A retrospective analysis of optimal timing of thoracic radiotherapy for driver gene‐negative metastatic non‐small cell lung cancer

Abstract

Background

The optimal timing of thoracic radiotherapy (TRT) in driver‐gene‐negative metastatic non‐small cell lung cancer (mNSCLC) patients was retrospectively investigated based on survival and safety profile.

Methods

The efficacy and safety data of driver‐gene‐negative mNSCLC patients treated with TRT during maintenance after first‐line therapy was collected. Patients whose primary tumor and metastatic lesions remained no progression during maintenance and then received TRT were categorized as the NP (no progression) group, while patients who experienced slow progression during maintenance without reaching progressive disease and then received TRT were categorized as the SP (slow progression) group. The efficacy and adverse events of TRT were analyzed.

Results

In total, 149 driver‐gene‐negative mNSCLC patients treated with TRT during maintenance were enrolled into the study, with 119 in the NP group and 30 in the SP group. After a median follow‐up of 30.83 (range: 26.62–35.04) months, the median progression‐free survival (PFS) in the NP group was 11.13 versus 9.53 months in the SP group (HR 0.599, p = 0.017). The median overall survival (OS) in the NP group was 32.27 versus 25.57 months in the SP group (HR 0.637, p = 0.088). The median PFS after radiotherapy (rPFS) was 6.33 versus 3.90 months (HR 0.288, p < 0.001). The adverse events were tolerable and manageable in both groups without significant difference (p > 0.05).

Conclusion

The addition of TRT during the pre‐emptive no progression phase was associated with a significantly longer PFS than during the delayed slow progression phase and had an acceptable safety profile. Our results might support the earlier initiation of TRT after induction therapy for some patients with driver‐gene‐negative mNSCLC.

• Evidence of TRT timing in patients with driver‐gene‐negative mNSCLC is inadequate.

• Timely addition of TRT might prolong the PFS of patients with metastatic NSCLC.

• The adverse events of timely TRT are tolerable and manageable.

INTRODUCTION

Worldwide, lung cancer is the primary cause of cancer‐related deaths. ¹ Non‐small cell lung cancer (NSCLC) constitutes around 85% of all lung cancer cases. ² Although many therapeutic advances have been recently made for lung cancer treatment in addition to traditional chemotherapy, metastatic NSCLC (mNSCLC) stills remains as an incurable disease for most patients. ³ The overall survival of patients with oncogenic driver mutations has been significantly extended during the past two decades due to the ongoing advancement of targeted therapies. ⁴ Immune checkpoint inhibitors, on the other hand, have significantly prolonged the survival of driver‐gene‐negative mNSCLC patients. ⁵ However, drug resistance is eventually inevitable for either targeted therapy or immunotherapy. During the whole process management of mNSCLC, local radiotherapy alongside other local ablative strategies play a considerable role in relieving symptoms and consolidating local lesions. ⁶ Radiotherapy following effective systemic therapy has been shown to be able to prolong survival in a selected group of mNSCLC patients. ⁶

A multi‐institutional randomized trial demonstrated that local consolidative therapy was beneficial to patients with three or fewer metastases who did not progress from first‐line systemic treatment when compared with drug maintenance therapy alone. ⁷ Accumulating evidence from retrospective studies suggest that disease progression following standard first‐line systemic therapy in mNSCLC patients most frequently occurs in the location of primary disease rather than in distant metastases. ⁸ , ⁹ A meta‐analysis found that addition of radiotherapy to the primary tumor could significantly improve the OS and PFS of patients with oligometastatic NSCLC. ¹⁰ In another study, radiotherapy for thoracic diseases resulted in a significant reduction in the risk of death by 56% and in the risk of disease progression by 58%, respectively. ¹¹ Hence, the addition of radiotherapy directed at the primary tumor could confer survival benefits in a selected group of patients with mNSCLC.

To date, there has been no evidence from randomized clinical trials supporting which timing is better for survival when integrating TRT into the comprehensive treatment of mNSCLC. ¹¹ A previous retrospective study has indicated that EGFR‐TKI plus earlier TRT (receiving radiotherapy before EGFR‐TKI resistance) achieved better PFS compared with delayed TRT (receiving radiotherapy after progressive disease) in stage IV EGFR‐mutant NSCLC patients and a lower incidence of radiation pneumonitis. ¹² Nevertheless, there have been few studies which investigated  optimal timing of consolidative TRT in patients with driver gene‐negative mNSCLC. In addition, previous studies mainly focused on selected mNSCLC patients usually with oligometastatic lesions (1–5 metastatic lesions) and the timing of local radiotherapy was controversial. However, in real‐world practice, a large proportion of patients are diagnosed with disease more than 5 metastatic lesions ¹³ and might receive consolidation TRT during maintenance treatment. The optimal timing of consolidation TRT for metastatic NSCLC patients remains largely unknown.

