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Consolidative Local Ablative Therapy Improves the Survival of Patients With Synchronous Oligometastatic NSCLC Harboring EGFR Activating Mutation Treated With First-Line EGFR-TKIs
Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, People’s Republic of ChinaDepartment of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China
The aim of the current study was to investigate whether consolidative local ablative therapy (LAT) can improve the survival of patients with stage IV EGFR-mutant NSCLC who have oligometastatic disease treated with first-line EGFR–tyrosine kinase inhibitor (TKI) therapy.
Methods
Patients with stage IV EGFR-mutant NSCLC and no more than five metastases within 2 months of diagnosis were identified. All patients were treated with first-line EGFR-TKIs. Consolidative LAT included radiotherapy, surgery, or both. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier curves.
Results
From October 2010 to May 2016, 145 patients were enrolled, including 51 (35.2%) who received consolidative LAT to all oligometastatic sites (all-LAT group), 55 (37.9%) who received consolidative LAT to either primary tumor or oligometastatic sites (part-LAT group), and 39 (26.9%) who did not receive any consolidative LAT (non-LAT group). The median PFS in all-LAT, part-LAT, and non-LAT groups were 20.6, 15.6, and 13.9 months, respectively (p < 0.001). The median OS in all-LAT, part-LAT, and non-LAT groups were 40.9, 34.1, and 30.8 months, respectively (p < 0.001). The difference was statistically significant between the all-LAT group and part-LAT or non-LAT group but was not between the part-LAT and non-LAT group. The median OS was significantly improved with consolidative LAT for primary tumor (40.5 versus 31.5 months, p < 0.001), brain metastases (38.2 versus 29.2 months, p = 0.002), and adrenal metastases (37.1 versus 29.2 months, p = 0.032). Adverse events (grade ≥ 3) due to radiotherapy included pneumonitis (7.7%) and esophagitis (16.9%).
Conclusions
The current study showed that consolidative LAT to all metastatic sites was a feasible option for patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidative LAT to partial sites or observation alone.
Landmark clinical trials have shown that advanced NSCLC patients with activating EGFR mutations have higher response rates and better progression-free survival (PFS) when treated with EGFR tyrosine kinase inhibitors (TKIs) compared with classical platinum-based chemotherapy.
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non–small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study.
Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
For patients with oligoprogressive disease, local ablative therapy (LAT) plus continuation of EGFR-TKIs could result in more than 6 months of additional clinical benefits.
Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non–small-cell lung cancer.
Therefore, LAT is a reasonable option for patients with oligoprogressive resistance to EGFR-TKIs.
Previous studies have revealed that stage IV disease with oligometastases can represent an indolent phenotype that could benefit from LAT for consolidation.
In a multicenter randomized controlled phase 2 study, local consolidation therapy with radiotherapy or surgery especially can significantly prolong PFS for patients with oligometastatic NSCLC (≤3 sites) who have disease control after initially systemic therapy.
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
However, data regarding the optimal consolidative LAT for patients with stage IV EGFR-mutant NSCLC who have oligometastatic disease during first-line EGFR-TKI therapy are sparse.
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
We hypothesized that consolidative LAT for patients with oligometastases could also offer survival benefits during first-line EGFR-TKI treatment. To address this issue, we investigated the survival outcomes of patients with stage IV EGFR-mutant NSCLC treated with first-line EGFR-TKI therapy with or without consolidative LAT.
Materials and Methods
Patients
A retrospective study was conducted in patients with stage IV EGFR-mutant NSCLC who had oligometastatic disease within 2 months of diagnosis from October 2010 to May 2016 at Shanghai Pulmonary Hospital. Patients who met the following criteria were enrolled: pathologically confirmed NSCLC with EGFR sensitizing mutation (exon 19 deletion or exon 21 L858R mutation), stage IV disease according to the 7th edition of the American Joint Committee on Cancer staging system, with synchronous oligometastatic disease (five or fewer metastases within 2 months of diagnosis in one to multiples organs, excluding primary tumor), 18 years of age or older, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 2 or less, and did not progress after initial first-line EGFR-TKI treatment. Tumor stage was assessed by systemic imaging (either contrast-enhanced computed tomography [CT] of the chest, abdomen, bone scan, or positron-emission tomography [PET]/CT) and brain imaging (either contrast-enhanced CT or magnetic resonance imaging).
