Analysis of the effect of surgery on the prognosis of non-small cell lung cancer patients with single-organ extrathoracic metastases based on the SEER database

doi:10.21203/rs.3.rs-3142582/v1

Purpose: We used the Surveillance, Epidemiology, and End Results (SEER) database to explore the effect of primary or metastatic tumor surgery vs. no surgery on the prognosis of non-small cell lung cancer (NSCLC) patients with single-organ extrathoracic metastases.

Methods: NSCLC patients with single-organ extrathoracic metastases were extracted from the SEER database. The characteristics of patients with different metastasis sites were balanced by progression-free survival, and the Kaplan‒Meier method and log-rank test were used to compare differences in cancer-specific survival (CSS). Multivariate Cox regression was performed to identify prognostic factors.

Results: There were 8592, 11886, and 2814 eligible patients with brain metastases, bone metastases, and liver metastases, respectively. Multivariate Cox regression analysis showed that surgical intervention was independently associated with the CSS of patients (P < 0.001). The surgical and nonsurgical groups were subjected to propensity score matching (PSM) (1:1). After PSM, the patients who underwent surgery in the brain metastasis and bone metastasis cohorts had a better CSS (P < 0.001). Different surgical modalities for primary tumors showed greater survival benefits before and after PSM than no surgery. After PSM, the CSS of the brain metastasis cohort receiving metastatic surgery was better than that of the nonsurgical group (P < 0.001). The median CSS of patients who underwent PMTR was longer than that of patients who underwent other surgical methods (P < 0.05).

Conclusion: In NSCLC patients with single-organ extrathoracic metastases, both primary tumor surgery and metastatic surgery exhibited better prognoses than no surgery.

SEER

non-small-cell lung cancer

single organ metastasis

primary tumor surgery

metastatic surgery

Systemic therapy is the accepted standard of care for patients with stage IV non-small cell lung cancer (NSCLC), for which surgical treatment is rarely recommended. In recent years, however, more aggressive treatment approaches, including local treatment of primary and metastatic tumors, have been suggested for selected stage IV patients, especially those with oligometastatic disease. Certain existing studies have suggested that metastatic NSCLC is highly heterogeneous, with some patients with limited areas of metastasis (oligometastasis) or progression (oligoprogression) potentially having a fairly favorable natural history of disease and prognosis. Therefore, local therapy may provide clinically meaningful disease control or cure for these patients[1]. In addition to relieving local symptoms or improving quality of life, an important aim is to improve the long-term survival of these patients. As early as 30 years ago, Patchell RA et al. published a prospective randomized study of survival outcomes evaluating the effect of surgery after whole-brain radiotherapy in patients with single brain metastases. The results showed that the recurrence rate at the primary tumor site was lower in the surgery group than in the radiation-therapy-alone group (P < 0.02)[2]. A multicenter, randomized, controlled phase 2 study found that local consolidation therapy (surgery or radiation therapy), compared with maintenance therapy alone, for NSCLC patients with three or fewer metastases after first-line systemic therapy significantly improved progression-free survival (PFS)[3]. Despite the current controversy, over the past 20 years, many radiation oncologists have used definitive stereotactic ablative radiotherapy (SABR) to treat oligometastatic disease. A small-sample phase 2 randomized clinical trial showed a significantly improved PFS of 9.7 months for limited metastatic NSCLC patients receiving SABR plus maintenance chemotherapy compared to 3.5 months for patients receiving maintenance chemotherapy alone[4]. These findings suggest that aggressive local therapy may benefit patients. However, other studies did not find a survival benefit with local therapy[5, 6].

For metastases at other sites, including solitary metastases in other organs, the rationality of surgical treatment is still controversial[3]. The indications for surgical treatment of lung cancer have been expanded, and a series of small retrospective studies have been published suggesting that some stage IV patients may benefit from surgical intervention[7–9]. However, most of these studies have been single-center studies of highly selected patients. Current detailed research is still lacking regarding the survival outcome in patients with oligometastatic NSCLC.

