Concurrent Chemoradiotherapy with Daily Low-Dose Carboplatin in Older Patients with Unresectable Locally Advanced Non-Small Cell Lung Cancer: Clinical Outcomes and Prognostic Significance of Systemic Inflammation Markers

1. Introduction

Lung cancer is the leading cause of cancer-related mortality worldwide [1]. Among these, unresectable, locally advanced non-small cell lung cancer (NSCLC) represents approximately 30–35% of the overall NSCLC cases [2]. The disease predominantly affects older adults; the median age at diagnosis is 71 years, and nearly 70% of patients are aged >65 years at presentation [3,4]. Platinum-based concurrent chemoradiotherapy (CCRT) is the standard of care for individuals with unresectable locally advanced NSCLC. Nevertheless, its therapeutic impact is modest, with a reported median overall survival (OS) of only 22–25 months and a 5-year OS rate of approximately 20% [5].

The randomized phase 3 Japan Clinical Oncology Group (JCOG) 0301 trial, conducted by the JCOG, demonstrated that CCRT consisting of 60 Gy thoracic irradiation with daily low-dose carboplatin (30 mg/m², 5 days per week for 4 weeks) provided superior survival and acceptable toxicity compared with radiotherapy alone in patients aged >70 years with unresectable stage IIIA–IIIB NSCLC and performance status (PS) 0–2 [6]. Based on these findings, the current Japanese guidelines recommend daily low-dose carboplatin–based CCRT for older patients with unresectable stage II/III NSCLC. In addition, the pivotal phase 3 PACIFIC trial established that consolidation therapy with durvalumab following definitive chemoradiotherapy significantly improved both progression-free survival (PFS) and OS compared with placebo [7,8]. Consequently, the National Comprehensive Cancer Network guidelines recommend durvalumab consolidation for patients with unresectable stage II/III NSCLC who maintain an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0–1 and exhibit no disease progression after CCRT.

A substantial proportion of patients with lung cancer develop a systemic inflammatory response (SIR) and cancer-associated weight loss, both of which are central components of cancer cachexia [9,10]. Therefore, numerous SIR-based indices—including the Glasgow Prognostic Score (GPS), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and Advanced Lung Cancer Inflammation Index (ALI)—have been evaluated as prognostic biomarkers. The GPS incorporates serum C-reactive protein (CRP) and albumin levels [9], and multiple studies have demonstrated its independent prognostic significance in advanced NSCLC [11,12,13,14,15,16]. However, the association between the GPS and treatment response to daily low-dose carboplatin–based CCRT in older patients with unresectable stage II/III NSCLC remains unclear. Similarly, although NLR has shown prognostic utility across various malignancies [17] and several studies have confirmed its prognostic relevance in NSCLC [18,19], its association with outcomes following CCRT in this specific population remains unclear. Systematic reviews have indicated that NLR predicts therapeutic efficacy and survival in NSCLC [20]. An elevated PLR, another marker of systemic inflammation, is associated with poor OS in lung cancer, particularly in NSCLC [21,22]. ALI, which reflects inflammatory and nutritional status, is also correlated with unfavorable OS in multiple cancer types [23], and baseline ALI is an independent predictor of poor prognosis in advanced NSCLC [24]. Moreover, prior work on body composition suggests that body mass index (BMI) influences survival outcomes in NSCLC [25,26]. Nevertheless, the potential prognostic associations between BMI, GPS, NLR, PLR, and ALI and therapeutic efficacy in older patients receiving daily low-dose carboplatin–based CCRT for unresectable stage II/III NSCLC have not yet been evaluated.

Therefore, this study aimed to investigate whether BMI, GPS, NLR, PLR, and ALI can serve as predictive markers for treatment effectiveness in patients receiving this regimen. Although daily low-dose carboplatin is widely used in Japan in older patients with unresectable stage II/III NSCLC, studies focusing on its real-world performance are scarce. Furthermore, the clinical effectiveness and toxicity profiles of this CCRT regimen in older patients have not been thoroughly characterized in real-world practice. Therefore, this retrospective analysis aimed to assess both the safety and therapeutic efficacy of daily low-dose carboplatin–based CCRT in routine clinical care for older patients with unresectable stage II/III NSCLC and to help refine the treatment strategies for this population.

