Unraveling the Impact of Sarcopenia-Induced Lymphopenia on Treatment Response and Prognosis in Patients with Stage III Non–Small Cell Lung Cancer: Insights for Optimizing Chemoradiation and Immune Checkpoint Inhibitor
Article information
Abstract
Purpose
Sarcopenia is a poor prognostic factor in non–small cell lung cancer (NSCLC). However, its prognostic significance in patients with NSCLC receiving immune checkpoint inhibitors (ICIs) and its relationship with lymphopenia remain unclear. We aimed to investigate the prognostic role of sarcopenia and its effect on lymphocyte recovery in patients with stage III NSCLC treated with concurrent chemoradiotherapy (CCRT) followed by ICI.
Materials and Methods
We retrospectively evaluated 151 patients with stage III NSCLC who received definitive CCRT followed by maintenance ICI between January 2016 and June 2022. Sarcopenia was evaluated by measuring the skeletal muscle area at the L3 vertebra level using computed tomography scans. Lymphocyte level changes were assessed based on measurements taken before and during CCRT and at 1, 2, 3, 6, and 12 months post-CCRT completion.
Results
Even after adjusting for baseline absolute lymphocyte count through propensity score-matching, patients with pre-radiotherapy (RT) sarcopenia (n=86) exhibited poor lymphocyte recovery and a significantly high incidence of grade ≥ 3 lymphopenia during CCRT. Pre-RT sarcopenia and grade ≥ 3 lymphopenia during CCRT emerged as prognostic factors for overall survival and progression-free survival, respectively. Concurrent chemotherapy dose adjustments, objective response after CCRT, and discontinuation of maintenance ICI were also analyzed as independent prognostic factors.
Conclusion
Our results demonstrated an association between pre-RT sarcopenia and poor survival, concurrent chemotherapy dose adjustments, and impaired lymphocyte recovery after definitive CCRT. Moreover, CCRT-induced lymphopenia not only contributed to poor prognosis but may have also impaired the therapeutic efficacy of subsequent maintenance ICI, ultimately worsening treatment outcomes.
Introduction
Sarcopenia, characterized by a loss of skeletal muscle quality, mass, and strength, is a prognostic factor associated with poor overall survival (OS) and progression-free survival (PFS) across various cancer types [1-3]. Additionally, sarcopenia can weaken the immune system, particularly by impairing lymphocyte development and maintenance, resulting in lymphopenia [4-6].
In recent decades, immune checkpoint inhibitors (ICIs), which activate the host immune system to target tumor cells, have demonstrated significantly favorable outcomes across several cancer types. ICIs have also improved treatment outcomes in non–small cell lung cancer (NSCLC). Specifically, maintenance ICIs following concurrent chemoradiotherapy (CCRT) have become a standard treatment for stage III NSCLC [7]. Several efforts have been made to identify factors for predicting prognosis after ICI in NSCLC; notably, our previous study identified radiotherapy (RT)-induced lymphopenia as a poor prognostic factor [8].
Several recent studies have highlighted the poor prognostic effect of sarcopenia in patients receiving ICI therapy, including those with gastrointestinal tract tumors, malignant melanoma, and NSCLC [9-11]. However, whether sarcopenia serves as a predictive factor for clinical outcomes in patients with stage III NSCLC receiving maintenance ICI remains unclear. In addition, the relationship between sarcopenia and poor lymphocyte recovery in patients receiving ICI remains largely unexplored. Therefore, this study was conducted to investigate the prognostic significance of sarcopenia and its effect on lymphocyte recovery in patients with stage III NSCLC treated with definitive CCRT followed by maintenance ICI.
Materials and Methods
1. Patient selection
Eligibility criteria included a diagnosis of stage III NSCLC, completion of definitive CCRT followed by maintenance ICI, and the availability of complete blood count (CBC) data at baseline and during CCRT, with a minimum follow-up period of 3 months. Exclusion criteria encompassed failure to complete the scheduled RT and lack of follow-up records post-RT. Maintenance ICI for stage III NSCLC has been administered at Yonsei Cancer Center and Gangnam Severance Hospital since 2016. Between January 2016 and June 2022, 177 patients who underwent definitive CCRT followed by maintenance ICI for stage III NSCLC were screened. Patients without CBC data at baseline and during CCRT (n=10), those with less than 3 months of follow-up (n=7), those who did not complete the scheduled RT (n=7), or those who did not have post-RT follow-up records (n=2) were excluded from this study. A total of 151 patients were retrospectively analyzed.