Here, we review the data for NSCLC patients with single-organ extrathoracic metastases from the Surveillance, Epidemiology, and End Results (SEER) database and qualitatively analyze them to assess the prognostic impact of various surgical treatment modalities on patients with single-organ extrathoracic metastases. Propensity score matching (PSM) was used to help evaluate the possible survival benefit of the surgical treatment of primary and/or metastatic lesions vs. no surgery.

1. Study population

The SEER database contains approximately 28% of cancer patients in the United States. This study used SEER*Stat software to extract cases from the database. Patients diagnosed with lung or bronchial malignancies according to the International Classification of Diseases in Oncology, 3rd edition (ICD-O-3) from January 2010 to December 2015 were selected. The inclusion criteria were 1) NSCLC confirmed by pathology; 2) stage M1b according to the 7th edition of the American Joint Committee on Cancer tumor–node–metastasis staging system; and 3) lung cancer as the first primary malignant tumor in the patient's lifetime. The exclusion criteria were 1) multiorgan metastases; 2) unknown primary tumor site or unknown metastatic organ involvement; 3) survival time of 0 months or unknown; 4) local diagnosis of T0; and 5) primary tumor surgery with local tumor destruction (SEER surgery codes 12, 13, 15, 19). In this study, the pathological types were subclassified according to the ICD-O-3 tissue type codes, which were as follows: adenocarcinoma—8140, 8141, 8230, 8244, 8245, 8250, 8251, 8252, 8253, 8254, 8255, 8260, 8290, 8310, 8323, 8480, 8481, 8490, 8507, 8550, 8570, 8571, 8574, 8576; squamous cell carcinoma—8052, 8070, 8071, 8072, 8073, 8074, 8075, 8083, 8123; and other NSCLC—8004, 8012, 8013, 8014, 8022, 8030, 8031, 8032, 8033, 8035, 8046, 8082, 8200, 8240, 8249, 8430, 8560.

The following patient information was collected: 1) sex; 2) age; 3) location of primary tumor; 4) pathological type; 5) degree of differentiation; 6) whether there were bone, brain, or liver metastases; 7) whether surgery was performed on the primary tumor; 8) metastatic surgery; 9) radiotherapy and chemotherapy; 10) survival time; 11) overall survival (OS) and cancer-specific survival (CSS); and 12) T stage and N stage.

2. PSM

In an observational study, there is always some selection bias that leads to an imbalance in baseline characteristics between the two groups, which affects the comparability between the two groups. This study used PSM to balance the baseline characteristics between the two groups[10]. The propensity score model included variables that may have an impact on prognosis: sex, age, primary tumor site, pathological type, degree of differentiation, primary tumor or metastatic surgery, radiotherapy, chemotherapy, T stage, and N stage. SPSS software was used for 1:1 pairing of surgery with no surgery patients. In this study, both the surgical group and the nonsurgical group underwent PSM.

3. Statistical analysis

All statistical analyses were performed with SPSS 25.0. In this study, CSS was used as the primary outcome. Data on clinicopathological characteristics were summarized, and Cox proportional hazards models were used to perform univariate and multivariate analyses to identify factors associated with CSS. In addition, hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. PSM was performed to reduce potential selection bias in patients. Surgical interventions included no surgery (NONE), primary tumor resection only (PTR), metastatic tumor resection only (MTR), and both primary and metastatic tumor resection (PMTR). The Kaplan–Meier (K‒M) method was used to evaluate the survival of different treatment groups before and after matching, and the log-rank test was used to compare the survival curves. P < 0.05 was considered statistically significant. For every factor, we determined its hazard ratio (HR) and 95% confidence interval (CI) using a Cox proportional hazards regression model. First, significant factors were identified using a univariate Cox proportional hazards model (P < 0.05). Second, dynamic properties were further analyzed using a multivariate Cox proportional hazards design.

1. Patient characteristics

In all, 23,291 NSCLC patients with single-organ extrathoracic metastases were included. The baseline characteristics of the patients are listed in Table 1; 11,886 patients (51.0%) had bone metastases, 8,592 (36.9%) had brain metastases, and 2,813 (12.1%) had liver metastases (Fig. 1).