2. Materials and Methods

2.1. Participants

This retrospective study involved a comprehensive review of electronic medical records. We identified consecutive patients with locally advanced NSCLC who received CCRT with low-dose carboplatin between April 2007 and December 2019 at three Japanese institutions: Saitama Medical University International Medical Center, Gunma Prefectural Cancer Center, and National Hospital Organization Asahikawa Medical Center. Patients were required to have a minimum follow-up period of 60 months, with data censored on December 31, 2024. The Institutional Ethics Committee of Saitama Medical University International Medical Center approved the study protocol (approval number 2024-048) and waived the need for written informed consent owing to the retrospective nature of this study. All the procedures conformed to the principles of the Declaration of Helsinki.

Eligible patients met the following criteria: (i) cytological or histological confirmation of NSCLC, (ii) unilateral hemithoracic disease with regional nodal involvement suitable for treatment within a single radiation field, and (iii) receipt of first-line CRT. Histological subtyping followed the 2015 World Health Organization classification, and clinical staging was based on the Eighth Edition of the Union for International Cancer Control tumor-node-metastasis (TNM) system [2]. Adverse event severity was graded using the Common Terminology Criteria for Adverse Events version 5.0. Institutional standards for CRT eligibility typically included neutrophil count ≥1.5×10³/mm³, platelet count ≥1.0×10⁵/mm³, serum creatinine ≤1.5 mg/dL, total bilirubin ≤2.0 mg/dL, and transaminases ≤100 U/L.

Pretreatment evaluation for TNM staging consisted of a physical examination, chest radiography, contrast-enhanced computed tomography (CT) of the chest and abdomen, CT or magnetic resonance imaging of the brain, and bone scintigraphy or 18F-fluorodeoxyglucose positron emission tomography.

2.2. Treatment

2.2.1. Chemotherapy

Chemotherapy selection, in accordance with approved product labeling, was determined by the treating physicians. The patients received daily intravenous low-dose carboplatin (30 mg/m² infused over 30 min) administered 1 h before radiotherapy for the initial 20 fractions. Treatment was discontinued in cases of disease progression, unacceptable toxicity, or withdrawal of consent. After the regulatory approval of durvalumab, eligible patients received consolidation therapy 1–42 days after completion of CRT. Durvalumab was intravenously administered at a dose of 10 mg/kg every 2 weeks for up to 12 months.

2.2.2. Radiotherapy

Radiotherapy was administered according to the JCOG0301 protocol [6]. Briefly, radiotherapy was administered to the thoracic lesion once daily, 5 days per week, over 6–9 weeks. The total dose to the planning target volume was 60 Gy delivered in 30 fractions. Both three-dimensional conformal radiotherapy and intensity-modulated radiotherapy were accepted to use with the institutional practice. Respiratory motion management strategies were implemented as necessary. Appropriate image guidance using on-board images, portal vision, and/or cone-beam CT was performed during the treatment session.

Regarding the dose constraints of the normal organs, the lung V20 (percentage of lung volume receiving ≥20 Gy) should be <30%, the heart V40 should be <20%, and the maximum dose to the spinal cord should be <45 Gy.

2.3. Assessment of Metabolic and Inflammatory Indices

The baseline BMI was calculated as body weight (kg) divided by height squared (m²). Following established Japanese population data, a BMI cutoff of 22.0 kg/m² was applied (high BMI ≥22.0, low BMI <22.0) [27]. Serum CRP and albumin levels measured on the day before or on the day of CRT initiation were used to compute the GPS, which was categorized as follows:

0: CRP <1.0 mg/dL and albumin ≥3.5 mg/dL

1: CRP elevation or hypoalbuminemia

2: CRP ≥1.0 mg/dL and albumin <3.5 mg/dL [9,10]

The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count, with a cutoff of 5.0 to differentiate low-risk (<5.0) and high-risk (≥5.0) groups [28,29]. The PLR was calculated similarly, with a cutoff of 185 used to classify patients into low-risk (<185) and high-risk (≥185) categories [21]. The ALI was defined as (BMI×albumin)/NLR, with a cutoff of 24 distinguishing low (<24) from high (≥24) ALI groups [23].

2.4. Evaluation of the Treatment Response

Tumor response was assessed based on the best overall response and maximum tumor shrinkage. Responses were classified according to the Response Evaluation Criteria in Solid Tumors, version 1.1 [30], as complete response, partial response, stable disease, progressive disease, or not evaluable. In case of treatment failure, subsequent therapy was selected at the discretion of the treating physician.