We hypothesized that the survival advantage of incorporating thoracic radiotherapy would be greater when the primary thoracic tumor remained without progression rather than the time point when the primary thoracic lesion began to enlarge slowly during maintenance therapy. Herein, we performed a retrospective study to analyze the optimal timing to incorporate thoracic radiotherapy during maintenance therapy for patients with driver‐ gene‐negative mNSCLC after standard first‐line systemic therapy induction.

METHODS

Patients

Electronic medical records were reviewed retrospectively to obtain information on clinicopathological and clinical features and responses of enrolled patients. A retrospective study was conducted in patients with driver‐gene‐negative mNSCLC treated with different timing of thoracic radiotherapy from March 2017 to March 2022 at Shandong Cancer Hospital and Institute. The following were the criteria for inclusion: (1) Pathologically confirmed stage IV driver‐gene‐negative NSCLC including nonsquamous NSCLC without driver gene mutations including EGFR, ALK, ROS1, BRAF, NTRK, MET, RET, HER2 per NCCN 2024v1 ¹⁴ and squamous cell carcinoma. (2) Received 4 to 6 cycles of standard front‐line systemic treatment. (3) Underwent thoracic radiation therapy. (4) Were 18 years old or older with a Karnofsky performance status (KPS) of at least 70. (5) Had adequate follow‐up data. (6) All patients included had controlled disease after first‐line systemic treatment and received thoracic radiotherapy before disease progression. Patients with multiple types of cancer and those with incomplete radiation dose and course were excluded from the study (Figure 1). The Ethics Committee of Shandong Cancer Hospital and Institute approved this research, which was carried out in compliance with the Declaration of Helsinki.

FIGURE 1.

Flow chart of the patient cohort. SCHI, Shandong Cancer Hospital and Institute; NP, no progression during maintenance group; SP, slow progression during maintenance group.

Systemic regimen

In driver‐gene‐negative mNSCLC, patients must have received standard systemic treatment, achieving complete response (CR), partial response (PR) or stable disease (SD) on imaging by Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 criteria. ¹⁵ For lung squamous cell carcinoma, patients received first‐line platinum‐based chemotherapy plus anti‐programmed cell death‐1(PD‐1)/programmed cell death‐ligand 1 (PD‐L1) immune checkpoint inhibitor (ICI). For driver‐gene‐negative lung adenocarcinoma, patients received ICI plus chemotherapy, ICI plus antiangiogenic agent and chemotherapy, antiangiogenic agent plus chemotherapy or chemotherapy alone. The medical oncology team determined the specific first‐line and maintenance therapies for patients. Maintenance treatment was administered until disease progression, severe toxic events, or death, unless otherwise noted.

Radiation timing

We divided the consolidation radiotherapy into two groups according to whether the tumor load increased before disease progression. The no progression during maintenance (NP) group was classified as no change or reduction in the sum of the maximum diameter of target lesions prior to consolidation radiotherapy. The slow progression during maintenance (SP) group was defined as those in which radiotherapy was added when the sum of the maximum diameter of the tumor target lesions had increased but within 20% according to RECIST 1.1 criteria. PFS was calculated as the time between from the start of systemic therapy and clinical progression or mortality from any cause, whereas OS was measured as the time interval from systemic therapy initiation to mortality from any cause or the last follow‐up. The rPFS was defined as the time between the first day of thoracic radiotherapy and clinical progression or mortality from any cause. The OS after radiotherapy (rOS) was measured as the time interval from thoracic radiotherapy initiation to mortality from any cause or the last follow‐up. Using the maximally selected test statistics from R package survminer and Jamovi (version 2.3.28), we determined the best cutoff points for survival analysis to identify a threshold for the sum of the maximum diameter of tumor target lesion growth within the 0%–20% range in the SP group. The calculated cutoff value was 0.098, which was then used to categorize the SP group into two subgroups, the low group (<0.098) and the high group (≥0.098).

