-line chemotherapy lived significantly longer, with a total OS from first-line therapy of 11.5 mo compared to 6.0 mo in patients with best supportive care alone (
Patients who progressed after the completion of first-line chemotherapy can gain survival benefit. The response and the PFS of the different second-line chemotherapies were similar. The patients who received the TPT-based regimen may gain longer overall survival than other resistance/refractory disease patients.
小细胞肺癌(small cell lung cancer, SCLC)占所有肺癌的10%-15%,倍增速度快,极易出现早期远处转移和获得性耐药,是一种恶性程度极高的肿瘤[
选取2010年1月-2013年12月于解放军第307医院肺部肿瘤内科住院诊治的SCLC患者。所有患者需符合以下条件:①均经细胞学或组织病理学确诊为SCLC;②年龄大于18周岁;③在治疗前经过了系统的分期检查,根据美国退伍军人肺癌研究组(Veterans Administration Lung Study Group, VALG)的标准分为局限期(limited disease, LD)与广泛期(extensive disease, ED)SCLC患者[
收集患者详细临床资料、主要的治疗相关毒性、随访时间及生存时间[总生存时间(overall survival, OS)、无进展生存时间(progression-free survival, PFS)]、疗效[完全缓解(complete response, CR)、部分缓解(partial response, PR)、稳定(stable disease, SD)、进展(progressive disease, PD)]。
对于敏感型复发的患者,二线治疗采用原一线方案或含CPT-11的方案;对于耐药/难治型复发的患者,二线治疗是不同于一线的新方案。一线方案均为顺铂或卡铂联合依托泊苷(Etoposide, VP-16)。二线方案分为4组:A组:含VP-16方案;B组:含CPT-11方案;C组:含PTX/DXL方案;D组:含TPT方案。四组中均有部分患者采用单药,部分患者采用联合卡铂或顺铂的双药方案。具体剂量:VP-16 60 mg/m2,静脉滴注,d1-d5;CPT-11 60 mg/m2-70 mg/m2,静脉滴注,d1,d8;PTX 150 mg/m2-175 mg/m2,静滴,d1;DXL 60 mg/m2-75 mg/m2,静滴,d1;TPT 0.75 mg/m2-1.2 mg/m2,d1-d5;。若联合顺铂:顺铂75 mg /m2,静滴,d1(或分3天给药);若联合卡铂:卡铂曲线下面积(area under the curve, AUC)=5-6,静滴,d1(或分3天给药)。BSC组患者可接受除特异性抗肿瘤药物以外的治疗方法,以最大限度的提高生活质量,包括营养支持、镇痛、止吐、输血、胸膜腔穿刺及为缓解症状所进行的局部姑息放射[
化疗前常规预防呕吐,化疗后出现的呕吐、血象异常及肝肾功异常等不良反应均按常规处理。本研究允许由于毒性引起的药物中断或剂量调整。
收集患者完整的临床资料;体力评分采用美国东部肿瘤协作组体力评分(Eastern Cooperative Oncology Group Performance Status, ECOG PS);所有患者均有影像学可评估的靶病灶,疗效评价依据实体肿瘤疗效评价标准1.1版(Response Evaluation Criteria in Solid Tumors, RECIST version 1.1)进行评估;不良反应按照1999年世界卫生组织(World Health Organization, WHO)抗癌药物毒性反应评定标准评价,分为0度-Ⅳ度;OS指患者开始治疗至死亡的时间(月);PFS指患者开始治疗至出现疾病进展的时间(月)。
主要研究终点为二线化疗的PFS、OS,次要研究终点为客观缓解率(objective response rate, ORR)、疾病控制率(disease control rate, DCR)和安全性分析。
采用SPSS 19.0统计软件进行数据统计分析。定性资料采用卡方检验或
309例SCLC患者均接受一线铂类联合依托泊苷化疗后出现复发或进展,其中152例进展后给予了二线方案化疗,其余157例进展后仅给予最佳支持治疗(best supportive care, BSC)。一线治疗时患者年龄为20岁-81岁,中位年龄为57岁。男性占69%(213例),广泛期患者占86%(266例),ECOG PS 0-1分的患者占77%(238例),ECOG PS 2-3分的患者占23%(71例)。
所有的入组患者均接受了铂类联合依托泊苷的一线方案化疗,其中207例(67%)接受了顺铂(cisplatin)联合依托泊苷化疗,其余103例(33%)接受了卡铂(carboplatin)联合依托泊苷化疗。一线化疗中位周期数为5.0,ORR为79%,中位PFS为6.5个月,中位OS为8.3个月。