2.5. Statistical Analyses

Categorical variables were analyzed using Fisher’s exact test, and continuous variables were analyzed using Welch’s t-test. PFS was defined as the interval from treatment initiation to disease progression or death from any cause, whereas OS was defined as the interval from treatment initiation to death or last follow-up. Survival curves were estimated using the Kaplan–Meier method and compared using the log-rank test. Statistical significance was set at a two-sided p-value < 0.05. All analyses were performed using the JMP software, version 11.0 (SAS Institute, Cary, NC, USA).

3. Results

3.1. Patient Characteristics and Treatment Efficacy

Fifty-two patients were included in this study. The baseline characteristics are summarized in Table 1.

The cohort comprised 41 men (78.8%) and 11 women (21.2%), with a median age of 76 (range, 71–86) years. Most patients (51/52, 98.1%) had an ECOG PS of 0–1, whereas one (1.9%) patient had a PS of 2. Adenocarcinoma and squamous cell carcinoma were observed at equal frequencies (23 patients each, 44.2%). Seven (13.5%) patients harbored driver alterations (EGFR, ALK, or ROS1), whereas the remaining patients were either negative or untested, and no additional oncogenic alterations were identified. The median BMI was 22.2 (range, 16.1–27.6) kg/m². Two (3.8%) patients were unable to complete the radiotherapy, and the median delivered dose was 60 Gy (range, 45–66 Gy). Twelve (23.1%) patients discontinued carboplatin prematurely, and the median number of carboplatin administrations was 20 (range, 4–20). At the data cutoff, 16 (30.8%) patients were alive. Twenty (38.5%) patients received durvalumab maintenance therapy, and 32 (61.5%) did not. Among the 20 patients receiving durvalumab, 13 (65.0%) were unable to complete 1 year of treatment. Causes of discontinuation included disease progression (6/13, 46.2%) and treatment-related adverse events (7/13, 53.8%) (Table S1). Patterns of distant recurrence following CRT are listed in Table S2. Among the 40 patients who developed distant metastases, the bone (12 patients, 30.0%) and brain (6 patients, 15.0%) were the most frequent sites. Table S3 summarizes the systemic therapies administered after recurrence. Treatment response data are presented in Table 2.

The overall response rate (ORR) was 51.9% (95% confidence interval [CI], 38.6–64.8%). There were no statistically significant differences in either the ORR or disease control rate between patients who received durvalumab maintenance therapy and those who did not.

3.2. Survival Analysis

All the patients had a minimum follow-up period of 60 months. Over a median follow-up period of 29.8 (range, 3.4–91.3) months, the median PFS and OS periods were 11.5 months (95% CI, 8.1–24.5) and 40.1 months (95% CI, 16.6–50.6), respectively (Figure 1a and Figure 1b).

At the data cutoff (December 31, 2024), 36 patients died and 16 survived. Univariate and multivariate analyses of PFS and OS are summarized in Table 3.

In the univariate analysis, GPS was significantly associated with PFS. Multivariate analysis confirmed that GPS (0–1 vs. 2) was an independent factor for PFS (hazard ratio, 0.36; p=0.0294). Univariate analysis identified significant associations between histology and GPS; however, multivariate analysis did not identify any independent predictors of OS. The Kaplan–Meier survival curves are shown in Figure 2.

Patients with a GPS of 0–1 had significantly longer PFS and OS than those with a GPS of 2 (both p<0.05). The median PFS periods were 13.7 months for GPS 0–1 and 5.6 months for GPS 2 (log-rank p=0.0165, Figure 2a), and the median OS periods were 45.6 and 13.0 months, respectively (log-rank p=0.0094, Figure 2b).

3.3. Toxicity

Treatment-related adverse events are shown in Table 4.

All 52 patients were evaluable for safety. Myelosuppression was the most common toxicity, with grade 3–4 decreased white blood cell counts in 25.0% of the patients, grade 3–4 decreased neutrophil counts in 23.1%, and febrile neutropenia in one (1.9%). Grade 3–4 decreased platelet counts were observed in nine (17.3%) patients. Severe nonhematological toxicities were rare; grade 3–4 skin rashes occurred in 3.8% of the patients. Treatment discontinuation due to adverse events occurred in 12 of the 52 (23.1%) patients. No treatment-related deaths occurred. Among the 20 patients receiving durvalumab maintenance therapy, 7 discontinued treatment because of adverse events, including 6 cases of pneumonitis and 1 of myositis (Table S1).