Radiation technique

External beam radiation was adopted to treat all the thoracic main illness locations. All patients enrolled were treated with intensity‐modulated RT (IMRT). Eclipse (Varian Medical Systems, Palo Alto, CA, version 13.5.35) provided diametric parameters. The treating radiologist chose either definitive dosages or palliative doses according to the condition of patients. The gross tumor volume (GTV) was calculated using all available computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography‐computed tomography (PET‐CT) data. The clinical tumor volume (CTV) contained subclinical lesions and potential tumor invasion sites. The planning target volume (PTV) was set as the CTV plus 5 mm. Radiotherapy included conventional fractional radiotherapy (CFRT) and hypofractionated radiotherapy (HPRT). Conventional fractionation is defined as 1.8–2 Gy/fraction. Moderate hypofractionation is defined as 2–5 Gy/fraction and ultra‐hypofractionation is defined as >5 Gy/fraction. ¹⁶ These patients received 45–60 Gy in total, split into five weekly fractions (once daily).

Follow‐up

Primary and metastatic lesions were imaged using CT or PET‐CT at baseline. Throughout treatment, the majority of patients in our study received radiological evaluations every 6 weeks. All patients were followed up until the cutoff date of December 1, 2022, or until death. Two senior radiologists independently assessed each surveillance scan for original lesion status and disease progression using the RECIST 1.1 criteria.

Statistical analysis

Descriptive statistics, expressed as numbers and percentages for categorical variables, were adopted in this research to present the distribution of patients' baseline and clinical characteristics. Tumor staging was basically assessed based on the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual. This research adopted RECIST 1.1 to assess tumor response to RT. The Kaplan–Meier method was adopted to assess survival, whereas univariate and multivariate analyses of survival were performed using a Cox hazard regression model. Treatment related toxicity was assessed based on National Cancer Institute Common Terminology Criteria for Adverse Events. SPSS (version 23.0, IBM Corporation) was employed for all statistical analyses.

RESULTS

Patient characteristics

Between March 2017 and March 2022, 149 patients with driver‐gene‐negative mNSCLC who received TRT were enrolled into the study after screening (Figure 1). The characteristics of the patients were listed in Table 1. The patients' median age was 60 (range: 54–66) years old with 71 patients (47.7%) aged under 60 years old. There were 111 (74.5%) male patients. There was a disparity in the number of patients enrolled in the two histological types (squamous cell carcinoma and adenocarcinoma). However, due to the limited number of cases and to prevent the loss of available survival data, propensity score matching (PSM) was not used. Histopathological diagnosis of adenocarcinoma and squamous cell carcinoma was found in 113 (75.8%) and 36 (24.2%) patients, respectively. Among all patients, 56 (37.6%) had brain metastasis, 42 (28.2%) had bone metastasis, and 13 (8.7%) had liver metastasis. Thirty‐nine of the 56 patients with baseline brain metastasis underwent local brain radiotherapy prior to disease progression. Among 42 patients with baseline bone metastasis, 21 received bone radiotherapy before disease progression. Prior to thoracic radiotherapy, a total of 25 patients (16.8%) did not receive maintenance systemic treatment. The proportions of 149 patients in the groups of oligometastatic disease and non‐oligometastatic disease were 53.7% (n = 80) and 46.3% (n = 69). The objective response rate (ORR) after systemic treatment before radiotherapy was 59.7% in the NP group versus 59.7% in the SP group. All other patient characteristics are presented in Table 1.

TABLE 1.

Baseline clinicopathological characteristics of enrolled patients.

