Abstract
Background
Immune checkpoint inhibitors (ICIs) as part of first-line treatment are becoming increasingly significant in metastatic non-small cell lung cancer (NSCLC). We aimed to investigate the efficacy and safety of thoracic radiotherapy (TRT) in addition to first-line ICIs in metastatic NSCLC.
Methods
From January 2017 to August 2023, we retrospectively collected the information of 82 patients with metastatic NSCLC who were treated with first-line ICIs and radiotherapy (RT). Patients were divided into the TRT group (n=35) and the non-TRT group (n=47). The efficacy and safety were analyzed. Propensity score matching (PSM) was applied. Inverse probability of treatment weighting (IPTW) was used as a sensitivity analysis.
Results
The median follow-up was 31.4 months (range, 4.0–81.4 months). Before PSM, the median overall survival (OS; 38.1 vs. 17.9 months, P=0.01) and median progression-free survival (PFS; 14.9 vs. 8.3 months, P=0.001) were significantly improved in the TRT group. After PSM, there were 18 patients in each group. Both the median OS [not reached (NR) vs. 26.8 months, P=0.02] and median PFS (16.3 vs. 7.5 months, P<0.001) still favored in the TRT group. The IPTW method yielded similar results [OS: hazard ratio (HR) =0.335, P=0.01; PFS: HR =0.442, P=0.02]. The most common grade 3 or worse toxicity was bone marrow suppression (18/82, 22.0%). No significant difference was found in grade 3 or worse treatment-related pneumonia between the two groups either before (5.7% vs. 6.4%, P>0.99) or after matching (0 vs. 5.6%, P>0.99).
Conclusions
The addition of TRT to first-line immunotherapy (IO) may be associated with improved survival in metastatic NSCLC. However, given the retrospective nature and limited sample size, these findings are exploratory and warrant validation in larger randomized trials.
Keywords: Non-small cell lung cancer (NSCLC), thoracic radiotherapy (TRT), immunotherapy (IO), survival, safety
Highlight box.
Key findings
• The addition of thoracic radiotherapy (TRT), which may synergistically enhance the systemic anti-tumor effects of immunotherapy (IO), was associated with improved survival without increasing the risk of severe treatment-associated pneumonia in treatment-naïve metastatic non-small cell lung cancer (NSCLC). However, these findings are exploratory and require validation in future trials.
What is known and what is new?
• IO has become the part of standard first-line treatment in metastatic NSCLC. Preclinical evidence showed that the combination of IO and radiotherapy may improve the anti-tumor effects while the optimal combination regimens, such as the choice of irradiated lesions, remains unknown.
• We investigated the real-world efficacy and safety of the addition of the thoracic radiation to the first-line IO for metastatic NSCLC. Propensity score matching was used to balance the bias.
What is the implication, and what should change now?
• This study provides exploratory evidence suggesting a potential survival benefit from adding TRT to first-line IO in treatment-naïve metastatic NSCLC. While the findings are not practice-changing at this stage, they underscore the need for well-designed prospective randomized trials to establish optimal patient selection, treatment sequencing, and integration strategies for TRT in this setting.
Introduction
Lung cancer is the most common malignant tumor leading to the highest cancer-related mortality globally (1). Over half of the lung cancer patients present with metastasis at the initial diagnosis (2), among which 80–85% are histologically subclassified as non-small cell lung cancer (NSCLC) (3). In the past decade, immunotherapy (IO), represented by immune checkpoint inhibitors (ICIs), has shown promising efficacy in numerous clinical trials (4-8), remarkably improving the survival of patients with metastatic NSCLC compared to traditional chemotherapy (9). ICI monotherapy has prolonged the median overall survival (OS) to 20.2–26.3 months and the median progression-free survival (PFS) to 7.7–8.2 months in patients with programmed cell death-ligand 1 (PD-L1) ≥50% (10). Furthermore, IO plus chemotherapy extended the median OS to 17.2–22.0 months and the median PFS to 7.2–8.5 months in patients regardless of PD-L1 status (10,11). With growing clinical evidence, various ICIs have become the part of standard first-line treatment in patients with non-oncogene-driven metastatic NSCLC (12-14).
Although IO has transformed the treatment of metastatic NSCLC, approximately only 30% patients respond to ICI monotherapy while the remainder derives little or no benefit due to primary or secondary resistance (15,16). With the preclinical evidence showing that local radiation affects both the tumor and its local microenvironment to produce systemic anti-tumor responses, often known as “abscopal effect”, the immune synergy makes the combination of radiotherapy (RT) and IO promising in future clinical application (15).
For patients who benefit from ICIs, intrathoracic tumor control remains a major difficulty. As shown in several retrospective studies, the lung is one of the most common sites of progression accounting for 53.8–61% failures in metastatic NSCLC patients treated with ICIs (17-20), which suggests that thoracic RT (TRT) may prevent disease recurrence and improve the survival. A retrospective study including 531 patients found that the history of TRT was linked to a longer median PFS (5.0 vs. 3.0 months, P=0.001) (21). Hwang et al. illustrated that TRT showed a tendency to reduce all-cause mortality in patients treated with ICIs [hazard ratio (HR) =0.66, P=0.06] (22). However, neither study limited the lines of IO and the situation of recurrence or metastasis, which may lead to substantial heterogeneity in patients and diminish the potential benefit of combination therapy. And, other studies were more focused on demonstrating the safety of TRT plus ICIs (23-25). Overall, there are few evidence exploring the efficacy from the addition of TRT to ICIs in treatment-naïve patients with metastatic NSCLC. To minimize population heterogeneity and present real-world experience of the IO era, this study evaluated the role of TRT in addition to first-line IO in patients with metastatic NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2255/rc).