Of the patients with bone metastases alone, 231 underwent PTR, 478 underwent MTR, and 15 underwent PMTR. Patients with brain metastases alone had the highest rate of surgical resection: 421 patients underwent PTR, 1607 underwent MTR, and 146 underwent PMTR. Patients with liver metastases alone had the lowest surgical resection rate, with 68 patients receiving PTR, 30 receiving MTR, and six receiving PMTR.

Table 1. Clinicopathological characteristics of NSCLC patients with single-organ extrathoracic metastases.
Variable	Bone metastases (N)	Brain metastases (N)	Liver metastases (N)	P values
Age at diagnosis				< 0.001
<60	2926	2955	598
≥60	8960	5637	2215
Sex				< 0.001
Female	4966	4188	1205
Male	2960	4404	1608
Left and right lungs				< 0.001
Left lung	5044	3538	1140
Right lung	6842	4054	1673
Location				< 0.001
Main bronchus	548	370	178
Upper lobe	7186	5486	1615
Middle lobe	558	416	135
Lower lobe	3594	2320	885
Pathological type				< 0.001
Squamous cell carcinoma	2327	1206	860
Adenocarcinoma	7914	5849	1405
Others	1645	1537	548
Degree of differentiation				< 0.001
Highly differentiated	270	164	54
Moderate differentiation	1508	1045	286
Poorly differentiated	3009	2718	784
Undifferentiated	115	122	25
Unknown	6984	4543	1664
T stage				< 0.001
T1	1615	1217	310
T2	3220	2689	761
T3	2816	2023	681
T4	3284	2088	805
TX	951	575	256
N stage				< 0.001
N0	2746	2251	645
N1	1074	790	235
N2	5230	3809	1309
N3	2374	1490	499
NX	462	252	125
PTR				< 0.001
No	11655	8171	2745
Sublobectomy	122	126	34
Lobectomy	99	278	30
Pneumonectomy	10	17	4
MTR				< 0.001
No	11408	6985	2783
Yes	478	1607	30
PMTR	15	146	6
Radiotherapy				< 0.001
No/Unknown	5401	1523	2219
Yes	6485	7069	594
Chemotherapy				< 0.001
NO/Unknown	4409	3487	1089
Yes	7477	5105	1724

2. Univariate and multivariate analyses of prognostic factors in the overall cohort

Univariate and multivariate analyses of prognostic factors in the overall cohort were performed to assess associations between baseline variables and survival outcomes. In this analysis, age at diagnosis (< 60 years or ≥ 60 years), sex, left or right lung tumor, primary tumor location (main bronchus, upper lobe, middle lobe, or lower lobe), pathological type (squamous, adenocarcinoma, or other NSCLC), degree of differentiation,PTR or not, MTR or not, T stage, N stage, chemotherapy treatment, radiotherapy treatment, and approaches of primary tumor resection were inputs for assessing the factors affecting CSS. Except for the left and right lungs, all other factors had statistically significant associations with CSS in univariate analysis. A simultaneous multivariate analysis of these variables showed that both PTR and MTR were independently associated with a better CSS in this cohort. In addition to tumor location in the left or right lung, other characteristics, such as age < 60, female sex, tumor location, adenocarcinoma, well-differentiated tumor, earlier T/N stage, chemotherapy treatment, radiotherapy treatment, and approaches of primary tumor resection were independent prognostic factors for CSS (Table 2).