Baseline characteristics were obtained from electronic records, including age at diagnosis, sex, smoking status, ECOG PS, histology, TNM stage, EGFR mutational status, oligometastatic sites, number of oligometastatic disease, and subsequent treatment. Treatment response was evaluated 6 to 8 weeks after the initiation of therapy according to Response Evaluation Criteria in Solid Tumors version 1.1. EGFR-TKIs used in this study included gefitinib (250 mg, once a day), erlotinib (150 mg, once a day), and icotinib (125 mg, three times a day).
EGFR mutations were tested by an amplification refractory mutation system (Amoy Diagnostics Co., Ltd., Xiamen, China) as described in our previous studies.
The Bim deletion polymorphism clinical profile and its relation with tyrosine kinase inhibitor resistance in Chinese patients with non–small cell lung cancer.
Continuation of gefitinib plus chemotherapy prolongs progression-free survival in advanced non–small cell lung cancer patients who get acquired resistance to gefitinib without T790M mutations.
All mutational analyses were performed at the Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, China. This study was approved by the ethics committee of Shanghai Pulmonary Hospital and written informed consent to use the clinical data for research was obtained from each participant before the medical intervention started.
The Procedures of LAT
The types of consolidative LAT included surgery, radiotherapy, or both and were determined in consultation with multidisciplinary teams (including medical oncologists, radiation oncologists, radiologists, and surgeons), according to patients’ age, cardiopulmonary function, tumor location, benefit-risk evaluation, as well as patient preference. The choice of dose-fractionation regimen was made by the treating radiotherapist, with curative intent when possible. Accepted definitive radiotherapy included standard-fractionation radiotherapy (60 Gy in 2-Gy fractions) or aggressive palliation radiotherapy (45 Gy in 3-Gy fractions, a biologically equivalent dose of approximately 60 Gy), stereotactic radiosurgery (SRS) (21 to 27 Gy in single-fraction; 26.5 to 33.0 Gy in 3-fraction; and 30 to 37.5 Gy in 5-fraction), and whole brain radiotherapy (WBRT) (30 Gy in 3-Gy fractions). SRS was usually used for tumors up to 5 cm in size and there was no limitation of tumor size for patients who received conventional radiation. For liver metastases, radiofrequency ablation was accepted.
According to consolidative LAT to residual sites, patients were divided into 3 groups: the all-LAT group (consolidative LAT to all residual disease, including primary tumor, lymph nodes, and metastatic sites as appropriate), the part-LAT group (consolidative LAT to either primary tumor or oligometastatic sites), and the non-LAT group (patients who did not receive any LAT).
Statistical Analysis
Descriptive statistics were used to summarize patient characteristics by treatment group. The categorical variables were compared using the chi-square test or Fisher’s exact test. PFS was defined as the time from treatment commencement of EGFR-TKI to confirmed disease progression or death of any cause. Overall survival (OS) was defined as the period from the date of the time from treatment commencement of EGFR-TKI to the date of death. Kaplan-Meier curve and log-rank test were used for survival analyses. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and corresponding 95% confidence intervals (CIs). To ensure baseline characteristics were well balanced between treatment groups (all-LAT versus part-LAT and non-LAT), propensity score matching (PSM) with a ratio of 1:1 was performed. The logistic regression model included T stage, N stage, EGFR mutational subtype, and the number of oligometastatic lesions. The matching (1:1) on the propensity score was performed using the nearest-neighbor method, with no replacement, and 0.1-caliper width. P values were 2-sided and considered significant if less than 0.05. All statistical analyses were performed using the SPSS statistical software, version 22.0 (IBM Corp., Armonk, New York).