患者一线治疗出现进展后,其中152例(49%)接受了二线化疗,其余157例(51%)仅接受了BSC。两组患者年龄结构和一线化疗中位PFS存在差异(分别为5.5个月和5.0个月,
二线化疗组与二线最佳支持治疗组患者特征
Clinical characteristics of patients who received second-line therapy with chemotherapy or BSC
Clinical characteristics | Second-line therapy | ||
Chemotherapy ( | BSC ( | ||
BSC: best supportive care; ECOG PS: Eastern Cooperative Oncology Group performance status; PFS: progression free survival. | |||
Age (yr) | < 0.001 | ||
≤60 | 98 (64.5%) | 64 (40.8%) | |
> 60 | 54 (35.5%) | 93 (59.2%) | |
Gender | 0.248 | ||
Male | 109 (71.7%) | 103 (65.6%) | |
Female | 43 (28.3%) | 54 (34.4%) | |
Smoking | 0.925 | ||
Smoker | 97 (63.8%) | 101 (64.3%) | |
Nonsmoker | 55 (36.2%) | 56 (35.7%) | |
Stage at diagnosis | 0.322 | ||
Limited disease | 23 (15.1%) | 19 (12.1%) | |
Extensive disease | 129 (84.9%) | 138 (87.9%) | |
First-line chemotherapy | 0.354 | ||
Cisplatin+etoposide | 100 (65.8%) | 111(70.7%) | |
Carboplatin+etoposide | 52 (34.2%) | 46 (29.3%) | |
Radiotherapy | 0.551 | ||
Yes | 127 (83.6%) | 135 (86.0%) | |
No | 25 (16.4%) | 22 (14.0%) | |
ECOG PS at diagnosis | 0.135 | ||
0-1 | 117 (77.0%) | 109 (69.4%) | |
2-3 | 35 (23.0%) | 48 (30.6%) | |
ECOG PS at second-line | 0.081 | ||
0-1 | 65 (14.4%) | 52 (33.1%) | |
2-3 | 87 (85.6%) | 105 (66.9%) |
二线化疗和二线BSC患者ORR分别为39.5%和5.1%,差异有统计学意义(
二线化疗组与二线最佳支持治疗组总生存曲线
152例二线接受化疗的患者,根据方案不同将其分为四组,A组35例(23%)采用含依托泊苷方案;B组56例(37%)采用含CPT-11的方案;C组32例(21%)采用含PTX/DXL的方案;D组29例(19%)采用含TPT的方案。各方案组间在年龄、性别、吸烟史、诊断时的分期、体力评分、一线方案、化疗周期数、是否联合铂类等组成上具有可比性,但A组患者一线中位PFS明显长于其他三组(
二线化疗各方案组患者临床特征
Clinical characteristics of patients who received different second-line chemotherapy regimens
Clinical characteristics | Second-line chemotherapy therapy | ||||
Group A ( | Group B ( | Group C ( | Group D ( | ||
Group A: VP-16-based rechallenge; Group B: CPT-11-based regimen; Group C: PTX/DXL-based regimen; Group D: TPT-based regimen. | |||||
Age (yr) | 0.985 | ||||
≤60 | 23 (65.7%) | 35 (62.5%) | 21 (65.6%) | 19 (37.9%) | |
> 60 | 12 (34.3%) | 21 (37.5%) | 11 (34.4%) | 10 (62.1%) | |
Gender | 0.723 | ||||
Male | 24 (68.6%) | 38 (67.8%) | 23 (71.9%) | 17 (58.6%) | |
Female | 11 (31.4%) | 18 (32.2%) | 9 (28.1%) | 12 (41.4%) | |
Smoking | 0.290 | ||||
Smoker | 22 (62.9%) | 36 (64.3%) | 21 (65.6%) | 13 (79.3%) | |
Nonsmoker | 13 (37.1%) | 20 (35.7%) | 11 (34.4%) | 16 (20.7%) | |