Table 2

Univariate and multivariate analyses of prognostic factors for survival in the overall cohort
Variable	Univariate analysis			Multivariate analysis
Variable	HR	95% CI	P	HR	95% CI	P
Age			< 0.001			< 0.001
< 60	1			1
≥ 60	1.303	1.262–1.345		1.186	1.148–1.225
Sex			< 0.001			< 0.001
Male	1			1
Female	0.806	0.784–0.830		0.849	0.825–0.874
Left or right lung			0.112			0.192
Left	1			1
Right	1.023	0.995–1.053		1.02	0.990–1.050
Location			< 0.001			0.004
Main bronchus	1			1
Upper lobe	0.823	0.770–0.879		0.898	0.840–0.960	0.002
Middle lobe	0.795	0.726–0.870		0.865	0.789–0.948	0.002
Lower lobe	0.851	0.794–0.912		0.921	0.859–0.987	0.02
Pathological type			< 0.001			< 0.001
Squamous cell carcinoma	1			1
Adenocarcinoma	0.689	0.664–0.714		0.777	0.749–0.807	< 0.001
Other NSCLC	0.902	0.861–0.945		0.923	0.880–0.968	0.001
Degree of differentiation			< 0.001			< 0.001
Undifferentiated	1			1
Poorly differentiated	0.791	0.695–0.901		0.806	0.707–0.919	0.001
Moderately differentiated	0.628	0.550–0.718		0.681	0.595–0.780	< 0.001
Well differentiated	0.506	0.430–0.595		0.534	0.453–0.630	< 0.001
Unknown	0.745	0.655–0.847		0.779	0.685–0.887	< 0.001
Approaches of primary tumor resection			< 0.001			< 0.001
None	1			1
Sublobectomy	0.637	0.637–0.830		0.819	0.716–0.936	0.003
Lobectomy/Bilobectomy	0.302	0.263–0.346		0.340	0.296–0.390	< 0.001
Pneumonectomy	0.539	0.358–0.811		0.627	0.416–0.944	0.025
MTR			< 0.001			< 0.001
No	1			1
Yes	0.72	0.685–0.758		0.798	0.758–0.840
T stage			< 0.001			< 0.001
T1	1			1
T2	1.201	1.146–1.259		1.193	1.137–1.251	< 0.001
T3	1.336	1.273–1.403		1.303	1.240–1.369	< 0.001
T4	1.367	1.303–1.433		1.311	1.248–1.376	< 0.001
TX	1.372	1.287–1.462		1.269	1.188–1.354	< 0.001
N stage			< 0.001			< 0.001
N0	1			1
N1	1.065	1.008–1.126		1.125	1.064–1.190	< 0.001
N2	1.221	1.178–1.266		1.256	1.210–1.302	< 0.001
N3	1.215	1.164–1.269		1.392	1.271–1.391	< 0.001
NX	1.225	1.131–1.326		1.121	1.033–1.216	0.006
Radiotherapy			< 0.001			< 0.001
No/Unknown	1			1
Yes	0.932	0.906–0.960		1.062	1.031–1.094
Chemotherapy			< 0.001			< 0.001
No/Unknown	1			1
Yes	0.433	0.421–0.446		0.416	0.403–0.428

3. Outcome of PTR after PSM

According to the multivariate analysis, age, sex, primary tumor location, pathological type, degree of differentiation, PTR, MTR, T stage, N stage, radiotherapy, and chemotherapy were independent prognostic factors. Therefore, when PSM was performed, these variables were included as predictor variables for complete matching. Table 3 shows the baseline characteristics after PSM according to whether PTR was performed. 676 patients in each of the surgical and nonsurgical groups were matched (Table 3).

Table 3

Baseline characteristics after PSM according to whether PTR was performed
Variable	Number of patients after PSM
	Nonsurgical	Surgical	P
	(n = 676)	(n = 676)	P
Age			0.821
< 60	245	249
≥ 60	431	427
Sex			0.957
Male	349	350
Female	327	326
Location			0.437
Main bronchus	14	19
Upper lobe	447	428
Middle lobe	28	38
Lower lobe	187	191
Pathological type			0.319
Squamous cell carcinoma	102	102
Adenocarcinoma	489	470
Others	85	104
Degree of differentiation			0.615
Undifferentiated	31	37
Poorly differentiated	190	187
Moderately Differentiated	331	321
Well differentiated	9	16
Unknown	115	115
MTR			0.779
No	554	550
Yes	122	126
T stage			0.993
T1	138	139
T2	261	254
T3	161	167
T4	97	98
TX	19	18
N stage			0.843
N0	318	305
N1	104	108
N2	201	210
N3	43	39
NX	10	14
Radiotherapy			0.733
No/Unknown	243	237
Yes	433	439
Chemotherapy			0.106
No/Unknown	212	240
Yes	464	436

3.1 CSS for PTR after PSM

After PSM, 1352 patients in the surgical group and the nonsurgical group were completely matched 1:1, and the results showed that the CSS of the patient undergoingPTR was longer than that of the nonsurgical patients (median CSS: 14 months vs. 8 months, P < 0.001, Fig. 2).