2. Treatment and follow-up
All patients underwent RT with a definitive aim of external beam RT and received conventional fractionation of 60-63 Gy in 30 fractions using intensity-modulated RT. Chemotherapy was administered concurrently with RT followed by maintenance ICI. The standard dosing regimen for concurrent chemotherapy included carboplatin at an area under the curve of 2 plus paclitaxel at 45-50 mg/m2 weekly or cisplatin at 50 mg/m2 administered on days 1, 8, 29, and 36. For maintenance ICI, durvalumab was administered at a dose of 10 mg/kg every 2 weeks.
After the treatment, patients were followed up every 2 to 4 months for the first 3 years and every 6 months thereafter. Radiological and blood examinations (including CBC) were performed at every follow-up. Computed tomography (CT) scans and/or positron emission tomography were performed to identify gross recurrent lesions, if clinically indicated.
Tumor response after CCRT (before maintenance ICI) was evaluated using Response Evaluation Criteria in Solid Tumors, ver. 1.1 [12], with the objective response rate defined as the proportion of patients who achieve either a complete or partial response to treatment. Radiation pneumonitis was diagnosed through imaging findings and the subjective symptoms reported by the patient. The grade of radiation pneumonitis was assessed using the Common Terminology Criteria for Adverse Events, ver. 5.0 [13].
3. Definition of sarcopenia
Sarcopenia was diagnosed using data from the CT scans acquired at the initial diagnosis or simulation CT before definitive CCRT. Baseline CT images were used to measure the cross-sectional area of the skeletal muscle at the level of the third lumbar (L3) vertebra. Using MIM Vista software (version 7.1.7, MIM Corp.), we quantified skeletal muscles defined by a range of –29 to +150 Hounsfield units, and muscle boundaries were manually corrected as needed (S1 Fig.) [14,15]. We calculated the L3 skeletal muscle index (L3-SMI) as follows:
Sarcopenia, defined by the international consensus of cancer cachexia, is confirmed when L3-SMI is < 55 cm2/m2 for men and < 39 cm2/m2 for women, but this criterion is based on Westerner population [16]. Asians with different intrinsic muscle mass require different standards; accordingly, we defined sarcopenia as an L3-SMI of < 49 cm2/m2 for men and < 31 cm2/m2 for women, which are Korean-specific cut-off values defined in other studies [17,18].
4. Definition of lymphopenia
Based on the Common Terminology Criteria for Adverse Events ver. 5.0, lymphopenia was defined as an absolute lymphocyte count (ALC) of less than 1.00×103 cells/µL; grade 1, 2, 3, and 4 lymphopenia were defined as ALC of 0.80-1.00×103 cells/µL, 0.50-0.80×103 cells/µL, 0.20-0.50×103 cells/µL, and < 0.20×103 cells/µL, respectively [13]. Grade 3 or higher lymphopenia was defined as severe lymphopenia.
5. Statistical analysis
Pearson χ2 test for categorical data and independent t test for continuous data were used to compare baseline characteristics of patients with and without sarcopenia. The correlation between L3-SMI and baseline ALC was analyzed using Pearson’s correlation coefficient. A partial correlation analysis was also performed to adjust for sex-related differences.
The primary endpoints were OS, defined as the time from the date of definitive CCRT initiation to either death due to any cause or to the last follow-up, and PFS, defined as the time from the date of definitive CCRT initiation to the date of either disease progression, death, or the last follow-up. OS and PFS were analyzed using the Kaplan-Meier method and log-rank tests.
Repeated-measures analysis of variance and a linear mixed model were used to compare the changes in ALC at each time point (before CCRT, during CCRT, and at 1, 2, 3, 6, and 12 months after CCRT completion).
A propensity score-matching (PSM) analysis was conducted to compare changes in ALC at each time point between patients with and without pre-RT sarcopenia while adjusting for clinical factors. Propensity scores were derived from a multivariable logistic regression model that included age, body mass index, and baseline ALC. Patients with and without pre-RT sarcopenia were matched in a 1:1 ratio based on their scores using nearest-neighbor matching with a caliper distance of 0.1 standard deviations of the logit of the propensity score. The balance of covariate distribution between the two groups was assessed using the standardized mean difference.