Results
Patient Characteristics
Overall, a total of 145 patients with oligometastatic diseases harboring EGFR sensitizing mutation treated with first-line EGFR-TKIs were enrolled (Fig. 1). The patient characteristics are presented in Table 1. The majority of patients (n = 118, 81.4%) had histology of adenocarcinoma and the median age was 60 years (range, 31 to 80 years). Briefly, 51.7% of patients were female, 74.5% had an ECOG PS 0 or 1, 55.9% were never-smokers, 36.5% had T1 stage, 32.4% had N0 stage, 52.4% had exon 19 deletion mutation, and 46.2% had only one-site metastasis. Fifty-seven point two percent of patients received first-line gefitinib, 20.7% received first-line erlotinib, and 22.1% received first-line icotinib. Seventy-five point nine percent of patients received subsequent treatment. Only 6.2% (n = 9) of patients received osimertinib as subsequent treatment.
Regarding the number of oligometastatic lesions in the 145 patients, 46.2% had one metastasis lesion, 44.1% had two metastases, 7.6% had two metastases, and 2.1% had four to five metastases. With respect to oligometastatic sites, 58.6% were presented in brain, 50.3% in bone, 27.6% in adrenal glands, 18.6% in contralateral lung, 9.1% in liver, 2.1% in cervical lymph nodes, 1.4% in axillary lymph nodes, 1.4% in chest wall, and 0.7% in pancreas. In brief, 44.8% (65 of 145) patients received consolidative LAT to the primary lung tumor during first-line EGFR-TKI treatment, 57.6% (49 of 85) received consolidative LAT to brain metastasis, 56.2% (41 of 73) to bone metastasis, 60% (24 of 40) to the adrenal metastasis, 44.4% (12 of 27) to the contralateral lung, and 35.7% (5 of 14) to the liver. The types of consolidative LAT used in the study are shown in Table 1.
Of the 145 patients, 35.2% received consolidative LAT to both primary tumor and all oligometastatic sites (all-LAT group), 37.9% received consolidative LAT to either primary tumor or oligometastatic sites (part-LAT group), and 26.9% did not receive any LAT (non-LAT group) when there was no progression after initial first-line EGFR-TKI treatment (Fig. 1). Patients who received consolidative LAT to primary lung tumor and all oligometastatic sites were more likely to have T1-2 stage (78.4% in the all-LAT group versus 54.5% in the part-LAT group versus 35.9% in the non-LAT group; p < 0.001), N0-1 stage (74.5% in the all-LAT group versus 45.5% in the part-LAT group versus 48.7% in the non-LAT group; p = 0.005). There was no significant difference between the three groups with respect to age, gender, ECOG PS, histology, smoking status, EGFR mutation, metastases number, the types of EGFK-TKIs, and subsequent treatment (Table 2).
Table 2Patients Characteristics of All-LAT Group, Part-LAT Group and No-LAT Group
Characteristic
LAT for lesions
P Value
All-LAT (n = 51)
Part-LAT (n = 55)
Non-LAT (n = 39)
No. (%)
No. (%)
No. (%)
Age (y)
<65
32 (62.7)
32 (58.2)
28 (71.8)
0.398
≥65
19 (37.3)
23 (41.8)
11 (28.2)
Gender
Male
21 (41.2)
29 (52.7)
20 (51.3)
0.448
Female
30 (58.8)
26 (47.3)
19 (48.7)
ECOG performance status
0-1
37 (72.5)
43 (78.2)
28 (71.8)
0.724
2
14 (27.5)
12 (21.8)
11 (28.2)
Histology
Adenocarcinoma
43 (84.3)
43 (78.2)
32 (82.1)
0.714
Nonadenocarcinoma
8 (15.7)
12 (21.8)
7 (17.9)
Smoking status
Nonsmoker
29 (56.9)
31 (56.4)
21 (53.8)
0.956
current or former smoker
22 (43.1)
24 (43.6)
18 (46.2)
T stage
T1-2
40 (78.4)
30 (54.5)
14 (35.9)
<0.001
T3-4
11 (21.6)
25 (45.5)
25 (64.1)
N stage
N0-1
38 (74.5)
25 (45.5)
19 (48.7)
0.005
N2-3
13 (25.5)
30 (54.5)
20 (51.3)
EGFR mutation
Exon 19 deletion
30 (58.8)
24 (43.6)
22 (56.4)
0.248
Exon 21 L858R
21 (41.2)
31 (56.4)
17 (43.6)
Metastases number
1
25 (49.0)
26 (47.3)
16 (41.0)
0.075
2-3
26 (51.0)
29 (52.7)
20 (51.3)
4-5
0 (0)
0 (0)
3 (7.7)
EGFK-TKIs
Gefitinib
28 (54.9)
28 (50.9)
27 (69.2)
0.328
Erlotinib
9 (17.6)
14 (25.5)
7 (18.0)
Icotinib
14 (27.5)
13 (23.6)
5 (12.8)
Second- or further-line treatment
Yes
41 (80.4)
41 (74.5)
28 (71.8)
0.614
No
10 (19.6)
14 (25.5)
11 (28.2)
ECOG, Eastern Cooperative Oncology Group; TKI, tyrosine kinase inhibitor; LAT, local ablative therapy.
