Chemoimmunotherapy With or Without Thoracic Radiotherapy for Elderly Patients in Advanced Non‐Small Cell Lung Cancer

ABSTRACT

The optimal integration of thoracic radiotherapy (TRT) with first‐line chemoimmunotherapy for elderly patients with driver‐negative advanced non‐small cell lung cancer (NSCLC) remains undefined. We conducted a real‐world study to assess the efficacy and safety of this triple‐modality therapy specifically in patients aged ≥ 65 years. We designed a retrospective analysis of elderly patients with stage IV, mutation‐negative NSCLC who underwent first‐line platinum‐based chemotherapy combined with immunotherapy at our institution between November 2019 and September 2024. Overall survival (OS) and progression‐free survival (PFS) were estimated using the Kaplan–Meier method, and differences between groups were compared with the log‐rank test. After a median follow‐up of 22.34 months, the addition of TRT yielded numerically longer but statistically non‐significant median PFS (12.20 vs. 10.17 months; p = 0.24) and OS (29.67 vs. 18.65 months; p = 0.09). Subgroup analysis suggested a potential survival trend with triple therapy in patients aged 65–70 years, whereas no benefit was observed in those aged ≥ 70 years. Notably, treatment discontinuation due to adverse events was significantly more frequent in the Chemo+ICI+TRT group, with pneumonia being the predominant cause. For elderly patients with advanced NSCLC, particularly those aged ≥ 70 years, incorporating TRT into first‐line chemoimmunotherapy did not significantly improve survival but substantially increased toxicity, often leading to treatment interruption. A potential benefit observed in patients aged 65–70 years requires prospective validation. These results highlight the critical need for personalized treatment intensity in geriatric oncology.

What's new?

Elderly patients constitute a significant proportion of the non‐small cell lung cancer population. However, there is limited evidence specifically addressing their treatment options. This real‐world retrospective study provides an age‐stratified analysis of thoracic radiotherapy plus first‐line chemoimmunotherapy in elderly patients with advanced non‐small cell lung cancer. The age of 70 emerged as a potential inflection point, with triple therapy conferring no survival advantage yet more frequent pneumonia‐related treatment discontinuation in patients aged 70 years or older. An encouraging survival trend in patients aged 65–70 years warrants prospective validation. The results underscore the need for treatment personalization in geriatric oncology.

Elderly patients constitute a significant proportion of the non‐small cell lung cancer population. However, there is limited evidence specifically addressing their treatment options. This real‐world retrospective study provides an age‐stratified analysis of thoracic radiotherapy plus first‐line chemoimmunotherapy in elderly patients with advanced non‐small cell lung cancer. The age of 70 emerged as a potential inflection point, with triple therapy conferring no survival advantage yet more frequent pneumonia‐related treatment discontinuation in patients aged 70 years or older. An encouraging survival trend in patients aged 65–70 years warrants prospective validation. The results underscore the need for treatment personalization in geriatric oncology.

Abbreviations

HRs

hazard ratios

ICI

immune checkpoint inhibitor

IMRT

intensity‐modulated radiation therapy

MDSCs

myeloid‐derived suppressor cells

NSCLC

non‐small cell lung cancer

OS

overall survival

PFS

progression‐free survival

TRT

thoracic radiotherapy

1. Introduction

Non‐small cell lung cancer (NSCLC) remains the leading cause of cancer‐related mortality worldwide, posing a major public health challenge despite advances in early diagnosis and treatment. A substantial proportion of patients are diagnosed at an advanced stage (stage IV) with distant metastases, at which point curative surgery is no longer feasible [1]. For those without driver gene mutations, platinum‐based chemotherapy combined with immunotherapy (Chemoimmunotherapy) has emerged as the standard first‐line treatment. This approach enhances the efficacy of immune checkpoint inhibitor (ICI), as confirmed in multiple phase III clinical trials [2, 3]. Building on this progress, researchers are now investigating whether adding thoracic radiotherapy (TRT) to chemoimmunotherapy can further improve clinical outcomes. The rationale for this triple‐modality therapy lies in the immunomodulatory effects of radiotherapy, which may synergize with ICIs to promote systemic anti‐tumor immunity [4].