Univariate and multivariate analyses were performed using the Cox proportional hazards model to determine prognostic factors for OS and PFS. Univariate and multivariate binary logistic regression analyses were performed to determine the risk factors associated with grade 3 or higher lymphopenia during definitive CCRT. For the multivariate analysis, a backward stepwise selection procedure was adopted.
Statistical significance was set at p < 0.05. IBM SPSS Statistics for Windows ver. 26.0 (IBM Corp.) was used for the statistical analysis.
Results
1. Baseline characteristics
The median age of all patients was 69 years (range, 34 to 92 years). Histologically, 57 cases (37.7%) of adenocarcinomas and 87 cases (57.6%) of squamous cell carcinomas were identified. Of the 151 patients, 59 (39.1%) had never smoked, 31 (20.5%) were former smokers who quit smoking before treatment, and 61 (40.4%) were active smokers who continued smoking after treatment. One hundred thirty-four patients (88.7%) showed anti-programmed death ligand-1 expression of at least 1%. Most patients received weekly paclitaxel with carboplatin for concurrent chemotherapy (147 patients, 97.4%). For the dosimetric factors, the median planning target volume (PTV), mean lung dose, and mean heart dose were 422.0, 13.0, and 9.1 Gy, respectively. According to the Korean-specific cutoff standard, 86 patients (57.0%) had pre-RT sarcopenia. The baseline characteristics of the patients are summarized in Table 1.
Baseline characteristics of total patients and patients with or without pre-RT sarcopenia
In the two groups categorized according to pre-RT sarcopenia, patients in the pre-RT sarcopenia group were older (median, 72 vs. 67 years; p=0.004), lower body mass index (median 22.4 vs. 24.0 kg/m2; p < 0.001), and had lower baseline ALC (median, 1.78 vs. 2.19×103 cells/µL; p < 0.001). Characteristics of the patients in the non-sarcopenia and sarcopenia groups are listed in Table 1.
Pearson’s correlation coefficient showed a negligible correlation between L3-SMI and baseline ALC (r=0.209) (Fig. 1). In the partial correlation analysis, there was no correlation between the L3-SMI and baseline ALC, even after adjusting for sex (r=0.221) (Fig. 1).
Scatter plot illustrating the relationship between L3 skeletal muscle index and baseline absolute lymphocyte count; a)Pearson’s correlation coefficient, b)Partial correlation coefficient after adjusting for sex.
The total number of patients whose concurrent chemotherapy doses were reduced, delayed, or omitted was 40 (26.5%), three (1.2%), and 17 (11.3%), respectively (S2 Table). These dose adjustments were significantly more prevalent in the sarcopenia group than in the non-sarcopenia group (p < 0.001). Additionally, 78 patients (51.7%) achieved an objective response after CCRT. However, the objective response rate was significantly lower in the sarcopenia group (45.3%) than in the non-sarcopenia group (60.0%) (p=0.047) (S2 Table).
2. Changes in ALC after treatment and risk factors for grade three or higher lymphopenia
For total patients, the mean of the ALC before initiating CCRT, during CCRT, and at 1, 2, 3, 6, and 12 months after CCRT completion were (2.02±0.68)×103 cells/µL, (0.41±0.21)×103 cells/µL, and (0.85±0.53)×103 cells/µL; (0.97±0.46)×103 cells/µL; (1.17±0.53)×103 cells/µL; (1.22±0.54)×103 cells/µL; and (1.34±0.61)×103 cells/µL, respectively. Changes in ALC according to pre-RT sarcopenia are shown in Fig. 2A. Patients without pre-RT sarcopenia showed significantly improved lymphocyte recovery after CCRT compared with patients with pre-RT sarcopenia (p=0.013). When comparing each time point between patients with and without pre-RT sarcopenia, ALC at one and 2 months after CCRT completion showed no significant difference (at 1 month mean, [0.82±0.51 vs. 0.90±0.56]×103 cells/µL; p=0.340; at 2 months mean, [0.91±0.48 vs. 1.04±0.43]×103 cells/µL, p=0.090). However, ALC at 3, 6, and 12 months after CCRT completion was significantly higher in patients without pre-RT sarcopenia, compared with those with pre-RT sarcopenia, due to differences in lymphocyte recovery (at 3 months mean, [1.03±0.49 vs. 1.35±0.54]×103 cells/µL, p < 0.001; at 6 months mean, [1.06±0.46 vs. 1.44±0.55]×103 cells/µL, p < 0.001; at 12 months mean, [1.22±0.56 vs. 1.49±0.64]×103 cells/µL, p=0.028).