Characteristics	NP	SP	Total	p‐value
	(N = 119)	(N = 30)	(N = 149)
Gender, n (%)
Male	86 (72.3)	25 (83.3)	111 (74.5)	0.214
Female	33 (27.7)	5 (16.7)	38 (25.5)
Age, n (%)
< 60	57 (47.9)	14 (46.7)	71 (47.7)	0.904
≥ 60	62 (52.1)	16 (53.3)	78 (52.3)
Smoker, n (%)
YES	60 (50.4)	19 (63.3)	79 (53.0)	0.205
NO	59 (49.6)	11 (36.7)	70 (47.0)
Histology, n (%)
Adeno	94 (79.0)	19 (63.3)	113 (75.8)	0.073
Squamous	25 (21.0)	11 (36.7)	36 (24.2)
Treatment group, n (%)
Chemo	43 (36.1)	10 (33.3)	53 (35.6)	0.174
Imm + chemo	29 (24.4)	13 (43.3)	42 (28.2)
Bev + chemo	37 (31.1)	6 (20.0)	43 (28.9)
Bev + imm + chemo	10 (8.4)	1 (3.3)	11 (7.4)
Metastasis sites, n (%)
Brain, n (%)
YES	41 (34.5)	15 (50.0)	56 (37.6)	0.116
NO	78 (65.5)	15 (50.0)	93 (62.4)
Bone, n (%)
YES	33 (27.7)	9 (30.0)	42 (28.2)	0.805
NO	86 (72.3)	21 (70.0)	107 (71.8)
Liver, n (%)
YES	8 (6.7)	5 (16.7)	13 (8.7)	0.085
NO	111 (93.3)	25 (83.3)	136 (91.3)
Lung, n (%)
YES	22 (18.5)	7 (23.3)	29 (19.5)	0.549
NO	97 (81.5)	23 (76.7)	120 (80.5)
Others, n (%)
YES	54 (45.4)	10 (33.3)	64 (43.0)	0.234
NO	65 (54.6)	20 (66.7)	85 (57.0)
Baseline brain metastasis treated with local radiotherapy, n (%)
YES	30 (25.2)	9 (30.0)	39 (26.2)	0.342
NO	11 (9.2)	6 (20.0)	17 (11.4)
Baseline bone metastasis treated with local radiotherapy, n (%)
YES	16 (13.4)	5 (16.7)	21 (14.1)	0.707
NO	17 (14.3)	4 (13.3)	21 (14.1)
Baseline liver metastasis treated with local radiotherapy, n (%)
YES	1 (0.8)	1 (3.3)	2 (1.3)	0.715
NO	7 (5.9)	4 (13.3)	11 (7.4)
Disease site metastatic status prior to TRT, n (%)
Oligo	61 (51.3)	19 (63.3)	80 (53.7)	0.236
Non‐oligo	58 (48.7)	11 (36.7)	69 (46.3)
Maintenance treatment, n (%)
YES	98 (82.4)	26(86.7)	124 (83.2)	0.572
NO	21 (17.6)	4 (13.3)	25 (16.8)
Clinical efficacy of first‐line systemic treatment, n (%)
Complete response	0 (0)	0 (0)	0 (0)	0.973
Partial response	71 (59.7)	18 (60.0)	89 (59.7)
Stable disease	48 (40.3)	12 (40.0)	60 (40.3)
Progressive disease	0 (0)	0 (0)	0 (0)
Objective response	71 (59.7)	18 (60.0)	89 (59.7)	0.973
Dose fractionation, n (%)
CFRT	86 (72.3)	23 (76.7)	109 (73.2)	0.393
Moderate‐HPRT	26 (21.8)	7 (23.3)	33 (22.1)
Ultra‐HPRT	7 (5.9)	0 (0.0)	7 (4.7)

Abbreviations: Adeno, adenocarcinoma; Bev, bevacizumab; CFRT, conventional fractional radiotherapy; Chemo, chemotherapy; Imm, immune checkpoint inhibitors; Moderate‐HPRT, moderate‐hypofractionated radiotherapy (>2 to <5 Gy/fraction); Non‐oligo, non‐oligometastatic disease (generally >5 metastatic lesions); NP, no progression during maintenance of thoracic disease; Oligo, oligometastatic disease (1–5 metastatic lesions); SP, slow progression during maintenance of thoracic disease without reaching progressive disease; Squamous, squamous carcinoma; TRT, thoracic radiotherapy; Ultra‐HPRT, ultra‐hypofractionated radiotherapy (>5 Gy/fraction).

Response evaluation

As shown in Table 2, 149 individuals could be evaluated for TRT response following radiation. Progressive disease (PD), PR and SD were determined in 12 (8.1%), 18 (12.1%) and 119 (79.9%) patients, respectively. In the NP group, 4.2% of patients had reached PD including 2.5% of patients with progressive disease beyond the primary lesion. In the SP group, 23.3% of patients had reached PD. The disease control rate (DCR) in the NP group was 95.8% compared to 76.7% in the SP group at 4 weeks after radiotherapy.

TABLE 2.

Comparison of clinical efficacy between the NP and SP groups (p < 0.001).

Response	NP, N (%)	SP, N (%)
Overall response
Complete response	0 (0)	0 (0)
Partial response	15 (12.6)	3 (10.0)
Stable disease	99 (83.2)	20 (66.7)
Progressive disease	5 (4.2)	7 (23.3)
Progression other than primary lesion primary lesion	3 (2.5)	7 (23.3)
Objective response	15 (12.6)	3 (10.0)
Disease control	115 (95.8)	23 (76.7)

Abbreviations: NP, no progression during maintenance of thoracic disease; SP, slow progression during maintenance of thoracic disease without reaching progressive disease.