Stage at diagnosis | 0.557 | ||||
Limited disease | 7 (20.0%) | 8 (14.3%) | 3 (9.3%) | 6 (20.7%) | |
Extensive disease | 28 (80.0%) | 48 (85.7%) | 29 (90.7%) | 23 (79.3%) | |
First-line chemotherapy | 0.983 | ||||
Cisplatin+etoposide | 21 (60.0%) | 35 (62.5%) | 20 (62.5%) | 17 (58.6%) | |
Carboplatin+etoposide | 14 (40.0%) | 21 (37.5%) | 12 (37.5%) | 12 (41.4%) | |
ECOG PS at diagnosis | 0.722 | ||||
0-1 | 27 (77.1%) | 40 (71.4%) | 26 (81.4%) | 23 (79.3%) | |
2-3 | 8 (22.9%) | 16 (28.6%) | 6 (18.6%) | 6 (20.7%) | |
Median PFS at 1st-line (mo) | 8.0 | 5.0 | 4.5 | 5.5 | < 0.001 |
ECOG PS at 2nd-line | 0.338 | ||||
0-1 | 22 (62.9%) | 25 (44.6%) | 15 (46.9%) | 13 (44.8%) | |
2-3 | 13 (37.1%) | 31 (55.4%) | 17 (53.1%) | 16 (55.2%) | |
No. of courses at 2nd-line | 0.870 | ||||
≤4 | 15 (42.9%) | 26 (46.4%) | 16 (50.0%) | 14 (48.3%) | |
5-6 | 20 (57.1%) | 30 (53.6%) | 16 (50.0%) | 15 (51.7%) | |
With platinum at 2nd-line | 0.141 | ||||
Yes | 29 (82.9%) | 51 (91.1%) | 28 (87.5%) | 21 (72.4%) | |
No | 6 (17.1%) | 5 (8.9%) | 4 (12.5%) | 8 (27.6%) |
所有二线化疗患者其二线化疗中位PFS为3.3个月,二线化疗中位OS为5.3个月。对于不同二线方案的疗效和生存分析,为规避复发类型不同所带来的影响,本研究将所有二线化疗患者分为敏感型复发和耐药/难治型复发分别分析(
不同复发类型小细胞肺癌患者不同二线方案的ORR、DCR、PFS、OS
ORR, DCR, Median PFS, Median OS in months for sensitive disease patients or resistance/refractory disease patients after different second-line regimens
Item | Sensitive disease ( | Resistance/refractory disease ( | ||||||
Group A ( | Group B1 ( | Group B2 ( | Group C ( | Group D ( | ||||
CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease; ORR: objective response rate; DCR: disease control rate; OS: overall survival. | ||||||||
CR | 1 (2.9%) | 2 (5.9%) | - | 0 (0%) | 0 (0%) | 1 (3.4%) | - | |
PR | 16 (45.7%) | 10 (29.4%) | - | 6 (27.3%) | 10 (31.3%) | 11 (37.9%) | - | |
SD | 7 (20.0%) | 8 (23.5%) | - | 5 (22.7%) | 8 (25.0%) | 6 (20.7%) | - | |
PD | 11 (31.4%) | 14 (41.2%) | - | 11 (50.0%) | 14 (43.8%) | 11 (37.9%) | - | |
ORR | 48.6% | 35.3% | 0.264 | 27.3% | 31.3% | 41.4% | 0.533 | |
DCR | 68.6% | 58.8% | 0.400 | 50.0% | 56.3% | 62.1% | 0.689 | |
PFS (mo) | 4.0 | 3.0 | 0.432 | 2.6 | 3.0 | 3.0 | 0.775 | |
OS (mo) | 6.5 | 4.5 | 0.508 | 3.8 | 4.5 | 5.3 | 0.056 |
SCLC敏感复发患者二线不同化疗方案生存曲线。A:PFS比较;B:OS比较
SCLC耐药/难治复发患者二线不同化疗方案OS曲线
同时我们将二线化疗的近期疗效同一线化疗的近期疗效做了相关性分析,发现两者呈正相关(
小细胞肺癌患者二线化疗的反应与一线化疗的关系
Correlation between response to first- and second-line chemotherapy