Elderly patients constitute a significant proportion of the NSCLC population, reflecting the aging demographics of many countries. However, this group remains consistently underrepresented in prospective clinical trials. As a result, there is limited high‐level evidence specifically addressing their treatment options. Due to age‐related physiological changes, including diminished organ function and immune senescence, the efficacy and safety profiles of anti‐tumor therapies in elderly patients may differ substantially from those observed in younger populations. In particular, the balance between therapeutic benefit and treatment‐related toxicity is less predictable in older adults. Consequently, it remains uncertain whether elderly patients can truly derive a net benefit from the triple therapy of chemoimmunotherapy plus TRT. To address this critical knowledge gap, we conducted a retrospective, real‐world study aimed at evaluating the efficacy and safety of first‐line chemoimmunotherapy with or without TRT, specifically in patients aged 65 years and older.

2. Materials and Methods

We conducted a retrospective review of the medical records of consecutive patients who fulfilled the following criteria: (1) NSCLC confirmed through cytology or histology; (2) clinical stage IV, without surgery or other treatment; (3) patients who started first‐line systemic therapy between November 2019 and September 2024; (4) patients 65 years and older at initiation of first‐line systemic therapy. Exclude patients with epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase rearrangement, or those who receive first‐line systemic therapy with molecular targeted drugs.

All the information was sourced from the patient's medical records, with the survival follow‐up period ended on November 30, 2025. Progression‐free survival (PFS) was defined as the period from receiving the first dose of systemic therapy to disease progression, death from any cause, or the last day of follow‐up. Overall survival (OS) was defined as the period from receiving the first dose of systemic therapy to death from any cause or the last day of follow‐up. During the follow‐up period, PFS and OS were estimated using the Kaplan–Meier method and compared using the log‐rank test. Cox proportional hazard models were used to determine hazard ratios (HRs) for OS and PFS. Statistical significance was assessed as p < 0.05. GraphPad Prism was used for statistical analyses.

3. Results

The patient characteristics are shown in Table 1. Our study included 149 elderly patients (median age 71.50) with stage IV, mutation‐negative NSCLC. All received first‐line chemoimmunotherapy, and 47 of them (31.54%) additionally received TRT (Chemo+ICI+TRT group), while 102 received chemoimmunotherapy alone (Chemo+ICI group). The patient group was predominantly male (83.22%) with a good performance status (93.96% ECOG 0–1). Common metastatic sites included bone, brain, and lung.

TABLE 1.

Clinical baseline characteristics of patients.

Characteristics	Patients, No. (%) (N = 149)
Age, median (range), y	71.50 (65–96)
65–70	65 (43.62%)
≥ 70	84 (56.38%)
Sex
Male	124 (83.22%)
Female	25 (16.78%)
Smoking history
Former/Active	93 (62.42%)
Never smoker	56 (37.58%)
ECOG scores
2	9 (6.04%)
0–1	140 (93.96%)
Histologic characteristic
Adenocarcinoma	85 (57.05%)
Squamous cell carcinoma	58 (38.93%)
NSCLC NOS	2 (1.34%)
Other	4 (2.68%)
PD‐L1 tumor proportion score, %
< 1	28 (18.79%)
1–49	47 (31.54%)
≥ 50	25 (16.78%)
Unknown	49 (32.89%)
Lung metastases
Yes	38 (25.50%)
No	111 (74.50%)
Brain metastases
Yes	47 (31.54%)
No	102 (68.46%)
Bone metastases
Yes	65 (43.62%)
No	84 (56.38%)
Liver metastases
Yes	28 (18.79%)
No	121 (81.21%)
First‐line treatment
Chemo + ICI	102 (68.46%)
Chemo + ICI + TRT	47 (31.54%)

Abbreviations: Chemo, chemotherapy; ECOG, Eastern Cooperative Oncology Group; ICI, immune checkpoint inhibitor; NSCLC NOS, non–small cell lung cancer not otherwise specified; PD‐L1, programmed death ligand–1; TRT, thoracic radiotherapy.