Survival analysis

Until the cutoff date of December 1, 2022, the cohort had a median follow‐up time of 30.83 months (ranging from 26.62 to 35.04 months). A total of 73 individuals were still alive at the latest follow‐up (62 in the NP group, 11 in the SP group). As shown in Figure 2a, the median PFS (mPFS) for the NP and SP groups, were 11.13 months (95% CI: 10.506–11.754) and 9.53 months (95% CI: 8.459–10.601), respectively. As shown in Figure 2b, the median OS (mOS) for the NP and SP groups were 32.27 months (95% CI: 25.055–39.485) and 25.57 months (95% CI: 18.662–32.478), respectively. As shown in the univariate and multivariate analyses, those who received TRT when the disease was still under control (NP) had substantially longer mPFS than those who received TRT when the disease began to enlarge (SP). Univariate and multivariate analysis of PFS showed that non‐oligometastatic disease was predictive of shorter PFS (p < 0.05) (Table 3). The median PFS was 11.30 and 10.23 months for the oligometastatic disease group and non‐oligometastatic disease group (p = 0.09), respectively. The median OS was 35.97 and 25.27 months for the oligometastatic disease group and non‐oligometastatic disease group (p = 0.018), respectively. Patients who received radiotherapy in the NP group had a better rPFS than those in the SP group (6.33 vs. 3.90 months, respectively, p < 0.001) (Figure 3a). Patients who received radiotherapy in the NP group had a better rOS than those in the SP group (25.43 vs. 21.25 months, respectively, p = 0.029) (Figure 3b). The median PFS and OS were 10.93 and 29.47 months for all 149 patients enrolled in this study (Figure 4). The immune plus chemotherapy treatment group exhibited the longest mPFS among the four treatment regimens (Figure 5a). However, the difference in PFS did not reach statistical significance. As shown in Figure 5b, the median PFS (mPFS) for the low and high groups were 10.90 months (95% CI: 9.122–12.678) and 7.5 months (95% CI: 5.207–9.793), respectively (p = 0.009).

FIGURE 2.

(a) Progression‐free survival (PFS) and (b) overall survival (OS) in patients given thoracic radiotherapy between the NP and SP groups.

TABLE 3.

Univariate and multivariate analyses in covariables associated with PFS and OS.

Variables	PFS			OS
	HR	95% CI	p‐value	HR	95% CI	p‐value
$\text{Univariate analysis}$
$\text{Gender}$
$\text{Male}$	1			1
$\text{Female}$	0.791	0.524–1.197	0.266	0.754	0.439–1.297	0.308
$\mathrm{Age}\left(\text{years}\right)$
$<60$	1			1
$\ge 60$	1.100	0.770–1.571	0.601	1.286	0.820–2.019	0.273
Smoker
YES	1			1
NO	0.946	0.663–1.350	0.759	0.958	0.607–1.511	0.852
Histology
Adeno	1			1
Squamous	1.092	0.722–1.652	0.677	1.060	0.627–1.791	0.828
Treatment group
Chemo	1		0.176	1		0.235
Imm + chemo	0.612	0.386–0.971	0.037	0.941	0.473–1.871	0.862
Bev + chemo	0.771	0.499–1.192	0.242	1.512	0.909–2.516	0.111
Bev + imm + chemo	1.028	0.505–2.096	0.906	0.566	0.134–2.386	0.438
Metastasis sites
Brain
YES	1			1
NO	1.041	0.719–1.508	0.830	0.920	0.577–1.467	0.920
Bone
YES	1			1
NO	0.759	0.513–1.121	0.166	0.632	0.383–1.042	0.072
Liver
YES	1			1
NO	0.461	0.253–0.840	0.011	0.410	0.195–0.864	0.019
Lung
YES	1			1
NO	0.891	0.579–1.371	0.600	1.338	0.745–2.404	0.330
Others
YES	1			1
NO	1.053	0.736–1.506	0.777	1.203	0.753–1.924	0.439
Disease site metastatic status prior to TRT
Oligo	1			1
Non‐oligo	1.603	1.120–2.294	0.010	1.730	1.091–2.742	0.020
Dose fractionation
CFRT	1		0.704	1		0.490
Moderate‐HPRT	0.840	0.549–1.286	0.422	0.779	0.439–1.383	0.394
Ultra‐HPRT	1.070	0.434–2.643	0.883	1.468	0.528–4.081	0.462
Timing of radiotherapy
NP	1			1
SP	1.668	1.092–2.550	0.018	1.569	0.931–2.645	0.091
Multivariate analysis
Bone			‐
YES	‐	‐	‐	1
NO	‐	‐	‐	0.831	0.475–1.452	0.515
Liver
YES	1			1
NO	0.624	0.331–1.175	0.144	0.624	0.279–1.395	0.250
Timing of radiotherapy
NP	1			1
SP	1.849	1.194–2.863	0.006	1.657	0.954–2.876	0.073
Disease site metastatic status prior to TRT
Oligo	1			1
Non‐oligo	1.642	1.116–2.414	0.012	1.630	0.949–2.801	0.077

Note: –: Not involved in the multivariable logistic regression model. Boldness indicates p‐value less than 0.05; Variates with p‐value < 0.1 in univariate analyses were then subjected to multivariate analysis.