The median follow-up time was 38 months (range, 9.0 to 66.8 months). For the entire cohort, the median PFS (mPFS) was 17.3 months (95% CI: 15.7–18.9) and median OS (mOS) was 35.9 months (95% CI: 33.0–38.8). The mPFS in the all-LAT, part-LAT, and non-LAT groups were 20.6 months (95% CI: 18.8–22.4), 15.6 months (95% CI: 13.8–17.4), and 13.9 months (95% CI: 11.3–16.5), respectively (p < 0.001). The mean OS (mOS) in the all-LAT, part-LAT, and non-LAT groups were 40.9 months (95% CI: 35.5–46.3), 34.1 months (95% CI: 29.4–38.8), and 30.8 months (95% CI: 25.2–36.4), respectively (p < 0.001) (Fig. 2). The difference was statistically significant between All-LAT group and Part-LAT or Non-LAT group but was not significant between the part-LAT and non-LAT groups (Fig. 2).
Figure 2Kaplan-Meier plot of (A) PFS and (B) OS in All-LAT, Part-LAT and Non-LAT. PFS, progression-free survival; OS, overall survival; LAT, local ablative therapy; CI, confidence interval; HR, hazard ratio.
To further clarify the beneficial populations from consolidative LAT, we subdivided patients by metastases sites. The mOS rates were significantly improved with the use of consolidative LAT for primary tumor (40.5 versus 31.5 months, HR = 0.49, 95% CI: 0.34–0.70, p < 0.001), brain metastases (38.2 versus 29.2 months, HR = 0.48, 95% CI: 0.30–0.76, p = 0.002), and adrenal metastases (37.1 versus 29.2 months, HR = 0.48, 95% CI: 0.23–0.94, p = 0.032). The mOS rates were also better in the consolidative LAT group rather than the non-LAT group but lacking of statistical significance in patients with bone metastases, contralateral lung metastases, and liver metastases (Figs. 3A–F).
Figure 3The OS by consolidative LAT sites. (A) Primary tumor. (B) Brain metastases. (C) Bone metastases. (D) Adrenal metastases. (E) Contralateral lung metastases. (F) Liver metastases. PFS, progression-free survival; OS, overall survival; LAT, local ablative therapy; HR, hazard ratio; CI, confidence interval.
After the matching, 42 matched cases from the all-LAT group and part-/non-LAT groups were compared and analyzed. After PSM, the baseline characteristics including T stage, N stage, EGFR mutational subtype, and the number of oligometastatic lesions were well balanced (Supplementary Table 1). Consistent with the survival outcomes in the unmatched group, the mPFS (20.1 versus 11.9 months, HR = 0.38, 95% CI: 0.24–0.62, p < 0.001) and mOS (39.7 versus 24.8 months, HR = 0.44, 95% CI: 0.27–0.71, p = 0.001) were also significantly improved in patients who were administered LAT to all metastatic sites than those administered partial LAT or no LAT (Supplementary Fig. 1).