Changes in absolute lymphocyte counts based on pre-radiotherapy (RT) sarcopenia before (A) and after (B) propensity score-matching. *p < 0.05 and ***p < 0.001; data are represented as mean±standard error.
After PSM, each group comprised 47 patients, demonstrating an adequate balance of all characteristics (S3 Table). No statistically significant difference was observed in baseline ALC between the two groups (mean, [1.90±0.62 vs. 2.01±0.50]×103 cells/µL, p=0.384). Changes in ALC according to pre-RT sarcopenia after PSM are depicted in Fig. 2B. Even after adjusting for baseline ALC using PSM, patients without pre-RT sarcopenia exhibited significantly improved lymphocyte recovery after CCRT compared with patients with pre-RT sarcopenia (p=0.041). Moreover, no significant differences were observed in ALC at 1 and 2 months post-CCRT completion between the two groups (1 month: mean, [0.76±0.46 vs. 0.82±0.42]×103 cells/µL, p=0.476; 2 months: mean, [0.92±0.41 vs. 0.99±0.41]×103 cells/µL; p=0.383). However, ALC at 3, 6, and 12 months after CCRT completion was significantly higher in patients without pre-RT sarcopenia than in those with pre-RT sarcopenia, reflecting differences in lymphocyte recovery (3 months: mean, [1.01±0.40 vs. 1.24±0.42]×103 cells/µL; p=0.009; 6 months: mean, [1.07±0.38 vs. 1.40±0.54]×103 cells/µL; p=0.001; 12 months: mean, [1.24±0.52 vs. 1.54±0.63]×103 cells/µL; p=0.046).
Most patients experienced lymphopenia during CCRT (n=148, 98%): grade 1 in eight patients (5.3%), grade 2 in 28 patients (18.5%), grade 3 in 91 patients (60.3%), and grade 4 in 21 patients (13.9%). Even after adjusting for baseline ALC using PSM, patients with pre-RT sarcopenia exhibited a significantly higher incidence of grade 3 or higher lymphopenia (91.5% vs. 68.1%, p=0.005). The factors associated with the development of grade 3 or higher lymphopenia during CCRT were analyzed (Table 2). Univariate analysis demonstrated that poor performance status (odds ratio [OR], 2.67; 95% confidence interval [CI], 1.13 to 6.31; p=0.026), advanced N category (OR, 2.45; 95% CI, 1.07 to 5.61; p=0.034), larger PTV (OR, 4.01; 95% CI, 1.78 to 9.02; p=0.001), higher mean lung dose (OR, 1.06; 95% CI, 1.04 to 1.29; p=0.007), pre-RT sarcopenia (OR, 3.74; 95% CI, 1.73 to 8.09; p=0.001), and lower baseline ALC (OR 0.24, 95% CI, 0.12 to 0.48; p < 0.001) were significant risk factors for grade 3 or higher lymphopenia. In multivariate analysis, larger PTV (OR, 3.95; 95% CI, 1.65 to 9.49; p=0.002), pre-RT sarcopenia (OR, 5.13; 95% CI, 2.14 to 12.27; p < 0.001), and a lower baseline ALC (OR, 0.17; 95% CI, 0.07 to 0.42; p < 0.001) were independent risk factors for grade 3 or higher lymphopenia (Table 2). The changes in ALC according to grade 3 or higher lymphopenia during CCRT are also shown in Fig. 3. When comparing each time point between patients with and without grade 3 or higher lymphopenia during CCRT, ALC at 1, 2, 3, and 6 months after CCRT completion was significantly higher in patients without grade 3 or higher lymphopenia during CCRT (at 1 month: mean, [0.79±0.50 vs. 1.05±0.56]×103 cells/µL; p=0.006; at 2 months: mean, [0.90±0.42 vs. 1.18±0.52]×103 cells/µL; p=0.001; at 3 months: mean, [1.06±0.50 vs. 1.47±0.51]×103 cells/µL; p < 0.001; and at 6 months: mean, [1.09±0.45 vs. 1.56±0.59]×103 cells/µL; p < 0.001).
Risk factors for the development of grade 3 or higher lymphopenia during chemoradiotherapy
Changes in absolute lymphocyte counts based on grade 3 or higher lymphopenia during concurrent chemo radiotherapy (CCRT). *p < 0.05 and ***p < 0.001; data are represented as mean±standard error.