3.2 CSS by PTR/no PTR in patients with different organ metastases after PSM

PSM was performed on patients with isolated bone metastases, and 326 patients in the surgical group and the nonsurgical group were matched exactly (1:1). The results suggested that among patients with isolated bone metastases, the CSS of patients receiving PTR was longer than that of nonsurgical patients (median survival time: 18 months vs. 10 months, P = 0.000, Fig. 3a). When PSM was performed on patients with only brain metastases, 464 patients in the surgical group and the nonsurgical group were matched exactly (1:1). The results suggested that for patients with isolated brain metastases, the CSS of patients treated with PTR was longer than that of nonsurgical patients (median survival time: 24 months vs. 8 months, P = 0.000, Fig. 3b). In the PSM of patients with isolated liver metastases, 34 patients in the surgical group and the nonsurgical group were completely matched (1:1). The results suggested that for patients with isolated liver metastases, the CSS of patients treated with PTR was not significantly different from that of nonsurgical patients, but the former still showed a longer survival trend (median survival time: 16 months vs. 5 months, P = 0.169, Fig. 3c). The above results suggested that in patients with isolated bone metastases, brain metastases, or liver metastases, the CSS of PTR was longer than that of no surgery.

3.3 Survival analysis of patients with primary tumors after different surgical methods

Before PSM, in the overall cohort, 22,571, 282, 407, and 31 patients had primary tumors without surgery, with wedge resection, with lobectomy, and with pneumonectomy, respectively. Lobectomy was the most common approach of primary tumor resection. Patients with primary tumors who underwent wedge resection, lobectomy, or pneumonectomy all showed longer survival than those who did not undergo surgery (P < 0.005). Among them, patients who received lobectomy had the best survival prognosis, and there was no significant difference in prognosis between wedge resection and pneumonectomy for primary tumors (P = 0.154, Fig. 4a).

Subgroup analysis was performed after PSM in patients with primary tumors undergoing wedge resection or no surgery. A total of 428 people were matched (1:1), 214 of whom underwent wedge resections, and the results suggested that patients who underwent wedge resection showed better survival than those who did not undergo surgery (median survival time: 10 months vs. 9 months, P = 0.024, Fig. 4b). Subgroup analysis was performed after PSM in patients with vs. without lobectomy of the primary tumor. A total of 568 people were matched (1:1), 284 of whom underwent lobectomy. The results showed that patients who underwent lobectomy of the primary tumor showed better survival than those without surgical treatment (median survival time: 33 months vs. 10 months, P = 0.000, Fig. 4c). Subgroup analysis was performed after PSM on patients who underwent pneumonectomy of the primary tumor or no surgery. Thirty-eight people were matched (1:1), 19 underwent pneumonectomy for primary tumors, and the results suggested that patients who underwent pneumonectomy showed better survival than those without surgical treatment (median survival time: 27 months vs. 8 months, P = 0.008, Fig. 4d).

4 CSS of patients with vs. without MTR before and after PSM

Before PSM, patients who underwent MTR had a significantly longer CSS than those without surgical treatment (median survival: 10 months vs. 6 months, P = 0.000, Fig. 5a). After PSM, two groups of 3546 patients were matched (1:1). Consistent with the results of the non-PSM cohort, patients who underwent PTR had a longer CSS than nonsurgical patients (median survival: 10 months vs. 7 months, P = 0.000, Fig. 5b).