After a median follow‐up of 22.34 months, the results showed that while survival times were numerically longer in the group that received radiotherapy, the differences were not statistically significant. The median PFS was 10.17 months for Chemo+ICI versus 12.20 months for Chemo+ICI+TRT. The median OS was 18.65 months versus 29.67 months, respectively. The statistical analysis found no significant difference in either PFS (p = 0.24) or OS (p = 0.09) between the two treatment strategies for the overall elderly cohort (Figure 1A,B).

FIGURE 1.

Survival analysis comparing two treatment regimens. The number of patients at risk at each landmark time point is provided below each curve, and censoring marks are added for all censored observations on the curves. (A, B). Progression‐free survival (PFS) and Overall survival (OS) for all included patients, stratified by treatment group only. (C, D) PFS and OS for the age subgroup of patients ≥ 70 years old. (E, F) PFS and OS for the age subgroup of patients 65–70 years old. To compare the survival differences between the two treatment groups, a Kaplan–Meier survival curve and log‐rank test were used. p values < 0.05 was taken as statistically significant. [Color figure can be viewed at wileyonlinelibrary.com]

A deeper analysis by age subgroup revealed important nuances. For patients aged 70 years and older, adding radiotherapy showed no survival advantage at all, with nearly identical PFS and no significant OS difference (Figure 1C,D). In contrast, for the slightly younger subgroup of patients aged 65 to 70 years, a positive trend was observed. Their median PFS and OS were numerically superior with the triple therapy (18.36 vs. 11.05 months for PFS; 31.35 vs. 26.22 months for OS). Although this trend did not meet the threshold for statistical significance (p = 0.11 for PFS; p = 0.06 for OS), the HRs suggested a potential benefit from radiotherapy in this specific age bracket (Figure 1E,F).

In this study, we compared patient characteristics between those who received TRT and those who did not, as summarized in Table S1. The decision to administer TRT to patients with metastatic diseases is mainly driven by two clinical indications. The first is palliative treatment to alleviate symptoms such as dyspnea, chest pain, or hemoptysis. The second is consolidation therapy aimed at achieving local control of residual intrathoracic lesions after systemic treatment. Among these patients, palliative radiotherapy accounts for 42.55% and consolidation radiotherapy for 57.45%, with intensity‐modulated radiotherapy (IMRT) being the treatment modality used for the majority of patients (Table 2). Importantly, the safety profile revealed a significant downside to adding radiotherapy. Treatment discontinuation due to severe adverse events was notably higher in the Chemo+ICI+RT group (36.17%) compared to the Chemo+ICI group (23.53%). Pneumonia was the most common severe complication leading to treatment stoppage, affecting 64.71% of those who discontinued in the radiotherapy group, compared to 37.50% in the non‐TRT group. Other reasons included severe bone marrow suppression and a decline in general health (Table S2).

TABLE 2.

Treatment regimens and radiotherapy parameters.

Characteristics	Patients, No. (%) (N = 47)
TRT indication
Palliative	20 (42.55%)
Consolidative	27 (57.45%)
Dose (Gy)
≥ 50	36 (76.59%)
< 50	9 (19.15%)
Unknown	2 (4.26%)
Radiotherapy techniques
IMRT	45 (95.74%)
Others	2 (4.26%)
Lung V20 (%)
≥ 10	23 (48.94%)
< 10	18 (38.29%)
Unknown	6 (12.77%)
Mean lung dose (cGy)
> 1000	5 (10.64%)
500–1000	27 (57.45%)
< 500	9 (19.15%)
Unknown	6 (12.77%)

Abbreviations: IMRT, intensity‐modulated radiation therapy; Lung V20, lung volume exposed to dose exceeding 20 Gy.

4. Discussion

The findings highlight the complex considerations in treating elderly NSCLC patients. In fact, the frailty and comorbidities of elderly patients substantially restrict their treatment choices. Firstly, aging may modify the pharmacokinetics and pharmacodynamics of medications. Moreover, smoking and age‐related comorbidities are prevalent among elderly lung cancer patients. Declines in liver, kidney, and lung function, as well as bone marrow reserve, may also elevate the risk of adverse drug interactions [5]. In contrast to prior studies that demonstrated a survival benefit with radiotherapy plus immunotherapy, our findings indicate that among elderly patients receiving first‐line chemoimmunotherapy, particularly those aged 70 years and older, the addition of consolidative TRT does not confer a significant survival advantage and is associated with meaningfully increased toxicity, frequently resulting in treatment interruption [6]. This increased risk, primarily from pneumonia, appears to offset any potential gain. The observed efficacy and safety patterns are consistent with other studies focused on elderly patients [7].