Univariate and Multivariate Analysis on PFS and OS
Univariate analysis identified female, ECOG PS of 0 or 1, histology of adenocarcinoma, N0-1 stage, nonsmoking status, exon 19 deletion, one metastatic lesion, and LAT for primary tumor as being significantly associated with better PFS. Multivariate analysis revealed LAT for primary tumor as an independent predictive factor for better PFS (HR = 0.36, 95% CI: 0.24–0.52, p < 0.001), as well as histology of adenocarcinoma (HR = 0.50, 95% CI: 0.32–0.78, p = 0.003), nonsmoking status (HR = 0.56, 95% CI: 0.36–0.87, p = 0.011), N0-1 stage (HR = 0.59, 95% CI: 0.41–0.86, p = 0.005), exon 19 deletion (HR = 0.61, 95% CI: 0.43–0.87, p = 0.006), and one metastatic lesion (HR = 0.49, 95% CI: 0.34–0.70, p < 0.001) (Table 3).
Table 3Univariable and Multivariable Analysis of Covariables Associated With PFS
Variable
Univariable Analysis
Multivariable Analysis
HR
95% CI
p
HR
95% CI
p
Age
<65 vs. ≥65
0.96
0.68-1.35
0.799
Gender
Male vs. Female
1.44
1.03 -2.00
0.031
0.85
0.56-1.30
0.457
ECOG performance status
0-1 vs. 2
0.65
0.44-0.95
0.026
0.71
0.47-1.05
0.088
Histology
Adenocarcinoma vs. nonadenocarcinoma
0.48
0.31-0.74
0.001
0.50
0.32-0.78
0.003
Smoking status
Nonsmoker vs. current or former smoker
0.72
0.51-1.00
0.049
0.56
0.36-0.87
0.011
T stage
T1-2 vs. T3-4
0.77
0.55-1.07
0.121
N stage
N0-1 vs. N2-3
0.61
0.44-0.86
0.004
0.59
0.41-0.86
0.005
EGFR mutation
Exon 19 deletion vs. Exon 21 L858R
0.63
0.45-0.88
0.007
0.61
0.43-0.87
0.006
Metastases number
1 vs. >1
0.60
0.43-0.83
0.002
0.49
0.34-0.70
<0.001
LAT for primary tumor
Yes vs. No
0.42
0.30-0.60
<0.001
0.36
0.24-0.52
<0.001
HR, hazard ratio; CI, confidence interval; LAT, local ablative therapy; ECOG, Eastern Cooperative Oncology Group; EGFR, ▪▪▪; PFS, progression-free survival.
Multivariate analysis on OS showed that histology of adenocarcinoma, nonsmoking status, N0-1 stage, exon 19 deletion, one metastatic lesion, receiving subsequent treatment, and LAT for primary tumor were associated with better OS (Table 4).
Table 4Univariable and Multivariable Analysis of Covariables Associated With OS
Variable
Univariable Analysis
Multivariable Analysis
HR
95% CI
p
HR
95% CI
p
Age
<65 vs. ≥65
0.83
0.58-1.19
0.30
Gender
Male vs. Female
1.58
1.11-2.25
0.011
0.97
0.62-1.51
0.899
ECOG performance status
0-1 vs. 2
0.77
0.57-1-1.15
0.20
0.91
0.59-1.40
0.676
Histology
Adenocarcinoma vs. nonadenocarcinoma
0.49
0.31-0.76
0.001
0.46
0.29-0.73
0.001
Smoking status
Nonsmoker vs. current or former smoker
0.66
0.46-0.94
0.021
0.60
0.37-0.96
0.034
T stage
T1-2 vs. T3-4
0.90
0.63-1.28
0.554
N stage
N0-1 vs. N2-3
0.68
0.48-0.97
0.031
0.66
0.45-0.95
0.027
EGFR mutation
Exon 19 deletion vs. Exon 21 L858R
0.52
0.36-0.74
<0.001
0.50
0.34-0.74
<0.001
Metastases number
1 vs. >1
0.56
0.39-0.80
0.002
0.51
0.35-0.76
0.001
LAT for primary tumor
Yes vs. No
0.49
0.34-0.70
<0.001
0.45
0.30-0.66
<0.001
Subsequent treatment
Yes vs. No
0.58
0.38-0.88
0.01
0.49
0.32-0.76
0.002
HR, hazard ratio; CI, confidence interval; LAT, local ablative therapy; ECOG, Eastern Cooperative Oncology Group; OS, overall survival.