Methods
Patient eligibility
From January 2017 to August 2023, the metastatic NSCLC patients treated with first-line ICIs and RT in two hospitals (the Peking University Cancer Hospital and The First Medical Center of Chinese PLA General Hospital), Beijing, China, were included in this study. According to whether received TRT (defined as radiation for lung lesions, involved locoregional lymph nodes and metastases of the chest wall) or not, they were divided into two groups: TRT group and non-TRT group.
Specifically, the inclusion criteria included: (I) age 18 years or older; (II) the patients with the Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2; (III) according to the 8th edition of the American Joint Committee on Cancer, the patients who were diagnosed as stage IV NSCLC with histological confirmation and radiographic evidence; (IV) the patients who received at least two cycles of IO as the first-line treatment, which began less than 3 months after the initial diagnosis; and (V) the patients who received RT during the first-line treatment. The patients would be excluded if they: (I) did not complete the prescribed radiation plan; (II) had other primary tumors or other autoimmune disorders; (III) harbored epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) gene mutations and received corresponding targeted therapy; (IV) previously received RT to thorax; and (V) progressed after previous antineoplastic therapy. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Boards at the Peking University Cancer Hospital (No. 2022YJZ46) and The First Medical Center of Chinese PLA General Hospital (No. S2023-697-01), and the requirement for informed consent was waived considering the retrospective nature of the present study.
Treatments
All patients received standard first-line systemic therapy comprising various ICIs with or without chemotherapy per current guidelines recommended determined specifically by the oncologists in the two hospitals. They were fully informed of their diagnosis and available treatment options, and therapeutic decisions were made in accordance with their informed preferences. In accordance with individualized consideration on pathological type and physical fitness of patients, multiple platinum-based chemotherapy regimens may be used. IO and chemotherapy were administered every 21 days for 4–6 cycles, after which patients achieving tumor controlled may receive ICI maintenance treatment until disease progression or occurrence of intolerable toxicity.
During first-line treatment, patients received RT on lesions of any site for relieving symptoms or reducing tumor burden. Patients in TRT group were performed conventional fractionated RT (CFRT) delivering total dose of 40.0–60.0 Gy in 10–30 fractions and stereotactic body RT (SBRT) delivering total dose of 50.0–60.0 Gy in 5–10 fractions, both given once daily (5 days per week). The exact dose fractionation schedules were individually determined by radiotherapists depending on the tumor location size, proximity to adjacent organ at risk, normal tissue tolerance, and the overall condition of the patients. The gross tumor volume (GTV) including the visible primary tumor and involved lymph nodes was determined according to initial images. The clinical tumor volume (CTV) that was exempt in SBRT comprised subclinical lesions and potential involved sites. Considering respiratory movements and other setup errors in the two hospitals, the planning target volume (PTV) was set as the GTV/CTV plus 5 mm. External beam was adopted with 6–10 MV photons from linear accelerators. For lung lesions, intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT) were administered. For brain lesions and bone lesions, gamma knife, and tomotherapy (TOMO) were also used, respectively (Table S1). To satisfy the dose-volume constraints of the organs at risk, the percentage of lung volume that received ≥20 Gy (V20) and ≥5 Gy (V5) was set to ≤28%, ≤60%, respectively. And the mean lung dose was set to ≤15 Gy. As various RT dose regimens were employed in multiple different sites, we calculated the standardized biologically effective dose (BED), where α/β equals to 10 Gy was adopted.
After progression, second-line chemotherapy, ICIs, targeted therapy, or supportive care were adopted. Also, patients underwent local RT on the sites of progression as salvage treatment.
Information collection and follow-up
Patients were staged with brain magnetic resonance imaging (MRI) with contrast and a whole-body 18F-positron emission tomography (PET)/computed tomography (CT), or a chest and abdomen enhanced CT at initial diagnosis. The baseline clinical characteristics were collected including sex, age, smoking status, ECOG PS, histological features, gene mutations, PD-L1 status, tumor-node-metastasis (TNM) staging, and the number of metastases. Patients with no more than 5 lesions in 1–3 distant organs were categorized to have oligometastatic disease. In addition, non-measurable lesions (e.g., malignant pericardial/pleural/peritoneal effusions and diffuse pleural/meningeal metastasis) were classified into polymetastatic disease. During the follow-up, enhanced CT and brain MRI were performed once every 1–2 months for the first 6 months and then once every 2 months afterward for 4 years.
Response, survival, and patterns of failure
The Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria was used to defined tumor response, which was assessed by the aforementioned imaging results. Objective response rate (ORR) was defined as the proportion of patients who achieved complete response (CR) or partial response (PR). Duration of response (DOR) was defined as the time from the CR or PR to initial progression, death, or the end of follow-up. PFS was defined as the time from the treatment, which referred to systemic therapy or RT whichever occurs first, to the occurrence of tumor progression, death, or the end of follow-up. Patients still alive without progression at the time of analysis were censored. Locoregional PFS (LRPFS) was defined as the time from the treatment to progression in the lung region or regional lymph nodes. Distant metastasis PFS (DMPFS) was defined as the time from the treatment to disease progression in metastatic sites. OS was defined as the time from the treatment to death or the end of follow-up. The treatment-related toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. The initial disease progression after ICIs was categorized into four patterns: (I) oligoprogression (up to 5 lesions in 3 organs) or polyprogression; (II) progression in existing lesions, new lesions, or both; (III) intrathoracic progression (including lung lesions, regional lymph nodes, and pleural lesions), extrathoracic progression, or both; and (IV) progression inside or outside the radiated field or both.
