IB期肺腺癌患者辅助治疗方案的筛选

doi:10.12122/j.issn.1673-4254.2024.05.22

摘要/Abstract

摘要：

目的探索ⅠB期肺腺癌患者的辅助治疗方案。方法收集2013年1月~2021年12月在我院行手术治疗的IB期肺腺癌患者，根据术后不同辅助治疗模式分为辅助靶向治疗组（EGFR-TKIs）、辅助化疗组（CT）和临床观察组（CO）。对比3组患者的临床资料和随访结果，无疾病生存期、总生存的分析采用Kaplan-Meier法并行log-rank检验，COX回归分析患者无疾病生存期（DFS）的预测因素。主要研究终点是5年DFS率，次要研究终点为DFS、3年总生存期（OS）以及辅助治疗的安全性。结果共纳入653例术后诊断为IB期肺腺癌患者，其中EGFR-TKIs组111例，CT组108例，CO组434例。中位随访时间43个月，TKIs组、CT组和CO组的5年DFS率分别为92.8%、80.7%及81.7%，TKIs组的5年DFS率显著高于CO组（P<0.01）。TKIs组、CT组和CO组的3年OS均无统计学差异。亚组分析显示，T3~4 cmN0M0中TKIs组、CT组和CO组的5年DFS率分别为92.6%、84.0%及81.4%，TKIs组的5年DFS率显著高于CO组（P<0.05），3组间的3年OS无统计学差异。而T2ViscPlN0M0中TKIs组、CT组和CO组的5年DFS率分别为95.1%、71.4%及83.5%，组间差异并无统计学意义，3组间的3年OS亦无统计学差异。多因素COX回归分析结果显示，年龄（P<0.05；HR 0.631，95% CI 0.401-0.993）、实性结节（P<0.01；HR 7.620，95% CI 3.037-19.121）、微乳头/实性成分（P<0.05；HR 1.776，95% CI 1.010-3.122）、脉管癌栓（P<0.05；HR 2.981，95% CI 1.198-7.419）及辅助治疗（P<0.01）是DFS的独立预测因素。安全性方面，皮疹、甲沟炎及腹泻仍然是靶向药物最常见的不良反应。化疗组不良反应主要为血液系统的抑制和胃肠道反应，3级以上不良反应率高于TKIs组（44.4% vs 9.0%）。结论辅助靶向治疗有助于提高T3~4 cmN0M0的IB期肺腺癌患者的DFS，但T2ViscPlN0M0患者并不能从靶向治疗中获益。辅助化疗并不能改善IB期肺腺癌患者的DFS和OS。

关键词: IB期, 肺腺癌, 辅助化疗, EGFR突变, 靶向治疗, 无疾病生存期

Abstract:

Objective To explore the optimal postoperative adjuvant regimens for patients with stage IB lung adenocarcinoma. Methods We respectively analyzed the data of 653 patients undergoing surgery for stage IB lung adenocarcinoma in our hospital from January, 2013 to December, 2021. The 5-year disease-free survival (DFS) and overall survival (OS) rates were compared among the patients receiving postoperative adjuvant therapy with epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs group, n=111), chemotherapy (CT group, n=108) and clinical observation (CO group, n=434). Results In TKIs, CT, and CO groups, the 5-year DFS rates were 92.8%, 80.7%, and 81.7%, respectively, significantly higher in TKIs group than in CO group (P<0.01). The 3-year OS rates of the 3 groups were 96.8%, 97.1%, and 91.7%, respectively. Subgroup analysis showed that in TKIs, CT, and CO groups, the 5-year DFS rates of patients with with T3-4 cmN0M0 were 92.6%, 84.0%, and 81.4%, respectively, significantly higher in TKIs group than in CO group (P<0.05); the 5-year DFS rates of T2ViscPlN0M0 patients were 95.1%, 71.4%, and 83.5%, respectively. Multivariate COX regression analysis showed that age (P<0.05; HR=0.631, 95% CI: 0.401-0.993), solid nodules (P<0.01; HR=7.620, 95% CI: 3.037-19.121), micropapillary or solid component (P<0.05; HR=1.776, 95% CI: 1.010-3.122), lymphovascular invasion (P<0.05; HR=2.981, 95% CI: 1.198-7.419), and adjuvant therapy (P<0.01) were independent predictors of DFS. The most common adverse effects included rashes, paronychia, and diarrhea for TKIs and hematological suppression and gastrointestinal reactions for chemotherapy, and TKIs were associated with a higher incidence of grade 3 or above adverse effects (44.4% vs 9.0%). Conclusion Adjuvant therapy with TKIs helps improve DFS in patients with stage IB (T3-4cmN0M0) lung adenocarcinoma but not in patients with T2ViscPlN0M0. Adjuvant chemotherapy does not improve DFS or OS in patients with stage IB lung adenocarcinoma.