With regard to toxicity, the most common toxicities included skin rash, diarrhea, neutropenia, fatigue, nausea, vomiting, alanine aminotransferase, and pneumonitis during EGFR-TKI therapy. The majority of toxicities were grade 1 to 2. Rates of severe (grade ≥3) rush and alanine aminotransferase were 6.2% and 2.7%, respectively. Adverse events (grade ≥3) due to the addition of radiotherapy were radiation pneumonitis and radiation esophagitis (7.7% and 16.9%, respectively). No EGFR-TKI–related interstitial lung disease later was observed both in patients who were administered LAT of radiotherapy to lung lesion or not. One patient discontinued gefitinib because of radiation pneumonitis. No grade 5 toxicity was recorded.
Discussion
To our knowledge, this is the first large-scale study to investigate whether consolidative LAT can improve the survival outcomes of patients with stage IV EGFR-mutant NSCLC who had oligometastases during first-line EGFR-TKI therapy. LAT to all residual disease (primary tumor, lymph nodes, and metastatic sites as appropriate) can prolong both mPFS and mOS whereas LAT to only primary tumor or oligometastatic sites (part-LAT group) could not when compared with patients who did not receive any LAT (non-LAT group).
There have been several studies that had retrospectively shown the efficacy of local consolidative therapy in oligometastatic NSCLC.
Propensity score-matched analysis of comprehensive local therapy for oligometastatic non–small cell lung cancer that did not progress after front-line chemotherapy.
An individual patient data meta-analysis, including 757 patients with oligometastatic NSCLC treated with ablative therapy to all sites of disease revealed a median 5-year OS rate of 29%, far greater than a historical control of 2%.
Few prospective studies have been reported. In a single-arm phase 2 prospective trial, 40 patients who had stage IV NSCLC with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy) were enrolled.
Radical treatment of non–small-cell lung cancer patients with synchronous oligometastases: long-term results of a prospective phase II trial (Nct01282450).
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
was the first randomized trial that compare aggressive LAT versus maintenance treatment or observation for 49 patients with stage IV NSCLC with three or fewer metastases remaining after first-line systemic therapy. The mPFS was significantly improved with the use of consolidative therapy (11.9 versus 3.9 months, HR = 0.35, 95% CI: 0.18–0.66, p = 0.0054). Adverse events were similar between groups, with no grade 4 adverse events or deaths due to treatment. Another phase 2 randomized trial including 29 patients also showed a significant benefit in PFS with the addition of consolidative radiotherapy to maintenance chemotherapy for patients with oligometastatic NSCLC (9.7 versus 3.5 months, HR = 0.30; 95% CI: 0.11–0.82, p = 0.01).
Toxic effects were not increased in the consolidative radiotherapy arm. These results suggested that consolidative LAT was a feasible and tolerable option for patients with oligometastatic NSCLC although the sample size was small. However, most of the studies mentioned above enrolled patients with unknown EGFR mutational status. Therefore, our study for the first time showed a role for consolidative LAT in patients with oligometastatic EGFR-mutant NSCLC. Furthermore, the improvement of mPFS (6.7 months) obtained from consolidative LAT in our study was in line with the results of the randomized trial (8.0 and 6.2 months, respectively).
Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.
Few studies have reported consolidative therapy by specific sites of metastases. Our relatively large sample study allowed us to perform a comprehensively subgroup analyses according to sites of metastases including brain, bone, adrenal, contralateral lung, and liver metastases. Consistent with previous studies, our study showed that consolidative LAT was associated with improved survival in patients with synchronous brain oligometastatic disease.