Statistical analysis
In order to control the potential confounders and selection bias, propensity score matching (PSM) analysis with a 1:1 matching ratio and a caliper set to 0.03 was performed. Propensity scores were calculated by logistic regression using four baseline characteristics (histological feature, N stage, brain metastases, and bone metastases). PSM was used to balance these covariates between the two groups. To further assess the robustness of the results, a sensitivity analysis of survival was performed using stabilized inverse probability of treatment weighting (IPTW).
Categorical variables were presented by numbers and percentiles, analyzed using Fisher exact or χ2 test. For continuous variables, which were analyzed using Student’s t-test or Mann-Whitney U test, medians and ranges or interquartile ranges (IQRs) were reported. OS and PFS were displayed by the Kaplan-Meier curves, with the log-rank test checking the comparison. The Cox proportional-hazards regression model was used for univariate analyses of OS and PFS. The analysis was performed by SPSS (version 29.0; IBM, NY, USA) and R (version 4.4.1; San Francisco, CA, USA). All tests were two-sided and a P value less than 0.05 was considered statistically significant.
Results
Baseline characteristics
Totally, 82 patients presenting with synchronously metastatic NSCLC were enrolled in this study, among which 35 patients (42.7%) were assigned into the TRT group. The median age of the total was 63 years (range, 33–82 years). Sixty-six patients (80.5%) were male and 64 patients had a history of smoking (78.0%). Fifty-one patients presented with adenocarcinoma (62.2%) followed by squamous cell carcinoma (32.9%). In all patients, 52 patients (63.4%) performed PD-L1 testing, among which, 19 patients (36.5%) and 18 patients (34.6%) were with PD-L1 status of 1–49% and 50% or more, respectively. Before matching, there were more patients in the TRT group without definitive results of gene testing (37.1% vs. 12.8%, P=0.04) and in the non-TRT group with brain metastases (59.6% vs. 20.0%, P<0.001) and bone metastases (48.9% vs. 22.9%, P=0.02) at baseline. After PSM, the baseline characteristics were all well-balanced (P>0.05). The characteristics of the two groups were depicted in Table 1.
Table 1. Baseline characteristics of patients before and after the matching.
| Variables | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| TRT group (n=35) | Non-TRT group (n=47) | P value | TRT group (n=18) | Non-TRT group (n=18) | P value | ||
| Age (years) | 0.13 | 0.50 | |||||
| <65 | 23 (65.7) | 23 (48.9) | 12 (66.7) | 9 (50.0) | |||
| ≥65 | 12 (34.3) | 24 (51.1) | 6 (33.3) | 9 (50.0) | |||
| Sex | 0.64 | 0.40 | |||||
| Male | 29 (82.9) | 37 (78.7) | 16 (88.9) | 13 (72.2) | |||
| Female | 6 (17.1) | 10 (21.3) | 2 (11.1) | 5 (27.8) | |||
| Smoking status | 0.36 | 0.69 | |||||
| Yes | 29 (82.9) | 35 (74.5) | 15 (83.3) | 13 (72.2) | |||
| No | 6 (17.1) | 12 (25.5) | 3 (16.7) | 5 (27.8) | |||
| ECOG PS | 0.17 | >0.99 | |||||
| 0 | 18 (51.4) | 17 (36.2) | 9 (50.0) | 8 (44.4) | |||
| 1–2 | 17 (48.6) | 30 (63.8) | 9 (50.0) | 10 (55.6) | |||
| Histological features | 0.10 | >0.99 | |||||
| Squamous | 15 (42.9) | 12 (25.5) | 3 (16.7) | 4 (22.2) | |||
| Non-squamous | 20 (57.1) | 35 (74.5) | 15 (83.3) | 14 (77.8) | |||
| PD-L1 status | 0.45 | 0.41 | |||||
| Negative | 6 (17.1) | 9 (19.1) | 3 (16.7) | 3 (16.7) | |||
| 1–49% | 10 (28.6) | 9 (19.1) | 8 (44.4) | 5 (27.8) | |||
| ≥50% | 5 (14.3) | 13 (27.7) | 2 (11.1) | 6 (33.3) | |||
| Unknown | 14 (40.0) | 16 (34.0) | 5 (27.8) | 4 (22.2) | |||
| Gene mutations | 0.04* | 0.23 | |||||
| EGFR/ALK/ROS1 | 1 (2.9) | 2 (4.3) | 1 (5.6) | 0 | |||
| No available genes | 21 (60.0) | 39 (83.0) | 12 (66.7) | 16 (88.9) | |||
| Unknown | 13 (37.1) | 6 (12.8) | 5 (27.8) | 2 (11.1) | |||
| T stage† | 0.94 | 0.73 | |||||
| T1–2 | 12 (35.3) | 17 (36.2) | 8 (44.4) | 6 (33.3) | |||
| T3–4 | 22 (64.7) | 30 (63.8) | 10 (55.6) | 12 (66.7) | |||
| N stage | 0.12 | >0.99 | |||||
| N0–1 | 12 (34.3) | 9 (19.1) | 4 (22.2) | 5 (27.8) | |||
| N2–3 | 23 (65.7) | 38 (80.9) | 14 (77.8) | 13 (72.2) | |||
| Distant metastases | 0.35 | 0.73 | |||||
| Oligometastatic | 20 (57.1) | 22 (46.8) | 12 (66.7) | 10 (55.6) | |||
| Polymetastatic | 15 (42.9) | 25 (53.2) | 6 (33.3) | 8 (44.4) | |||
| Brain metastasis | <0.001* | >0.99 | |||||
| Yes | 7 (20.0) | 28 (59.6) | 7 (38.9) | 7 (38.9) | |||
| No | 28 (80.0) | 19 (40.4) | 11 (61.1) | 11 (61.1) | |||
| Bone metastasis | 0.02* | >0.99 | |||||
| Yes | 8 (22.9) | 23 (48.9) | 8 (44.4) | 8 (44.4) | |||
| No | 27 (77.1) | 24 (51.1) | 10 (55.6) | 10 (55.6) | |||
Data are presented as n (%). †, before matching, one patient in the TRT group did not have visible primary lesion and were staged to Tx. *, significant P value (P<0.05). ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; N, node; PD-L1, programmed cell death-ligand 1; ROS1, ROS proto-oncogene 1; T, tumor; TRT, thoracic radiotherapy.