Abbreviations: Adeno, adenocarcinoma; Bev, bevacizumab; CFRT, conventional fractional radiotherapy; Chemo, chemotherapy; CI, confidence interval; HR, hazard ratio; Imm, immune checkpoint inhibitors; Moderate‐HPRT, moderate‐hypofractionated radiotherapy (>2 to <5 Gy/fraction); non‐oligo, non‐oligometastatic disease (generally >5 metastatic lesions); NP, no progression during maintenance of thoracic disease; Oligo, oligometastatic disease (1–5 metastatic lesions); OS, overall survival; PFS, progression‐free survival; SP, slow progression during maintenance of thoracic disease without reaching progressive disease; Squamous, squamous carcinoma; TRT, thoracic radiotherapy; Ultra‐HPRT, ultra‐hypofractionated radiotherapy (>5 Gy/fraction).

FIGURE 3.

(a) Progression‐free survival after radiotherapy (rPFS) and (b) overall survival after radiotherapy (rOS) in patients between the NP and SP groups.

FIGURE 4.

(a) Progression‐free survival (PFS) and (b) overall survival (OS) in 149 driver gene‐negative advanced NSCLC patients received thoracic radiotherapy.

FIGURE 5.

(a) Progression‐free survival (PFS) in the four groups of patients with different treatment regimens. (b) Progression‐free survival (PFS) in two group of patients in SP group. The low group was defined as the sum of the maximum diameter of tumor target lesion growth within the range of 0%–9.8%, while the high group was defined as the sum of the maximum diameter of tumor target lesion growth ranging from 9.8% to 20% according to RECIST 1.1 criteria.

Subgroup analysis of patients with different timing of radiotherapy

The PFS subgroup analysis showed that the NP group was superior to the SP group in the subgroup of male, adenocarcinoma histology, less than 60 years old, presence of bone metastases, absence of liver metastasis and CFRT (p < 0.05) (Figure 6a). Additionally, the OS subgroup analysis showed that the NP group was favored over the SP group in patients less than 60 years old (p < 0.05) (Figure 6b). The mPFS in patients who received brain radiotherapy was 12.40 months in the NP group and 9.53 months in the SP group (p = 0.009) (Figure 6a). The mOS was 26.80 months in the NP group and 25.57 months in the SP group (p = 0.559) (Figure 6b). The mPFS in patients who received bone radiotherapy was 10.27 months in the NP group and 8.27 months in the SP group (p = 0.089) (Figure 6a). The mOS was 25.10 months in the NP group and 16.10 months in the SP group (p = 0.964) (Figure 6b). Only two patients with baseline liver metastasis received liver radiotherapy. Therefore, subgroup analyses of local radiotherapy for liver metastasis was not reported. For patients with oligometastatic metastases, the mPFS was 11.57 months in the NP group and 10.20 months in the SP group, with no statistical significance (p = 0.07) (Figure 6a). The mOS for patients with oligometastatic disease was 41.03 months in the NP group and 26.57 months in the SP group, with no statistical significance (p = 0.051) (Figure 6b). For patients with non‐oligometastatic metastases, the mPFS was 10.70 months in the NP group and 8.27 months in the SP group, showing a significant difference (p = 0.01) (Figure 6a). The mOS for patients with non‐oligometastatic metastases was 25.50 months in the NP group and 16.10 months in the SP group, showing no statistical significance (p = 0.225) (Figure 6b).

FIGURE 6.

(a) Progression‐free survival (PFS) and (b) overall survival (OS) in subgroup analysis of patients with different timing of radiotherapy.

Toxicity assessment

The most common adverse event was grade 2 hematological toxicities, which was observed in 41.2% of the NP group patients (n = 49) and 40.0% of the SP patients (n = 12). Eight patients (6.7%) developed grade 1 gastrointestinal toxicity in the NP group. The incidence of grade 2 gastrointestinal toxicity was 46.2% in the NP group and 36.7% in the SP group. Additional common adverse events included pneumonitis, esophagitis, and dermatitis, but there was no statistically significant difference between the two groups (p > 0.05) (Table 4).

TABLE 4.

Comparison of toxicity between the NP group and SP group.