Survival outcome of MTR in patients with different metastatic organs

Subgroup analysis was performed after PSM for patients with isolated brain metastases. A total of 2244 patients were matched (1:1). Patients who underwent MTR had a longer CSS than nonsurgical patients (median survival: 11 months vs. 8 months, P = 0.000, Fig. 6a). Among patients with only brain metastases, surgical treatment was associated with a better OS. After PSM of patients with isolated bone metastases, 756 patients were matched (1:1). There was no significant difference in CSS between patients receiving MTR and those without surgery (P = 0.648, Fig. 6b). After PSM of patients with only liver metastases, 20 patients were matched (1:1). The CSS of patients undergoing MTR was not significantly different from that of patients without surgical treatment (P = 0.270, Fig. 6c). The results suggest that when patients had liver metastases or isolated bone metastases, MTR did not prolong CSS compared with no surgery. .

5. Survival analysis of patients undergoing PTR or MTR with different surgical methods

By the K‒M univariate method, stratification was performed according to the surgical method. The CSS of each subgroup significantly differed from all others by pairwise comparison (Fig. 7; Table 4): The median CSS of patients received NONE, PTR, MTR, and PMTR group was 6 months, 17 months, 9 months, and 25 months, respectively (P < 0.05).

Table 4

Surgical approach and CSS of patients with single-organ extrathoracic metastases.
	No (%)	CSS (months)	P
Surgery			< 0.05
NONE	20623 (88.5%)	6
PTR	553 (2.4%)	17
MTR	1948 (8.4%)	9
PMTR	167 (0.7%)	25
Note: NONE: no surgery; PTR: primary tumor resection only; MTR: metastatic tumor resection only; PMTR: primary and metastatic tumor resection.

Compared with patients without surgery, the HR was 0.453 (P < 0.001) for patients with PTR alone, 0.749 (P < 0.001) for patients with MTR alone, and 0.343 (P < 0.001) for patients with primary and metastatic tumor resection.

For patients with advanced NSCLC, the traditional treatment is usually systemic therapy[11, 12]. The concept of the oligometastatic state has undergone constant change ever since Hellman and Weichselbaum first proposed it in 1995[13]. It was first described as isolated metastases in a single organ; however, this definition is not generally accepted. Recently, oligometastases were changed to mean no more than 5 metastases in no more than 3 organs at PL02 of the 2022 World Conference on Lung Cancer (WCLC). In recent years, an increasing number of clinical studies have indicated that there is a limited number of metastases and metastatic organs in patients with oligometastases, and these metastases are organ-specific and do not have the relevant characteristics of systemic dissemination tendency, which determines the clinical application of local treatment[1]. Therefore, these patients have been increasingly regarded as a distinct group that could benefit from treatment that intends to cure the disease, rather than palliative care, to achieve a better clinical outcome[14]. The results of multiple retrospective analyses showed that most of the failure patterns after first-line systemic therapy for metastatic NSCLC occurred at the baseline disease site (primary or metastatic lesion)[15, 16]. In patients with limited metastasis, elimination of the primary lesion and metastases can help reduce cells or remove metastases that may transfer to other sites in the future. Therefore, relevant research on improving the long-term survival rate of patients by improving the local treatment of primary tumor lesions and metastases has gradually become more important [17]. A single-institution randomized phase II study found that for patients with limited metastatic NSCLC (primary plus up to five metastatic sites), systemic therapy followed by maintenance therapy plus stereotactic ablative radiotherapy conferred a greater survival benefit than consolidation therapy alone[3, 4, 18]. Randomized controlled studies have been conducted on the impact of standard maintenance therapy versus local consolidative radiation therapy and standard maintenance therapy in 1–5 sites of oligometastatic NSCLC[4, 5]. Aggressive local therapy was determined to be a favorable prognostic factor by the authors of a meta-analysis that looked at the prognostic variables of synchronous oligometastatic NSCLC[19]. The above results suggest that for patients with single-organ metastases, local therapy plays an important role in improving local control and OS. Surgical resection is the most common local treatment modality for patients with stage IV NSCLC. Buero found that resection of solitary adrenal metastasis should be considered if the primary lung cancer is resectable[20]. There have been few clinical studies on single-organ metastasis of NSCLC, and there is no large, prospective, randomized controlled study on it. This is worthy of further study to explore the best surgical intervention times and surgical methods for such patients.