Key words: stage IB, lung adenocarcinoma, adjuvant chemotherapy, epidermal growth factor receptor mutation, targeted therapy, disease-free survival

申磊磊, 陈莹, 云天洋, 郭俊唐, 柳曦, 张涛, 梁朝阳, 刘阳. IB期肺腺癌患者辅助治疗方案的筛选[J]. 南方医科大学学报, 2024, 44(5): 989-997.

Leilei SHEN, Ying CHEN, Tianyang YUN, Juntang GUO, Xi LIU, Tao ZHANG, Chaoyang LIANG, Yang LIU. Selection of postoperative adjuvant therapy for patients with stage IB lung adenocarcinoma: analysis of 653 cases[J]. Journal of Southern Medical University, 2024, 44(5): 989-997.

图/表 10

参考文献 35

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Characteristic No.	TKIs group (n=111)	CT group (n=108)	CO group (n=434)	P
Gender				0.003
Male	38 (34.2)* ^#	57 (52.8)	226 (52.1)
Female	73 (65.8)* ^#	51 (47.2)	208 (47.9)
Age (year)	60.66±9.05*	57.45±9.07 ^#	61.08±8.95	0.001
≤65	72 (64.9)*	88 (81.5) ^#	287 (66.1)	0.006
>65	39 (35.1)*	20 (18.5) ^#	147 (33.9)	0.006
Smoking history	26 (23.4)	40 (37.0)	135 (31.1)	0.091
Family history of lung cancer	16 (14.4)	12 (11.1)	47 (10.8)	0.584
CEA abnormality	18 (16.2) ^#	9 (8.3)	33 (7.6)	0.019
Diabetes mellitus	7 (6.3)	7 (6.5)	51 (11.8)	0.096
Hypertension	31 (27.9)	22 (20.4)	121 (27.9)	0.280
Cardiovascular disease	8 (7.2)	5 (4.6)	26 (6.0)	0.687
Cerebrovascular disease	4 (3.6)	2 (1.9)	14 (3.2)	0.797
PET-CT	8.00 (3.60, 10.00)	6.85 (3.13, 9.00)	4.85 (2.20, 8.60)	0.175
Tumor location				0.154
RUL	34 (30.6)	34 (31.5)	139 (32.0)
RML	14 (12.6)	5 (4.6)	31 (7.1)
RLL	11(9.9)	22 (20.4)	79 (18.2)
LUL	30 (27.0)	32 (29.6)	104 (24.0)
LLL	22 (19.8)	15 (13.9)	81 (18.78)
CTR	1 (1, 1)	1 (1, 1)	1 (0.87, 1)	0.105
Solid nodule	71 (64.0)	81 (75.0) ^#	271 (62.4)	0.049
Surgical procedure				0.412
Sublobectomy	15 (13.5)	9 (8.3)	43 (9.9)
Lobectomy	96 (86.5)	99 (91.7)	391 (90.1)
LND
Stations	5 (5, 6)	5.5 (3.25, 6)	5 (4, 6)	0.859
Numbers	9 (6, 16)	9.5 (4.5, 16)	10 (7, 16)	0.507
pNx	30 (27.0)	30 (27.8)	114 (26.3)	0.956