Response to first-line | Response to second-line | ||||
CR | PR | SD | PD | Not evaluable | |
CR | 2 (13.3%) | 6 (40.0%) | 5 (33.3%) | 1 (6.7%) | 1 (6.7%) |
PR | 0 (0) | 49 (53.8%) | 35 (38.5%) | 5 (5.5%) | 2 (2.2%) |
SD | 0 (0) | 1 (3.7%) | 13 (48.1%) | 12 (44.4%) | 1 (3.7%) |
PD | 0 (0) | 2 (10.5%) | 6 (31.6%) | 11 (57.9%) | 0 (0) |
所有二线化疗患者未出现治疗相关性死亡事件。121例(79.6%)二线化疗患者在治疗过程中出现毒副反应,其中最常见的血液学毒性为白细胞减少症和贫血,Ⅲ度-Ⅳ度白细胞减少症和贫血发生率分别为32.4%和22.6%,Ⅲ度-Ⅳ度血小板减少的发生率为17.7%,四组患者Ⅲ度-Ⅳ度血液学毒性并无差异(
不同二线方案组间的Ⅲ度-Ⅳ度不良反应
Grade Ⅲ-Ⅳ toxicities in 152 patients receiving second-line chemotherapy
Toxicity | Group A | Group B | Group C | Group D | |
ALT: alanine transaminase; AST: aspartate transaminase. | |||||
Hematologic | |||||
Leukopenia | 12 (34.3%) | 23 (41.1%) | 15 (46.9%) | 9 (31.0%) | 0.565 |
Anemia | 9 (25.7%) | 14 (25.0%) | 6 (18.8%) | 5 (17.2%) | 0.770 |
Thrombocytopenia | 7 (20.0%) | 12 (21.4%) | 5 (15.6%) | 3 (10.3%) | 0.609 |
Non-hematologic | |||||
Fatigue | 18 (51.4%) | 22 (39.2%) | 13 (40.6%) | 10 (34.5%) | 0.545 |
Nausea or vomiting | 14 (40.0%) | 18 (32.1%) | 9 (28.1%) | 7 (24.1%) | 0.557 |
Diarrhea | 9 (25.7%) | 25 (44.6%) | 5 (15.6%) | 8 (27.6%) | 0.029 |
ALT increased | 4 (11.4%) | 8 (14.3%) | 4 (12.5%) | 3 (10.3%) | 0.956 |
AST increased | 4 (11.4%) | 7 (12.5%) | 3 (9.4%) | 4 (13.8%) | 0.956 |
二线化疗进展后有52例患者(34.2%)接受了三线化疗。这其中接受四线以及四线以上治疗的患者仅有12例(7.9%)。接受了三线以上化疗的这部分患者,其二线化疗的ORR为38%,其二线化疗的中位PFS、中位OS分别为3.0个月和5.5个月,与接受二线化疗的所有患者无统计学差异。
美国国家癌症网络(National Comprehensive Cancer Network, NCCN)小细胞肺癌指南(2014.V2)对于复发或晚期的SCLC二线治疗,推荐包括托泊替康、紫杉醇、多西紫杉醇、伊立替康、长春瑞滨、吉西他滨、异环磷酰胺、替莫唑胺、依托泊苷口服剂型等多种联合或单药化疗,但仅推荐托泊替康为1类证据,这是基于两项Ⅲ期临床试验得出的[
本研究主要目的为通过对真实临床实践中SCLC病例的回顾性分析,探讨经一线标准方案治疗后出现复发或进展的SCLC患者的二线治疗情况,从而为临床治疗提供参考。主要研究终点为二线化疗的PFS、OS,次要研究终点为ORR、DCR和安全性分析。
我们首先比较二线采取化疗和BSC的患者之间的生存差异,结果表明SCLC患者一线治疗失败后,采取二线化疗可以给患者带来生存获益(median OS: 11.5 months
对于二线采取化疗的患者,我们分析了其PFS、OS、ORR和DCR。这部分患者二线化疗总体的ORR为39.5%,总体DCR为59.2%,符合文献报道的7%-73%[
本研究所有接受二线化疗患者的二线PFS和OS分别为3.3个月和5.3个月,这与国外已发表的文献[
二线化疗最常见的血液学毒性为白细胞减少症和贫血,最常见的非血液学毒性为乏力。四个方案组患者二线化疗的Ⅲ度-Ⅳ度血液学毒性发生率接近;在胃肠道反应方面,采用含CPT-11组的患者的迟发型腹泻发生率高于其他三组,表明采用该方案时需密切关注对腹泻的控制。
本研究虽为单中心回顾性研究,但也有其优势,比如在患者的来源、治疗方案的实施和疗效评估、副反应处理等方面均存在较好的一致性。通过对不同二线治疗方案的ORR、DCR、PFS和OS,以及毒副反应等进行分析,表明二线化疗可以给一线治疗失败的SCLC患者带来生存获益,其在SCLC二线治疗中具有重要地位;并且初步提示SCLC二线化疗各方案疗效和生存获益相似,采用含TPT的方案可能会给患者带来更好的总生存获益。我们期待更多中心及更多患者纳入分析,以进一步验证研究结果,并进行多中心、前瞻性的科学研究来说明SCLC二线化疗的最佳方案选择。