3.4. Subsequent Treatment After Chemoradiotherapy

Post-CRT treatments are summarized in Table S3. Of the 40 patients who experienced recurrence, best supportive care was frequently selected; however, 26 (65.0%) received systemic therapy. Nivolumab monotherapy was the most common subsequent regimen, followed by platinum-based combination chemotherapy. Nine patients received up to third-line therapy, and four patients received more than four lines of treatment.

4. Discussion

This study assessed the real-world efficacy and safety of CCRT with daily low-dose carboplatin in older patients with unresectable stage II/III NSCLC and evaluated the prognostic utility of BMI, GPS, NLR, PLR, and ALI. Multivariate analysis identified the GPS as an independent predictor of PFS, highlighting its potential as a clinically meaningful biomarker. To the best of our knowledge, this is the first study to explore the prognostic relevance of these inflammation- and nutrition-based indices, specifically in patients receiving daily low-dose carboplatin CCRT for unresectable locally advanced NSCLC.

Findings from the JCOG0301 randomized phase 3 trial demonstrated that adding daily low-dose carboplatin to thoracic radiotherapy provided significant clinical benefits with acceptable toxicity in older patients with locally advanced NSCLC, yielding a median PFS period of 8.9 months and a median OS period of 22.4 months [6]. In our cohort, the median PFS and OS periods were 11.5 months and 40.1 months, respectively—outcomes that appear more favorable than those reported in JCOG0301. Several factors may explain this discrepancy. Our cohort included patients who received durvalumab maintenance therapy (n=20), individuals with stage II disease (n=4), patients experiencing postoperative recurrence (n=7), and those who subsequently received modern systemic therapies not available during the JCOG0301 trial period—including third-generation EGFR tyrosine kinase inhibitors (TKIs), second-generation ALK TKIs, and immune checkpoint inhibitor monotherapy. These agents have demonstrated substantial efficacy in advanced NSCLC [31,32,33,34,35,36] and likely contributed to the improved OS observed in this study. The effect of durvalumab maintenance may also have influenced PFS prolongation.

The PACIFIC trial showed that durvalumab maintenance following platinum-based CCRT significantly extended PFS and OS compared with placebo, with median PFS periods of 16.8 and 5.6 months and median OS periods of 47.5 and 29.1 months, respectively [7,8]. In our analysis, patients receiving durvalumab maintenance therapy exhibited a numerical, but not statistically significant, improvement in PFS and OS. There are several possible explanations for these results. First, our cohort was considerably older (median age, 76 years) than the PACIFIC population (median age, 64 years), consistent with the PACIFIC subgroup analysis in which age >65 years was correlated with a diminished OS benefit [37]. Another potential factor is the chemoradiation regimen. The PACIFIC trial did not administer a daily, low-dose carboplatin regimen. Although a retrospective study provided real-world data on durvalumab consolidation maintenance after chemoradiotherapy [38], including patients who received a daily low-dose carboplatin regimen, no focused analysis was performed on this population. Therefore, the clinical significance of durvalumab maintenance therapy following chemoradiotherapy with low-dose carboplatin remains unclear. However, a recent Japanese phase II study (NEJ039A) reported that durvalumab maintenance therapy after chemoradiotherapy with daily low-dose carboplatin was effective and well-tolerated in older patients with unresectable locally advanced NSCLC [39]. In this study, the median PFS and OS periods were 12.3 and 28.1 months, respectively. The average follow-up period from the first enrollment was 19.0 months in this study. Although the median observation periods differed and direct comparison with that study’s results was not possible, the PFS was similar to that in our cohort. Furthermore, a recent retrospective study comparing patients who received durvalumab maintenance therapy after CCRT with daily low-dose carboplatin versus those who did not suggested that durvalumab maintenance therapy after CCRT with daily low-dose carboplatin did not provide a significant clinical benefit in older patients with unresectable stage II/III NSCLC [40]. This was a small, retrospective study that compared 16 patients who received durvalumab maintenance therapy with 20 patients who did not. Owing to the small sample size in this retrospective study, it is possible that no statistically significant difference was observed. Our current analysis, which compared 20 patients who received durvalumab maintenance therapy with 32 who did not, was also a small-sample retrospective study and may have yielded similar results.