Treatments
The median interval between original diagnosis and systemic treatment initiation was 20 days (range, 1–92 days). In the first-line treatment, all patients received at least two cycles of ICIs for a median time of 205 days (range, 20–2,335 days). Most of them (72 patients, 87.8%) concurrently underwent various platinum-based chemotherapy according to the histology type per standard regimens in the guidelines. The median cycles of chemotherapy during the first-line treatment were 4 (range, 2–8). The majority (73 patients, 89.0%) were performed RT within 1 month before or after the administration of ICIs.
Patients received CFRT (52 cases, 63.4%) or hypo-fractionated RT (HFRT; 30 cases, 36.6%) according to different lesion locations. In the TRT group, 29 patients accepted CFRT at a median dose of 2.0 Gy (range, 1.8–4.0 Gy) per fraction with a median BED of 60.0 Gy (range, 56.0–84.0 Gy) for PTV, while 7 patients received HFRT with a median BED of 100.0 Gy (range, 95.2–105.0 Gy). The PTV size was 356.8 mL (range, 41.1–1,283.8 mL) and 51.9 mL (range, 17.5–79.9 mL) for CFRT and HFRT, respectively. In the non-TRT group, the irradiated sites included brain (29 cases), bone (14 cases), adrenal gland (4 cases), distant lymph nodes and soft tissues (2 cases). The detailed information of treatment was listed in Tables S1,S2.
Efficacy and survival
The median follow-up of the total was 31.4 months (range, 4.0–81.4 months). Figure 1 illustrates the survival outcomes of the included patients. The median OS and PFS were 31.1 months [95% confidence interval (CI): 21.3–not reached (NR)] and 11.3 months (95% CI: 8.6–14.3), respectively (Figure 1A,1B). Before PSM, the patients in the TRT group presented significantly better OS (median, 38.1 vs. 17.9 months; 1-year OS rates, 94.3% vs. 75.7%; 2-year OS rates, 76.0% vs. 42.0%; P=0.01; Figure 1C). Also, improved PFS was observed in the TRT group (median, 14.9 vs. 8.3 months; 1-year PFS rates, 63.7% vs. 28.8%; 2-year PFS rates, 34.9% vs. 14.4%; P=0.001; Figure 1E). The ORR at 6 weeks and the best ORR were 27.3%, 77.1% in the TRT group and 36.2%, 63.8% in the non-TRT group, respectively (P>0.05, Table 2). However, the median DOR favored patients in the TRT group (median, 13.1 vs. 6.1 months; 1-year DOR rates, 57.0% vs. 29.2%; 2-year DOR rates, 38.0% vs. 14.6%; P=0.004; Figure 1G). After matching, better survival was still achieved in the TRT group (Figure 1D,1F,1H), including OS (median, NR vs. 26.8 months, P=0.02), PFS (median, 16.3 vs. 7.5 months, P<0.001), and DOR (median, 17.0 vs. 4.9 months, P=0.008). Unlike the ORR evaluated at 6 weeks (27.8% vs. 27.8%), the best ORR in the TRT group was numerically high than those in the non-TRT group, although the difference was non-significant (83.3% vs. 55.6%, P=0.15). In addition, sensitivity analysis using IPTW also demonstrated a significant advantage in OS (HR =0.335; 95% CI: 0.142–0.787; P=0.01) and PFS (HR =0.442; 95% CI: 0.225–0.870; P=0.02) for patients who received TRT, consistent with the findings from the PSM analysis.
Figure 1.
Kaplan-Meier curves of clinical outcomes including OS, PFS, and DOR. OS of the whole patients (A) and two groups before (C) and after (D) matching. PFS of the whole patients (B) and two groups before (E) and after (F) matching. DOR of the two groups before (G) and after (H) matching. DOR, duration of response; OS, overall survival; PFS, progression-free survival; PSM, propensity score matching; TRT, thoracic radiotherapy.
Table 2. Treatment responses of the patients.
| Variables | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| TRT group (n=35) | Non-TRT group (n=47) | P value | TRT group (n=18) | Non-TRT group (n=18) | P value | ||
| Responses, after 6 weeks’ treatment† | 0.74 | >0.99 | |||||
| PR | 9 (27.3) | 17 (36.2) | 5 (27.8) | 5 (27.8) | |||
| SD | 23 (69.7) | 29 (61.7) | 13 (72.2) | 13 (72.2) | |||
| PD | 1 (3.0) | 1 (2.1) | 0 | 0 | |||
| ORR (%) | 27.3 | 36.2 | 0.40 | 27.8 | 27.8 | >0.99 | |
| Best responses | 0.39 | 0.15 | |||||
| PR | 27 (77.1) | 30 (63.8) | 15 (83.3) | 10 (55.6) | |||
| SD | 7 (20.0) | 16 (34.0) | 3 (16.7) | 8 (44.4) | |||
| PD | 1 (2.9) | 1 (2.1) | 0 | 0 | |||
| ORR (%) | 77.1 | 63.8 | 0.20 | 83.3 | 55.6 | 0.15 | |
Data are presented as n (%), unless otherwise stated. †, before matching, the responses of two patients in TRT group were not available after 6 weeks of systemic treatment. ORR, objective response rate; PD, progression disease; PR, partial response; SD, stable disease; TRT, thoracic radiotherapy.