Adverse events	NP	N (%)	SP	N (%)	p‐value
Hematological toxicity
Grade 1	29	(24.4%)	11	(36.7%)	0.320
Grade 2	49	(41.2%)	12	(40.0%)
Liver dysfunction	8	(6.7%)	4	(13.3%)	0.234
Gastrointestinal toxicity
Grade 1	8	(6.7%)	0	(0.0%)	0.152
Grade 2	55	(46.2%)	11	(36.7%)
Radiation pneumonitis
Grade 2	21	(17.6%)	5	(16.7%)	0.764
Grade 3	2	(1.7%)	0	(0.0%)
Radiation esophagitis	25	(21.0%)	5	(16.7%)	0.596
Radiation dermatitis	2	(1.7%)	0	(0.0%)	0.476

Abbreviations: NP, no progression during maintenance of thoracic disease; SP, slow progression during maintenance of thoracic disease without reaching progressive disease.

DISCUSSION

The efficacy of cytotoxic chemotherapy for mNSCLC is suboptimal with a median PFS of only 4–6 months. ¹⁷ , ¹⁸ Although immunotherapy has greatly improved the survival of some patients, most patients with driver‐gene‐negative mNSCLC would progress within less than 10 months upon first‐line systemic therapy. ¹⁹ , ²⁰ , ²¹ , ²² Therefore, it is crucial to search for new treatment modality to delay disease progression after first‐line therapy and improve survival.

Several studies have provided evidence supporting the role of local consolidative therapy in the treatment of mNSCLC. For example, the study carried out by Gomez et al. presented a much longer PFS and OS in patients with oligometastatic NSCLC treated with systemic therapy in combination with radical local treatment of both primary tumor and metastasis. ²³ Similarly, the study by Lyengar et al. reported that addition of consolidative radiation or surgery yielded a much longer PFS of 14.2 months in oligometastatic NSCLC. ⁸ Another study by Collen et al. presented a median PFS of 11.2 months in mNSCLC patients treated with SBRT following induction chemotherapy. ²⁴ Previous studies indicated that local consolidative radiotherapy was associated with enhanced survival with acceptable safety profile in oligometastatic NSCLC. ²³ , ²⁴ , ²⁵

In non‐oligometastatic mNSCLC with multiple metastatic lesions, it is usually difficult or impossible to control all the lesions with local ablative therapies. However, the radiation treatment for primary lung tumors might be able to improve PFS by regulating antitumor immunity in these non‐oligometastatic patients. The study by García‐Mulero et al. concluded that the lung was the most immunogenic organ. ²⁶ In addition, patterns of failure studies have demonstrated that disease progression most often occurs at the primary lesion in mNSCLC. ⁹ This clinical scenario offers the idea of combining thoracic radiotherapy with first‐line systemic therapy, which may potentially enable patients to sustain first‐line therapy for an extended duration. A secondary analysis of two prospective studies about non‐oligometastatic stage IV NSCLC revealed that thoracic radiotherapy could extend patient survival based on the effectiveness of systemic chemotherapy. ²⁷ A retrospective study of 79 patients with non‐oligometastatic epidermal growth factor receptor (EGFR) mutant NSCLC showed that patients with stable disease during first‐line targeted therapy had significantly improved PFS after receiving SBRT for primary lung tumors. ²⁸ Another retrospective study in an expanded sample showed that patients with non‐oligometastatic EGFR‐mutant NSCLC benefited from thoracic radiotherapy during EGFR‐TKI treatment. ¹²

A few studies have also investigated the optimal timing of local radiotherapy to be integrated in the comprehensive treatment of mNSCLC. Several studies have shown that induction chemotherapy followed by radiotherapy is an effective method for its advantage in identifying treatment responders. ⁷ , ²⁹ Consolidative radiotherapy is usually administered to responders 3 months after systemic therapy. ³⁰ Patel et al. suggest that the optimal time to add local radiation for metastatic NSCLC may be when pre‐emptive local therapy is used during systemic therapy to address the disease areas most likely to lead to disease progression. ³¹ In the study of Wei et al., 45 mNSCLC patients with EGFR activating mutations received radiation therapy to the primary lesion before disease progression and it was found that the pre‐emptive RT group had a significantly better median PFS than the delayed RT group (22.3 months vs. 12.9 months). ²⁸ Zhou et al. found that non‐oligometastatic NSCLC patients with EGFR mutations benefited more from thoracic radiotherapy while using EGFR inhibitors compared with those who received radiotherapy after progressive disease. ¹² These findings suggest that the timely addition of thoracic radiotherapy might be associated with better survival. However, existing studies have focused on the role and the timing of consolidation radiotherapy in driver‐gene‐positive mNSCLC, research on the optimal timing of consolidative TRT in driver‐gene‐negative NSCLC was limited.