By analyzing the surgical treatment and prognosis of NSCLC patients with single-organ extrapulmonary metastases in the SEER database, this study aimed to explore the potential benefits of primary tumor resection and metastatic tumor resection for single-organ extrathoracic metastatic NSCLC on survival after different surgical methods. Univariate and multivariate analyses of prognostic factors in the overall cohort were performed to assess the association between baseline variables and survival outcomes. The univariate analysis showed that all factors except laterality of the lung location had significant associations with OS. Multivariate analysis of these variables showed that age < 60 years, female sex, tumor location, adenocarcinoma, well-differentiated tumor, earlier T/N stage, chemotherapy treatment, and whether primary tumor resection and metastatic tumor resection were performed were independent prognostic factors for CSS. These results must be viewed with caution because the lack of specific information on radiotherapy in the SEER database and the grouping of patients who were not known to receive radiotherapy with those who definitely did not may have contributed to some bias in the results.

For patients with single-organ extrapulmonary metastases (brain metastases, bone metastases, liver metastases), the results of this study showed that regardless of which organ was involved, a longer CSS was observed with surgical resection of the primary tumor than without surgery. We believe that this result is due, on the one hand, to the higher local control rates associated with local primary site surgery, and for patients with oligometastases, local surgical management may reduce the initial tumor load of potentially circulating tumor cells[1]. Moreover, the benefits of surgical resection include the ability to confirm histology and retrieve tissue for thorough molecular testing to direct subsequent treatments[14]. Similar clinical findings were found in patients with oligometastatic prostate cancer[21]. Prior series studies have revealed that the best candidates for surgical resection are younger individuals without N2 disease and bone metastases. It is important to carefully weigh the risks of surgical intervention as well as the amount of tissue that must be removed to achieve an R0 resection[14, 22, 23]. Although in our study on patients with isolated liver metastases, the CSS of patients treated with PTR was not significantly different from that of nonsurgical patients, we believe that the results may be due to the small sample size. However, additional study findings will be required in the future to validate the significance of primary lesion surgery due to the limits of the database itself.

We performed 1:1 PSM between the different surgical methods of the primary tumor and the patients without surgery. Before and after PSM, patients who underwent wedge resection, lobectomy, or pneumonectomy of the primary tumor showed longer survival than those who did not undergo surgery (P < 0.005). Among them, patients who received lobectomy had the best survival prognosis, and there was no significant difference in prognosis between wedge resection and pneumonectomy of the primary tumor (P = 0.154). Sun et al. studied stage IV NSCLC patients with extrathoracic metastases and found that patients who underwent lobectomy or bilobectomy had the best survival, while those with local tumor destruction had the worst survival, and those who underwent wedge resection had similar survival as patients undergoing pneumonectomy (P = 0.152), which is consistent with our results, but previous studies only performed K‒M analysis[24].

The extent of distant metastasis is an important factor in determining whether MTR should be performed. In clinical practice, the extent of extrathoracic metastatic disease is assessed by counting the number of metastatic organs and the number of metastatic foci. Hanagiri et al. found that the 5-year survival rate after surgery was as high as 50% in NSCLC patients with only one metastasis[25]. Vazquez BJ et al. retrospectively analyzed OS in patients with metastatic lung cancer who underwent adrenalectomy at the Mayo Clinic in Rochester; the researchers compared these patients with stage-matched patients in the SEER database who underwent PTR without resection of distant disease and found that the 3-year total survival rates were 52% and 25%, respectively, and the median OS was 3.5 years and 1.1 years, respectively (P = 0.002)[26]. Local treatment of adrenal metastases in NSCLC has become a treatment option, and if the lung tumor is curable, local treatment of adrenal metastases is supported by category 2B evidence[27]. According to the patients' extrathoracic metastasis status, we evaluated the prognostic effect of MTR in patients with different organ metastases. Before and after PSM, patients who underwent MTR had a significantly longer CSS than those without surgical treatment. When we explored the survival results of patients with different metastatic organs undergoing MTR, the results suggested that for patients with isolated brain metastases, surgical treatment of brain metastasis was related to the OS rate, while for patients with liver metastasis or isolated bone metastases, MTR did not prolong CSS in patients without it.