Prior subgroup analyses from trials such as KEYNOTE‐189 and IMpower150 have demonstrated that ICIs combined with chemotherapy are clinically effective in older patients, with efficacy comparable to younger cohorts, albeit with heightened considerations for toxicity [8, 9]. Nevertheless, data on the safety and efficacy of additional TRT in elderly NSCLC patients is limited. Retrospective studies suggest that older patients receiving TRT combined with ICIs experience acceptable toxicity, although careful patient selection is necessary to avoid excessive treatment‐related complications [10]. Emerging data also suggest that the inflammatory profile of elderly patients, including increased levels of immunosuppressive cells such as myeloid‐derived suppressor cells (MDSCs), may modulate treatment responses to ICI and radiotherapy combinations [11]. This study contributes to the growing body of literature emphasizing that elderly patients, often underrepresented in clinical trials, should not be excluded from innovative combination therapy approaches. Future prospective studies focusing specifically on elderly patients are needed to further validate the efficacy and safety of this multimodality approach, as well as to explore novel biomarkers predictive of response and toxicity risks in this unique population.

This study has several limitations. First, detailed data on baseline comorbidities, including cardiovascular and pulmonary conditions, as well as geriatric assessment parameters, were lacking. Elderly patients receiving TRT may represent a healthier subgroup, which could introduce bias in survival comparisons. Second, as a retrospective study, the possibility of unmeasured confounders and selection bias cannot be excluded. The absence of detailed comorbidity data and geriatric assessments further limits our ability to address confounding factors specifically in elderly patients. Future prospective research incorporating comprehensive geriatric assessments is warranted. Notably, the lack of survival benefit with the addition of TRT was observed despite our cohort having predominantly good performance status (95% with ECOG 0–1). This suggests that even relatively fit elderly patients may not derive the same benefit from consolidative TRT as younger populations reported in previous trials. In addition, our study demonstrated numerical differences in median PFS and OS. However, the lack of statistical significance suggests potential underpowering, likely due to the small sample size. Although initial power calculations were performed, factors such as enrollment constraints and outcome variability may have influenced the results. These findings should therefore be interpreted with caution, and larger future studies are needed to confirm their clinical relevance.

In conclusion, this real‐world analysis suggests that first‐line chemoimmunotherapy alone may represent a more suitable balance of efficacy and tolerability for most elderly patients with advanced NSCLC. The addition of TRT was associated with increased toxicity without a demonstrable significant survival benefit for the overall group. While a possible benefit was noted in patients aged 65–70, this requires prospective validation. For older and potentially frailer patients, especially those over 70, the triple‐modality approach may be less appropriate. These results underscore the need for treatment personalization in geriatric oncology and should be confirmed in future randomized clinical trials specifically designed for the elderly population.

Author Contributions

Zhiru Gao: writing – original draft. Linlin Yang: methodology. Linlin Wang: writing – review and editing, supervision.

Funding

This study was supported by National Key Technologies Research and Development Program (Grant number 2022YFC2404605), National Natural Science Foundation of China (Grant number 82172865), Post‐Marketing Clinical Research Special Project on Innovative Drugs (Grant number WKZX2023Cx020012), Natural Science Foundation of Shandong Province (Grant number ZR2023LZL002, ZR2024MH007, and ZR2021LZL009), Collaborative Academic Innovation Project of Shandong Cancer Hospital (Grant number ZF002), and Noncommunicable Chronic Diseases‐National Science and Technology Major Project (Grant number 2024ZD0519904).

Ethics Statement

The study was approved by the Ethics Committee of Shandong Cancer Hospital (approval number SDTHEC2021003186). As it was a retrospective analysis, informed consent was not required.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Patient characteristics between TRT and no‐TRT groups.

Table S2: The proportion of patients interrupting treatment due to adverse events.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.