In the univariate analysis (UVA), factors including TRT (P=0.01), in combination with chemotherapy (P=0.02), longer duration of IO (P<0.001), higher PTV dose (P=0.006), smaller PTV volume (P=0.02), achieved PR through first-line ICIs (P=0.01) and reuse of ICI after progression (P=0.02) were correlative with better OS (Figure 2A). The UVA illustrated that TRT (P=0.001), moderately differentiated (P=0.002), without supraclavicular lymph nodes involved (P=0.04), shorter interval between initial diagnosis and treatment (P=0.01), in combination with chemotherapy (P<0.001), longer duration of IO (P<0.001) and higher PTV dose (P=0.003) were associated with better PFS (Figure 2B).
Figure 2.
UVA of factors influencing OS (A) and PFS (B). *, significant P value (P<0.05). CI, confidence interval; BED, biologically effective dose; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IO, immunotherapy; LNs, lymph nodes; oligo, oligometastatic; OS, overall survival; PD-L1, programmed cell death-ligand 1; PFS, progression-free survival; poly, polymetastatic; PR, partial response; PTV, planning target volume; TRT, thoracic radiotherapy; UVA, univariate analysis.
Safety
In total, 25 patients (30.5%) experienced grades 3–4 treatment-related toxicity adverse events (AEs), among which the most common toxicity was bone marrow suppression (18 cases), mostly classified as possibly related to chemotherapy agents (Table S3). Although the sum of patients experiencing AEs was similar between the two groups (TRT vs. non-TRT, before PSM: 97.1% vs. 95.7%, P>0.99; after PSM: 94.4% vs. 94.4%, P>0.99), a trend of intergroup differences in the distinct severity of AEs was observed both before and after matching. Specifically, numerically more patients in the TRT group experienced grades 3–5 toxicities (before PSM: 42.9% vs. 25.5%, P=0.10; after PSM: 44.4% vs. 22.2%, P=0.29). In terms of grade 3 or higher pneumonia related to RT or ICIs, there was no significant difference between the two groups either before or after matching (Table 3). However, more patients experienced grades 1–2 pneumonia in the TRT group (before PSM: 28.6% vs. 10.6%, P=0.04; after PSM: 33.3% vs. 0%, P=0.03). Regarding long-term adverse effects, 33.3% of patients with pneumonitis experienced onset more than 90 days after TRT. Notably, there were more patients who discontinued IO due to ICI-related toxicities in the TRT group (before PSM: 40.0% vs. 10.6%, P=0.002; after PSM: 27.8% vs. 5.6%, P=0.18). Besides, the TRT group had a higher incidence of grades 1–2 radiation esophagitis (20.0% vs. 2.1%, P=0.02) and grades 3–5 myelosuppression (34.3% vs. 12.8%, P=0.02) before matching.
Table 3. Treatment-related pneumonia of the patients.
| Pneumonia | Before matching | After matching | |||||
|---|---|---|---|---|---|---|---|
| TRT group (n=35) | Non-TRT group (n=47) | P value | TRT group (n=18) | Non-TRT group (n=18) | P value | ||
| Grade 1 | 1 (2.9) | 0 | 0.43 | 1 (5.6) | 0 | >0.99 | |
| Grade 2 | 9 (25.7) | 5 (10.6) | 0.07 | 5 (27.8) | 0 | 0.045* | |
| Grades 1–2 | 10 (28.6) | 5 (10.6) | 0.04* | 6 (33.3) | 0 | 0.03* | |
| Grade 3 | 1 (2.9) | 3 (6.4) | 0.83 | 0 | 1 (5.6) | >0.99 | |
| Grade 4 | 0 | 0 | – | 0 | 0 | – | |
| Grade 5 | 1 (2.9) | 0 | 0.43 | 0 | 0 | – | |
| Grades 3–5 | 2 (5.7) | 3 (6.4) | >0.99 | 0 | 1 (5.6) | >0.99 | |
| Any grade | 12 (34.3) | 8 (17.0) | 0.07 | 6 (33.3) | 1 (5.6) | 0.09 | |
Data are presented as n (%). *, significant P value (P<0.05). TRT, thoracic radiotherapy.
Totally, 2 grade 5 toxic events (2.4%) were observed and considered at least possibly related to anti-tumor treatment. One patient in the non-TRT group developed acute muscle weakness of lower limbs with dyspnea after 13 cycles of pembrolizumab for maintenance treatment. Although high-dose steroid pulse and supportive care were given after admission, the patient eventually died of multiple organ failure, which was considered to be caused possibly by ICI-related myositis and myocarditis. The other patient in the TRT group received radiation to the primary lesion and involved lymph nodes with a total dose of 45 Gy in 15 fractions after 6 cycles of pembrolizumab monotherapy. This patient developed pneumonitis possibly related to RT or ICIs 3 months after the last radiation and eventually died of it despite the use of glucocorticoid.