To further explore the correlation between different surgical methods of primary tumor and metastatic tumor and survival prognosis, for K‒M univariate analysis, the patients were stratified according to the surgical method, and the pairwise comparison of CSS significantly differed between all the subgroups. The median CSS after NONE,PTR, MTR, and PMTR was 6 months, 17 months, 9 months, and 25 months, respectively (P < 0.05), and the CSS of patients undergoing primary and metastatic tumor resection was the longest.

This study found an association, rather than a causal relationship, between surgical intervention and long-term survival in NSCLC patients with single-organ extrathoracic metastases. Interpretation of the current results must fully account for the systemic treatment of NSCLC, including chemotherapy, targeted therapy, and immunotherapy. Further prospective controlled trials are needed to confirm these findings.

This study was a retrospective study with several limitations. First, although we used PSM to balance the baseline characteristics of the surgical versus nonsurgical groups, selection bias was still unavoidable. Potential confounders, such as smoking, lung function, physical status, and patient comorbidities, that may lead to selection bias are not available in the SEER database. Because the SEER database does not contain information on TNM stage 8 of the patients, we chose to use the 7th edition for analysis. Second, information on multimodal management other than surgery was very limited, and there were no clear details on chemoradiotherapy that would have allowed the assessment of the impact of systemic therapy on patient survival.

Primary tumor resection is associated with better survival in NSCLC patients with single-organ extrathoracic metastases. Especially for patients with isolated brain metastases, primary tumor surgery combined with metastatic surgery is associated with the best survival. Lobectomy or bilobectomy of the primary tumor is superior to wedge resection and pneumonectomy.

SEER: Surveillance, Epidemiology, and End Results

NSCLC: non-small cell lung cancer

CSS: cancer-specific survival

PSM: propensity score matching

HRs: hazard ratios

Cis: confidence intervals

NONE: no surgery

PTR: primary tumor resection only

MTR: metastatic tumor resection only

PMTR : both primary and metastatic tumor resection

Ethics approval and consent to participate

Not applicable since SEER is a free and open public database.

Consent for publication

Not applicable.

Conflict of interest

The authors declare that there are no conflicts of interest.

Data Availability Statement

The original data came from the SEER database. All data discussed in the manuscript are included within this published article. The dataset from the SEER database generated and analyzed during the current study is available in the SEER dataset repository (https://seer.cancer.gov/data-software/).

Funding

This study was supported by the Natural Science Foundation of Fujian Province (Grant No. 2022J011023) and the Natural Science Foundation of Fujian Province (Grant No. 2022J01412).

Author contribution

"Lijing Zheng, Weishuai Wu, and Shiyin Luo contributed to the conception and design of the study. Yuanfeng Lin and Jingyu Wu organized the database. Chen Huang, Shiyin Luo and Weishuai Wu performed the statistical analysis. Lijing Zheng and Qianshun Chen wrote the first draft of the manuscript. Yidan Lin, Shiyin Luo, Xunyu Xu and Yongmei Dai wrote sections of the manuscript. All authors contributed to manuscript revision and read and approved the submitted version."

Acknowledgments

We are grateful to the SEER program for approving the registration and to the SEER database.

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No competing interests reported.

Analysis of the effect of surgery on the prognosis of non-small cell lung cancer patients with single-organ extrathoracic metastases based on the SEER database

Status:

Version 1

Abstract

Figures

Introduction

Materials and Methods

1. Study population

2. PSM

3. Statistical analysis

Results

1. Patient characteristics

2. Univariate and multivariate analyses of prognostic factors in the overall cohort

3. Outcome of PTR after PSM

3.1 CSS for PTR after PSM

3.2 CSS by PTR/no PTR in patients with different organ metastases after PSM

3.3 Survival analysis of patients with primary tumors after different surgical methods

4 CSS of patients with vs. without MTR before and after PSM

Survival outcome of MTR in patients with different metastatic organs

5. Survival analysis of patients undergoing PTR or MTR with different surgical methods

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Status:

Version 1