In this study, we found that patients who received TRT had longer mPFS (10.93 months) than historical data. Consolidative TRT given during no progression (NP) stage significantly improved PFS compared to TRT given during slow progression (SP) stage (11.13 months vs. 9.53 months, p = 0.017). Furthermore, patients who received radiotherapy within the 0%–9.8% range of tumor target lesion growth exhibited a longer median PFS compared to those within the 9.8–20% range (10.90 months vs. 7.50 months, p = 0.009). However, we did not observe a significant OS difference between two timing groups (32.27 months vs. 25.57 months, p = 0.088). It's understandable that the difference between later‐line treatment will significantly influence overall survival.

There are several potential reasons why adding TRT during the no progression stage is more beneficial than during slow progression stage. Firstly, consolidative radiotherapy shifts the tumor growth curve from a sigmoidal pattern to exponential growth, enhancing the anticancer activity of systemic therapy which is dependent on tumor growth rate. ³² Once the tumor has stabilized or responded to initial systemic therapy, maintenance therapy alone could not eradicate treatment‐resistant malignant cells, potentially leading to progression. However, radiotherapy to the primary site can target and reduce resistant cells, mitigating the risk of subsequent progression or metastasis. ³³ , ³⁴ Hence, the timely incorporation of consolidation radiotherapy during the maintenance phase is likely to be more effective than delaying radiotherapy until slow progression occurs. Secondly, consolidation radiotherapy has the potential to enhance the sensitivity of subsequent maintenance therapy for residual disease. Residual tumor after early systemic therapy can contribute to the growth of distant micro‐metastases. By reducing the burden of residual tumor, timely TRT might delay the progression of distant micro‐metastatic disease. ²³

In addition to survival benefit, toxicity is a crucial factor for treatment decision‐making while considering consolidative TRT. The occurrence rate of pneumonia in patients undergoing SBRT and ICI treatment was 17%. ³⁵ The incidence of grade 1–2 radiation pneumonia in patients receiving concomitant thoracic radiotherapy with EGFR‐TKI differed with 29.8% in the pre‐emptive radiotherapy group and 75.8% in the delayed radiotherapy group. ¹² In this study, the incidence of grade 2 radiation pneumonitis in the slow progression group (17.6%) was comparable to that in the fast progression group (16.7%). Grade 3 adverse effects were reported in only 1.7% of all patients. Among the two patients who experienced grade 3 radiation pneumonia, the pneumonia showed improvement within 2 weeks after the commencement of corticosteroid therapy and supportive care. No new radiation adverse events were identified in this study. Additionally, our study reported no cases of fatal pneumonia, and all adverse events were treated promptly and well‐tolerated, indicating the safety of adding radiotherapy during the stabilization phase after first‐line treatment of advanced NSCLC.

This study had several limitations. Firstly, it was a single‐center retrospective analysis with a relatively small sample size. Secondly, a total of 53 patients undergoing immunotherapy treatments were recruited in this study. However, the limited duration of follow‐up restricts the maturity of OS data for immunotherapy patients. Thirdly, the electronic medical records of the majority of patients did not contain PD‐L1 expression data. Therefore, it was not possible to assess the comparative survival benefits of patients treated with thoracic radiotherapy based on PD‐L1 expression levels and identify a potentially superior subgroup. Finally, the radiotherapy regimens employed in this study varied among individual patients, resulting in the inclusion of unmeasured confounders in the subsequent assessment of long‐term outcomes.

In summary, in driver gene‐negative mNSCLC patients who received maintenance treatment after first‐line systemic therapy, the addition of thoracic radiotherapy during the pre‐emptive no progression phase was associated with a significantly longer PFS than during the delayed slow progression phase and had an acceptable safety profile. Our results might support the earlier initiation of thoracic radiotherapy after induction therapy for some of the$\text{patients with}$ driver gene‐negative$\text{mNSCLC}.$

AUTHOR CONTRIBUTIONS

Study concept and design: Xue Meng and Jisheng Li. Methodology: Wen Zhao and Hongxin Li. Data curation: Yanan Wang and Wen Zhao. Acquisition and analysis of data: Yanan Wang and Zhenhua Gao. Drafting the manuscript: Yanan Wang. Writing—review and editing: Jisheng Li. All authors have read and agreed to the published version of the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no conflicts of interests.

Wang Y, Gao Z, Zhao W, Li H, Meng X, Li J. A retrospective analysis of optimal timing of thoracic radiotherapy for driver gene‐negative metastatic non‐small cell lung cancer. Thorac Cancer. 2024;15(8):642–653. 10.1111/1759-7714.15235

DATA AVAILABILITY STATEMENT

The raw data during the current study are available by contacting the corresponding author upon reasonable request.