Patterns of first failure and the second-line treatment
Figure 3 shows the LRPFS and DMPFS of patients before and after matching. During the follow-up, 23 patients (65.7%) in the TRT group and 39 patients (83.0%) in the non-TRT group underwent disease progression. Before matching, the TRT group showed better DMPFS (TRT vs. non-TRT, median, 31.5 vs. 9.2 months, P=0.001; Figure 3C) than the non-TRT group, but the LRPFS between the two groups was similar (median, 18.4 vs. 11.9 months, P=0.12; Figure 3A). After matching, both LRPFS (median, 18.4 vs. 10.7 months, P=0.04; Figure 3B) and DMPFS (median, 18.2 vs. 7.5 months, P=0.01; Figure 3D) favored the TRT group. Also, sensitivity analysis using IPTW demonstrated significant improvements in LRPFS (HR =0.294; 95% CI: 0.145–0.597; P=0.001) and DMPFS (HR =0.494; 95% CI: 0.248–0.983; P=0.045) among patients who received TRT, in line with the results of the PSM analysis. We further analyzed the patterns of first failure. For all patients, first progression commonly occurred in the primary lesion (n=22, 23.9%), brain (n=19, 20.7%), lung (n=12, 13.0%), and regional lymph nodes (n=11, 12.0%), with similar sites observed in both groups, regardless of the matching (Figure S1A,S1B). The incidence of oligoprogression did not differ between the two groups before or after matching (P>0.05; Figure S1C, S1D). Disease progression due to new lesions was slightly more common (before PSM: 22.9% vs. 27.7%, P=0.62; after PSM: 33.3% vs. 44.4%, P=0.73; Figure S1E,S1F). Notably, the incidence of intrathoracic recurrence was similar in both groups (before PSM: 25.7% vs. 21.3%, P=0.64; after PSM: 22.2% vs. 22.2%, P>0.99). However, the extrathoracic progression was more frequent in the non-TRT group (before PSM: 20.0% vs. 40.4%, P=0.049; after PSM: 22.2% vs. 27.8%, P=0.29; Table S4). More patients in the non-TRT group experienced progression outside the PTV (before PSM: 22.9% vs. 53.2%, P=0.006; after PSM: 27.8% vs. 61.1%, P=0.09), while both inside and outside PTV progression were the main patterns in the TRT group (Figure S1G,S1H).
Figure 3.
Kaplan-Meier curves of LRPFS and DMPFS. LRPFS of the two groups before (A) and after (B) matching. DMPFS of the two groups before (C) and after (D) matching. DMPFS, distant metastasis progression-free survival; LRPFS, locoregional progression-free survival; PSM, propensity score matching; TRT, thoracic radiotherapy.
Apart from patients who altered their treatment due to personal preferences (n=2) and those who died before starting second-line treatment (n=11), others received active treatment after progression, mainly targeted therapy (n=30, 58.8%) and chemotherapy (n=27, 52.9%). Detailed information on the second-line treatment is demonstrated in Figure 4.
Figure 4.
Sankey diagram of the treatment flow and type of progression. CT, chemotherapy; IT, immunotherapy; RT, radiotherapy; TRT, thoracic radiotherapy; TT, target therapy.
Discussion
To our knowledge, this is the first study to evaluate the efficacy of adding TRT to first-line ICIs with or without chemotherapy in metastatic NSCLC. Compared to other sites, radiation to the thorax improved OS and PFS in patients treated with the current treatment strategies, either before or after PSM, without significantly increasing the risk of severe treatment-related pneumonitis. Although the reduction in intrathoracic recurrence at initial failure was not significant in the TRT group, better LRPFS after matching indicated that TRT delayed local recurrence. Moreover, the TRT group demonstrated a lower incidence of extrathoracic progression and improved DMPFS, indicating that TRT may enhance the systemic antitumor effects of ICIs and thereby improve prognosis. Currently, most prospective studies evaluating the combination of ICI and RT included patients with various solid tumors or after multiple lines of treatment, which made it challenging to exactly interpret the efficacy of immuno-RT in patients with newly diagnosed stage IV NSCLC. This study enrolled patients with metastatic NSCLC who received first-line IO per standard regimens from the latest guidelines and provided evidence to reflect the efficacy and safety of the addition for TRT in a real-world situation.
The results of the present study seemed improved, indicating the synergistic potential from the combination of ICI and RT. The PEMBRO-RT study showed that the addition of RT to pembrolizumab in patients progressed after chemotherapy improved PFS from 1.9 to 6.6 months and OS from 7.6 to 15.9 months, respectively (26). Similarly, the MDACC study reported a numerical but non-significant improvement in PFS with concurrent RT (pembrolizumab/RT vs. pembrolizumab alone: 9.1 vs. 5.1 months, P=0.52) for patients previously chemotherapy-treated or newly diagnosed (27). Of note, in both studies, most irradiated sites were in the thorax including the primary lesion, intrathoracic lymph nodes, and lung metastases (58/76 cases). Although neither of them met their prespecified ORR endpoints, the pooled analysis showed a significant improvement in the abscopal response rate (41.7% vs. 19.7%, P=0.004) and survival results (median OS: 19.2 vs. 8.7 months, P<0.001; median PFS: 9.0 vs. 4.4 months, P=0.045) with the combination of ICIs and RT (28). The superiority survival outcomes in our study, in both PFS or OS, may be attributed to the inclusion of only newly diagnosed patients, most of whom (87.8%) received a combination of chemotherapy and IO. Recently, Salari et al. found that patients with brain metastasis-only NSCLC who received definitive treatment of the primary site achieved a median OS of 35 months, comparable to the median OS of 38 months in our TRT group (29). However, the ICI utilization rate in Salari’s study was only 53%, and the presence of brain metastases in our TRT group was lower (23%), both of which may influence comparability. Several studies about the combination of IO and TRT were listed in Table 4.