Aggressive therapy for patients with non–small cell lung carcinoma and synchronous brain-only oligometastatic disease is associated with long-term survival.
Furthermore, although previous data have shown that NSCLC patients with isolated adrenal metastasis treated with ablative treatment (surgery or stereotactic body radiation therapy) had favorable prognoses, our study for the first time shows that consolidative LAT to adrenal metastasis can significantly improve the survival outcomes compared with the non-LAT group.
Our study also included five patients with liver metastases, which is a subpopulation with dismal prognosis. The mOS of these five patients was 31.2 months, which was similar to those without.
A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non–small-cell lung cancer.
undertook a randomized, controlled trial of 105 patients (EGFR mutational status unknown) with one to four brain metastases. The results showed that SRS followed by chemotherapy did not improve OS in oligo-brain metastases NSCLC patients compared with upfront chemotherapy (14.6 versus 15.3 months, p = 0.418). Recently, Magnuson et al.
performed a retrospective multi-institutional analysis about the optimal sequence of SRS, WBRT, and EGFR-TKIs in patients with EGFR-mutant NSCLC who developed brain metastases. This multi-institutional analysis showed that upfront SRS resulted in the longest OS compared with upfront WBRT or EGFR-TKIs (46 versus 30 versus 25 months, p < 0.001). Although the timing of LAT was not involved in our study, of the 39 patients who did not received LAT during first-line EGFR-TKI therapy (the non-LAT group), 25 (64.1%) developed disease progression when receiving salvage LAT. The result implied deferral of LAT may be associated with inferior PFS and OS.
Our study showed that only consolidative LAT to all sites can delay disease progression, which emphasizes the important role of precise staging of NSCLC before consolidative LAT. Our observations implied that for patients with occult metastases that had not been found out, they may not derive survival benefits from consolidative LAT. Therefore, it is very important to select patients with true oligometastases before the administration of consolidative LAT. Because of the great sensitivity of PET/CT for the staging of mediastinal lymph nodes and distant and occult metastases, PET/CT and brain magnetic resonance imaging (due to the limitations of PET in the brain) could be pivotal for confirming oligometastatic disease.
Although PET/CT was not routinely used for staging in our present study, we recommend the use of PET/CT before consolidation.
There are several limitations that should be acknowledged. First, this was a retrospective study in a single institution, which inevitably resulted in a selection bias. For example, there were some imbalances in baseline characteristics among these three groups, including T stage and N stage. Patients in the part-LAT or non-LAT groups had more advanced T and N stage. These imbalances may cloud the pure effect of LAT on the survival of patients with EGFR-mutant oligometastatic NSCLC. Therefore, a PSM method was performed to balance these baseline characteristics. After the matching, the mPFS and mOS rates were still significantly better in patients who were administered LAT to all metastatic sites. Furthermore, multivariate Cox regression analyses identified LAT as being independently associated with PFS and OS. Although the positive effect of consolidative LAT on survival may be diluted by some baseline characteristics in favor of the all-LAT group, our study, as least in part, showed a role of consolidative LAT for patients with EGFR-mutant oligometastatic NSCLC, as the survival benefits were in line with the improvements observed in unselected patient population. Second, this study did not use predefined treatment choice according to different oligometastatic types. In our institution, the types of consolidative LAT were determined in consultation with multidisciplinary teams, an effort to minimize the treatment heterogeneity. Third, the sample size was not large enough to detect statistical difference in some subgroups.
In conclusion, we found that consolidative LAT to all metastatic sites was a feasible option for patients with EGFR-mutant oligometastatic NSCLC during first-line EGFR-TKI treatment, with significantly improved PFS and OS compared with consolidative LAT to partial sites or observation alone.
Acknowledgments
This study was partially supported by Shanghai Municipal Health and Family Planning Commission Foundation (201440385), Shanghai Sailing Program (16YF1409600), and the National Natural Science Foundation of China (81703020).
Supplementary Data
Supplementary Fig. 1Kaplan-Meier plot of (A) PFS and (B) OS in All-LAT and Part/Non-LAT group after propensity score matching.
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