Characteristic No.	TKIs group (n=111)	CT group (n=108)	CO group (n=434)	P
Gender				0.003
Male	38 (34.2)* ^#	57 (52.8)	226 (52.1)
Female	73 (65.8)* ^#	51 (47.2)	208 (47.9)
Age (year)	60.66±9.05*	57.45±9.07 ^#	61.08±8.95	0.001
≤65	72 (64.9)*	88 (81.5) ^#	287 (66.1)	0.006
>65	39 (35.1)*	20 (18.5) ^#	147 (33.9)	0.006
Smoking history	26 (23.4)	40 (37.0)	135 (31.1)	0.091
Family history of lung cancer	16 (14.4)	12 (11.1)	47 (10.8)	0.584
CEA abnormality	18 (16.2) ^#	9 (8.3)	33 (7.6)	0.019
Diabetes mellitus	7 (6.3)	7 (6.5)	51 (11.8)	0.096
Hypertension	31 (27.9)	22 (20.4)	121 (27.9)	0.280
Cardiovascular disease	8 (7.2)	5 (4.6)	26 (6.0)	0.687
Cerebrovascular disease	4 (3.6)	2 (1.9)	14 (3.2)	0.797
PET-CT	8.00 (3.60, 10.00)	6.85 (3.13, 9.00)	4.85 (2.20, 8.60)	0.175
Tumor location				0.154
RUL	34 (30.6)	34 (31.5)	139 (32.0)
RML	14 (12.6)	5 (4.6)	31 (7.1)
RLL	11(9.9)	22 (20.4)	79 (18.2)
LUL	30 (27.0)	32 (29.6)	104 (24.0)
LLL	22 (19.8)	15 (13.9)	81 (18.78)
CTR	1 (1, 1)	1 (1, 1)	1 (0.87, 1)	0.105
Solid nodule	71 (64.0)	81 (75.0) ^#	271 (62.4)	0.049
Surgical procedure				0.412
Sublobectomy	15 (13.5)	9 (8.3)	43 (9.9)
Lobectomy	96 (86.5)	99 (91.7)	391 (90.1)
LND
Stations	5 (5, 6)	5.5 (3.25, 6)	5 (4, 6)	0.859
Numbers	9 (6, 16)	9.5 (4.5, 16)	10 (7, 16)	0.507
pNx	30 (27.0)	30 (27.8)	114 (26.3)	0.956

Characteristic	TKIs group (n=111)	CT group (n=108)	CO group (n=434)	P
Tumor diameter(mm)	30.89±5.87	32.10±6.23 ^#	29.74±5.80	0.001
>3 cm	68 (61.3)	75 (69.4)	260 (59.9)	0.192
≤3 cm	43 (38.7)	33 (30.6)	174 (40.1)	0.192
≥1 high-risk factors	105 (94.6)	102 (94.4)	397 (91.5)	0.389
Mucous component	8 (7.2)	11 (10.3)	35 (8.1)	0.706
Micropapillary or solid component	50(45.0)*	67 (62.0) ^#	154 (35.5)	<0.001
VPI	82 (73.9)	88 (81.5)	333 (76.7)	0.397
LVI	7 (6.3) ^#	9 (8.3) ^#	7 (1.6)	<0.001
STAS	12 (10.8) ^#	11 (10.2) ^#	19 (4.4)	0.011
Ki-67 index(≥20%)	36 (42.9)	40 (44.9)	120 (36.8)	0.289
EGFR mutation	111 (100)* ^#	18/44 (40.9) ^#	78/110 (70.9)	<0.001
19 del	52/111 (46.8)	5/18 (27.8)	31/78 (39.7)	-
21 L858R	58/111 (52.2)	8/18 (44.4)	41/78 (52.5)	-
20 T790M/20 ins	0/0	0/3	1/2	-
G719X/S861I/L861Q	1/0/0	1/0/1	1/1/1	-
ALK mutation	0* ^#	4/40 (10)	9/101 (8.9)	0.011
KRAS mutation	1/48 (2.0)	4/37 (10.8)	7/88 (7.9)	0.252
TP53 mutation	9/26 (34.6)	8/20 (40)	15/46 (32.6)	0.893
PD-L1	0 (0, 5)	1.5 (0, 5)	0 (0, 3)	0.240
IASLC grade				0.002
1	9 (8.1) ^#	4 (3.7) ^#	23 (5.3)
2	66 (59.5) ^#	50 (46.3) ^#	280 (64.5)
3	36 (32.4) ^#	54 (50.0) ^#	131 (30.2)