Table 4. Summary of combination of systemic treatment and TRT studies.
| Study | Year | N | Patients | Radiation to the thorax | Systemic treatment | Follow-up (months), median | ORR (%) | OS (months), median | PFS (months), median | Treatment-related AEs |
|---|---|---|---|---|---|---|---|---|---|---|
| Farooqi et al. | 2000–2017 | 124 | Synchronous oligometastatic NSCLC | RT, median BED 74.3 Gy | Systemic therapy, unspecified | 55.1 | – | 25.3 | 11.0 | G1+ pneumonitis: 30 cases; G3 pneumonitis: 3 cases |
| Liu et al. | 2003–2012 | 243 | Metastatic NSCLC | RT, ≥40 Gy in 2-Gy fractions | CT | 14.0 | – | 13.0; 1-year rate: 55.2%; 2-year rate: 17.8% | – | – |
| Blake-Cerda et al. | 2014–2019 | 47 | Synchronous oligometastatic NSCLC (extrathoracic CR; EGFR/ALK+ included) | SBRT, 45–60 Gy/3–5 F (primary and lung metastases) | CT/TKI | 19.0 | 87.2 | NR | 34.3 | G3 pneumonitis: 7.7% |
| Wang et al. | 2016–2019 | 68 (total: 133) | Synchronous oligometastatic NSCLC without brain metastases, EGFRm | RT, 25–40 Gy/5 F (to all lesions) | First-generation TKIs | – (total: 23.6) | – | 25.5 | 20.2 | G3–4 pneumonitis: 7.4%; no G5 events |
| Sun et al. | 2016–2022 | 59 (total: 118) | Synchronous oligo-organ metastatic NSCLC, EGFRm | RT, 60 Gy/30 F | TKI (icotinib) | – (total: 27.53) | – | 34.4 | 17.1 | G3–4 AEs: 11.9%; G3–4 pneumonitis: 5.1% |
| Theelen et al. | 2015–2018 | 36 (total: 76) | Metastatic NSCLC; progressed after CT | SBRT, 8 Gy/3 F (intrathoracic RT: 20/36) | Pembrolizumab | – (total: 23.6) | 36 | 15.9 | 6.6 | Pneumonia: 26%; G3–5 pneumonia: 11% |
| Welshet al. | 2015–2018 | 40 (total: 72) | Metastatic NSCLC; both newly diagnosed and previously treated | SBRT, 50 Gy/4 F or RT, 45 Gy/15 F (lung RT: 38/40) | Pembrolizumab | – (total: 20.4) | 22 | – | 9.1 | G3: 7 events; G4: 2 events in 1 patient |
| Tian et al. | 2012–2019 | 54 (NSCLC = 31) | After multiple lines of treatment (RT and ICIs included) | SBRT | ICIs | 9.23 | – | – | – | G3–5 pneumonitis: 10.7%; any grade pneumonitis: 33.9% |
| Korpics et al. | 2016–2020 | 123 (NSCLC =41) | Metastatic; after multiple lines of treatment (RT and ICIs included) | Multisite SBRT | ICIs | 12.2 | – | 1-year rate: 57.8%; 2-year rate: 39.0% | – | G3–5 pneumonitis: 8.1% |
| Kievit et al. | 2018–2020 | 15 | Stage IV NSCLC; progressed after CT | SBRT, 20 Gy/1 F (9 cc of the primary) | ICIs (80% doublet-ICIs) | 10 | 13 | 10 | 2 | G1–2: 7 cases; G3: 2 cases |
| Salari et al. | 2008–2022 | 53 (total: 103) | Brain-only metastatic NSCLC | 94.3% SBRT, BED ≥58.5 | 53% ICIs | 2.1 years | – | 35; 2-year rate: 60.6% | – | – |
AE, adverse event; ALK, anaplastic lymphoma kinase; BED, biologically effective dose; CR, complete response; CT, chemotherapy; EGFR, epidermal growth factor receptor; EGFRm, EGFR mutation; G, grade; ICI, immune checkpoint inhibitor; N, number; NR, not reached; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; SBRT, stereotactic body radiotherapy; TKI, tyrosine kinase inhibitor; TRT, thoracic radiotherapy.
For safety analysis, the combination of TRT and ICIs generally demonstrates an acceptable safety profile, although it may increase the risk of mild pneumonitis and radiation esophagitis. Recently, the meta-analysis including 38 studies found that the incidences of any grade and grades 3–5 pneumonitis in advanced NSCLC patients receiving ICIs combined with RT were 20.7–24.5% and 3.3–8.3%, respectively (30). The incidence rates of any-grade and grades 3–5 pneumonitis in our study were 24.4% and 6.1%, respectively. The addition of TRT mainly increased the incidence of grades 1–2 pneumonitis (before PSM: 28.6% vs. 10.6%, P=0.04; after PSM: 33.3% vs. 0, P=0.03), but the incidence of grades 3–5 pneumonitis was similar between the two groups regardless of matching, which was comparable to the results of other studies (25,31). The present study suggests that the addition of TRT does not increase the risk of severe pneumonitis for metastatic NSCLC patients receiving the first-line IO.
Although a subset of patients with metastatic NSCLC may achieve durable responses to ICIs, many still fail to benefit due to primary or acquired resistance (32). In terms of the patterns of failure in advanced NSCLC treated with ICIs, Chai et al. detected that progression occurred primarily in preexisting lesions (58%), with the lung (53.8%) and lymph nodes (19.8%) being the most frequent sites of failure (18). However, few randomized prospective studies have specifically evaluated the combination of TRT and ICIs in metastatic NSCLC. Fortunately, in various solid tumors including small cell lung cancer, breast cancer, prostate cancer, and renal cell cancer, studies confirmed that LRT targeting to the primary lesion can prolong the survival (33-35), possibly due to tumor-derived factors that shape a microenvironment favorable for metastatic spread (36,37). These results implied that local control of thoracic lesions may delay disease recurrence and improve survival in metastatic NSCLC. Furthermore, both preclinical and clinical studies illustrated that the effect of ICIs was negatively related to tumor burden (38,39), suggesting that RT targeting the primary tumor (often the largest tumor burden) may be the optimal approach to maximize the benefit of IO while considering the toxicity and efficacy trade-off (40).