The GPS has emerged as a significant predictor of PFS. Studies have demonstrated the prognostic significance of the GPS in NSCLC, irrespective of the disease stage, and it is commonly used as a prognostic marker in clinical research [10,11,12,13,14,15,16]. The GPS is associated with altered drug metabolism, adipokine levels, elevated cytokine levels, weight loss, muscle wasting, and compromised PS [10,41,42,43,44,45,46]. Previous studies have evaluated the GPS in the context of first-line cytotoxic drug treatment for NSCLC, whereas no study has evaluated the GPS with respect to CCRT with daily low-dose carboplatin. In the present study, the GPS 2 group (n=9) was smaller than the GPS 0–1 group (n=43). This may be because locally advanced NSCLC, unlike metastatic NSCLC with distant metastases, is characterized by lesions confined to the unilateral thoracic region.

The GPS is an indicator calculated from serum CRP and albumin levels, both of which can be routinely and easily measured in daily clinical practice in most medical institutions. Multivariate analysis demonstrated that the GPS was independently associated with PFS (Table 3). Although PS has long been considered a primary prognostic factor in both clinical trials and real-world practice, its assessment is inherently subjective and dependent on the physician’s judgment. In the population analyzed here, only one of the 52 patients had a PS of 2, precluding the evaluation of patients with poor PS. In contrast to the PS, the GPS is an objective and highly reproducible index that stratifies patients using a simple three-point scoring system. This objectivity may allow for a more accurate and standardized pretreatment risk assessment than conventional prognostication based on PS alone [47]. Notably, a GPS of 2, defined by elevated CRP levels and hypoalbuminemia at treatment initiation, was associated with inferior treatment efficacy, suggesting that systemic inflammation and nutritional status substantially influence the outcomes. These findings support the clinical integration of the GPS into treatment decision-making for patients with locally advanced NSCLC receiving CCRT with daily low-dose carboplatin.

In contrast, other inflammation- and nutrition-related indices, including NLR, PLR, ALI, and BMI, were not independently associated with survival in the multivariate analyses. Although prior studies on advanced NSCLC have suggested the prognostic relevance of these markers, the results have been inconsistent, likely reflecting heterogeneous patient populations, variable treatment settings, and differing cutoff values [18,19,21,22,24,25,26]. The relatively small sample size of the present cohort may have limited the statistical power. Future investigations in larger, well-defined cohorts treated with uniform CCRT regimens are required to establish optimal cutoff values and account for ethnic differences, particularly with respect to BMI, when extrapolating these indices beyond Japanese populations.

Daily low-dose carboplatin treatment was well-tolerated. No grade ≥3 pneumonitis was observed, in contrast with the 1% incidence reported in JCOG0301. Rates of grade ≥3 hematological toxicities and febrile neutropenia were also lower than those observed in JCOG0301. No treatment-related death occurred during the study period. These findings suggest that daily low-dose carboplatin combined with thoracic radiotherapy is a safe and feasible treatment regimen for older patients. Among patients receiving durvalumab maintenance therapy, seven of 20 discontinued treatment due to adverse events, predominantly pneumonitis (n=6). Although no grade 4–5 events were observed, the high rate of pneumonitis-related discontinuation warrants caution when administering durvalumab maintenance therapy to older patients after low-dose carboplatin CCRT.

This study has some limitations. This retrospective design introduced potential variability in clinical assessments and outcome documentation. The small sample size limits the statistical power and may obscure differences between clinical subgroups. Finally, the introduction of modern systemic therapies, including durvalumab consolidation, during the study period may have influenced the long-term outcomes in ways that cannot be fully disentangled.

5. Conclusions

CCRT with low-dose carboplatin is an effective and well-tolerated treatment option for older patients with unresectable stage II/III NSCLC. The GPS is a simple, objective, and clinically valuable predictor of PFS, outperforming other inflammation-based indices and offering a practical tool for pretreatment risk stratification. Although durvalumab maintenance therapy is feasible, a survival benefit is not clearly observed in this older population. Collectively, these findings support the continued use of daily low-dose carboplatin CCRT in routine practice and highlight the importance of incorporating the GPS into individualized treatment planning for older patients with locally advanced NSCLC.