Characteristic	TKIs group (n=111)	CT group (n=108)	CO group (n=434)	P
Tumor diameter(mm)	30.89±5.87	32.10±6.23 ^#	29.74±5.80	0.001
>3 cm	68 (61.3)	75 (69.4)	260 (59.9)	0.192
≤3 cm	43 (38.7)	33 (30.6)	174 (40.1)	0.192
≥1 high-risk factors	105 (94.6)	102 (94.4)	397 (91.5)	0.389
Mucous component	8 (7.2)	11 (10.3)	35 (8.1)	0.706
Micropapillary or solid component	50(45.0)*	67 (62.0) ^#	154 (35.5)	<0.001
VPI	82 (73.9)	88 (81.5)	333 (76.7)	0.397
LVI	7 (6.3) ^#	9 (8.3) ^#	7 (1.6)	<0.001
STAS	12 (10.8) ^#	11 (10.2) ^#	19 (4.4)	0.011
Ki-67 index(≥20%)	36 (42.9)	40 (44.9)	120 (36.8)	0.289
EGFR mutation	111 (100)* ^#	18/44 (40.9) ^#	78/110 (70.9)	<0.001
19 del	52/111 (46.8)	5/18 (27.8)	31/78 (39.7)	-
21 L858R	58/111 (52.2)	8/18 (44.4)	41/78 (52.5)	-
20 T790M/20 ins	0/0	0/3	1/2	-
G719X/S861I/L861Q	1/0/0	1/0/1	1/1/1	-
ALK mutation	0* ^#	4/40 (10)	9/101 (8.9)	0.011
KRAS mutation	1/48 (2.0)	4/37 (10.8)	7/88 (7.9)	0.252
TP53 mutation	9/26 (34.6)	8/20 (40)	15/46 (32.6)	0.893
PD-L1	0 (0, 5)	1.5 (0, 5)	0 (0, 3)	0.240
IASLC grade				0.002
1	9 (8.1) ^#	4 (3.7) ^#	23 (5.3)
2	66 (59.5) ^#	50 (46.3) ^#	280 (64.5)
3	36 (32.4) ^#	54 (50.0) ^#	131 (30.2)

Distribution	Icotinib (n=65)	Gefitinib (n=28)	Furmonertinib/ almonertinib (n=1/2)	Osimertinib (n=15)	Chemotherapy (n=108)
Duration
1 year/2 cycles	25 (38.5)	6 (21.4)	1 (33)	3 (20)	6 (5.6)
2 years/3 cycles	36 (55.4)	16 (57.1)	2 (66)	12 (80)	8 (7.4)
3 years/4 cycles	2 (3.1)	5 (17.9)	0	0	94 (87)
5 years	2 (3.1)	1 (3.6)	0	0	-
Economy cost (RMB/year)	3.9×10⁴	1.4×10⁴	Not applicable	6.4×10⁴	Not applicable
Adverse events
Rash	24 (36.9)	11 (40)	2 (66)	3 (20)	0
Paronychia	11 (16.9)	7 (25)	1 (33)	4 (26.7)	0
Interstitial pneumonia	0	0	0	0	0
Thrombocytopenia	1 (1.5)	1 (3.6)	0	1 (1.5)	21 (19.4)
Leukopenia	1 (1.5)	1 (3.6)	0	1 (1.5)	64 (59.3)
Diarrhea	13 (20)	6 (30)	1 (33)	6 (40)	5 (4.6)
Nausea	2 (3)	2 (7.1)	0	3 (20)	60 (55.6)
Decreased appetite	1 (1.5)	1 (3.6)	1 (33)	2 (13.3)	20 (18.5)
Grade ≥3	5 (7.7)	4 (14.3)	0	1 (6.5)	48 (44.4)