Encouraging results from preclinical and clinical studies have made the combination of IO and RT a promising solution (41,42). Recently, Sun et al. demonstrated that adding concurrent TRT to first-line EGFR-TKIs significantly improved the prognosis (OS: HR =0.62, P=0.03; PFS: HR =0.57, P=0.004) in patients with EGFR-mutated, oligo-organ metastatic NSCLC (43). This finding has sparked interest in the potential systemic efficacy of additional TRT for metastatic NSCLC in the clinic. Also, a meta-analysis of 21 studies involving 924 patients with synchronous oligometastatic NSCLC showed that the addition of TRT markedly improved OS (HR =0.44; 95% CI: 0.33–0.60; P<0.001) and PFS (HR =0.42; 95% CI: 0.33–0.55; P<0.001) (44). The result was consistent with our study, whereas the meta-analysis did not address the effect of IO. The retrospective study by Zhu et al. comparing the effects of different irradiation sites on patients treated with ICIs presented that lung irradiation brought numerically but non-significantly longer OS than bone and brain (36.4 vs. 23.6 vs. 20.2 months, P>0.05) (45). But the study did not balance the baseline characteristics between groups and included more patients with EGFR/ALK mutations (27.2%), which may lead to an overestimate of the survival benefit. In the current study, the PSM was used to balance the baseline factors and to reduce potential selection bias. The PFS and OS of the patients received TRT were significantly better than those in the non-TRT group before and after matching.
Several mechanisms may underlie the potential benefit of combining TRT with IO in metastatic NSCLC. Firstly, radiation enhances the tumor responses of ICIs through increasing the release of tumor neoantigens (46). Previous theories showed that the ubiquitous and shared mutations of the tumor, namely “trunk” mutations exist in both primary tumor and the metastasis whereas the private “branch” mutations can be found at the metastatic sites (47). TRT for NSCLC patients may result in better tumor responses by skewing the immune system to recognize the most relevant neoantigens of the tumor through targeting the primary tumor addressing trunk mutations (24). Secondly, immune heterogeneity exists among different metastatic organs, which will affect the response to IO. Evidence suggests that the lung is more immunogenic and more likely to induce the abscopal effect. Hence, when all lesions cannot be eradicated simultaneously, the prioritizing irradiation on the lung may promote the synergy of RT and IO (48). Thirdly, the relatively resistant tumor cells may survive systemic therapy and subsequently become the source of metastasis. Residual tumor cells that are resistant to IO but radiosensitive can be killed by TRT (49). In addition, studies show that TRT in advanced patients who are not suitable for surgery may relieve the immunosuppression caused by the primary lesion so that enhance the effect of IO (50,51).
This study has several limitations. Firstly, the retrospective nature may cause potential confounders, recall bias, and selection bias. Moreover, this study exclusively included patients who received RT, and these individuals may differ in clinical characteristics from those who did not. Such inherent differences could potentially lead to an overestimation of treatment efficacy. Despite efforts to balance baseline characteristics through PSM, residual and unmeasured systematic differences in clinical status, patient preferences, or treatment accessibility may persist, thereby limiting the capacity to draw definitive causal inferences from our findings. Secondly, although data from multiple centers were incorporated to enhance the sample size, the overall cohort remained relatively small, limiting the statistical power and generalizability of the findings. Therefore, subgroup analyses exploring the specific combination regimens of TRT and ICIs could not be performed. Moreover, as some long-term AEs were collected via telephone follow-up, which may have introduced reporting bias, future prospective studies are warranted to provide more accurate and comprehensive assessments of delayed toxicities associated with the combination therapy. Finally, due to the economic considerations in real-world circumstance, the gene mutation and PD-L1 status of some patients remained unknown, which limits the validity of the conclusions. Therefore, future larger prospective randomized trials with standardized treatment protocols, stratified study designs, and comprehensive biomarker profiling are warranted to validate the long-term efficacy and safety of the combination treatment and enable more robust subgroup analyses.
Conclusions
In conclusion, this retrospective multicenter study suggests that the addition of TRT to first-line IO with or without chemotherapy may be associated with improved survival in patients with metastatic NSCLC. However, given the small sample size and potential treatment heterogeneity, these findings are exploratory and should be interpreted with caution. Larger prospective randomized trials with standardized protocols and integrated biomarker analysis are warranted to validate these observations and optimize therapeutic strategies.
Supplementary
The article’s supplementary files as
Acknowledgments
We would like to thank all participants for their active cooperation and all hospital staffs for their assistance in the study.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Boards at the Peking University Cancer Hospital (No. 2022YJZ46) and The First Medical Center of Chinese PLA General Hospital (No. S2023-697-01), and the requirement for informed consent was waived considering the retrospective nature of the present study.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2255/rc
Funding: This work was supported by the Beijing Hospitals Authority’s Ascent Plan (to W.W.) (No. DFL20220902), the Capital’s Funds for Health Improvement and Research (to W.W.) (No. 2024-2-2156), and the Beijing Hospitals Authority Clinical Medicine Development of special funding support (to W.W.) (No. ZLRK202327).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2255/coif). W.W. was supported by the Beijing Hospitals Authority’s Ascent Plan, the Capital’s Funds for Health Improvement and Research, and the Beijing Hospitals Authority Clinical Medicine Development of special funding support. The other authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2024-2255/dss
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