3. Treatment outcomes and prognostic factors for OS and PFS
A total of 51 patients (33.8%) developed radiation pneumonitis after CCRT, including 25 patients (16.6%) with grade 1, 20 patients (13.2%) with grade 2, and six patients (4.0%) with grade 3 or higher radiation pneumonitis. No statistical correlation was observed between radiation pneumonitis and pre-RT sarcopenia (p=0.700). Discontinuation owing to adverse events occurred in 21 patients (13.9%), 14 (66.7%) of whom discontinued specifically because of radiation pneumonitis.
Over a median follow-up duration of 17.6 months (range, 2.6 to 53.8 months), 43 patients (28.5%) died. During the follow-up period, 74 patients (49.0%) experienced disease progression, of whom 60 (81.1%) had locoregional failure and 48 (64.9%) had distant failure. The 2-year OS and PFS rates among all patients were 69.6% and 39.9%, respectively. Patients with pre-RT sarcopenia had significantly worse OS (2-year OS, 61.8% vs. 80.3%; p=0.005) (Fig. 4A) and PFS (2-year PFS, 37.1% vs. 44.8%; p=0.044) (Fig. 4B) than those without pre-RT sarcopenia. Patients with grade 3 or higher lymphopenia during CCRT showed no statistical difference in OS (2-year OS, 67.2% vs. 76.5%; p=0.187) (Fig. 4C) but had significantly worse PFS (2-year PFS, 34.4% vs. 55.4%; p=0.003) (Fig. 4D) than patients without grade 3 or higher lymphopenia during CCRT.
Kaplan-Meier curves depicting overall survival (OS) and progression-free survival (PFS). OS (A) and PFS (B) in patients with or without pre-radiotherapy (RT) sarcopenia. OS (C) and PFS (D) in patients with or without grade 3 or higher lymphopenia during chemoradiotherapy.
In the univariate analysis for OS, several factors were identified as poor prognostic indicators: pre-RT sarcopenia (hazard ratio [HR], 2.57; 95% CI, 1.29 to 5.10; p=0.007), concurrent chemotherapy dose adjustments (HR, 4.08; 95% CI, 2.19 to 7.59; p=0.007), stable or progressive disease after CCRT (HR, 0.09; 95% CI, 0.04 to 0.23; p < 0.001), grade 3 or higher radiation pneumonitis after CCRT (HR, 4.88; 95% CI, 1.72 to 13.88; p=0.003), and discontinuation of maintenance ICI owing to adverse events (HR, 3.81; 95% CI, 1.98 to 7.32; p < 0.001). In the multivariate analysis, these factors remained significant poor prognostic indicators for OS: pre-RT sarcopenia (HR, 2.35; 95% CI, 1.14 to 4.84; p=0.020), concurrent chemotherapy dose adjustments (HR, 2.51; 95% CI, 1.29 to 4.91; p=0.007), stable or progressive disease after CCRT (HR, 0.09; 95% CI, 0.04 to 0.24; p < 0.001), grade 3 or higher radiation pneumonitis after CCRT (HR, 3.46; 95% CI, 1.02 to 11.79; p=0.047), and discontinuation of maintenance ICI owing to adverse events (HR, 2.47; 95% CI, 1.19 to 5.15; p=0.016).
In the univariate analysis for PFS, several factors emerged as poor prognostic indicators: pre-RT sarcopenia (HR, 1.55; 95% CI, 1.01 to 2.39; p=0.046), grade 3 or higher lymphopenia during CCRT (HR, 2.23; 95% CI, 1.30 to 3.83; p=0.004), concurrent chemotherapy dose adjustments (HR, 2.70; 95% CI, 1.78to 4.10; p < 0.001), stable or progressive disease after CCRT (HR, 0.38; 95% CI, 0.25 to 0.59; p < 0.001), and discontinuation of maintenance ICI owing to adverse events (HR, 2.74; 95% CI, 1.65 to 4.56; p < 0.001). In the multivariate analysis, the following factors remained significant poor prognostic indicators for PFS: grade 3 or higher lymphopenia during CCRT (HR, 2.27; 95% CI, 1.29 to 3.99; p=0.004), concurrent chemotherapy dose adjustments (HR, 1.70; 95% CI, 1.06 to 2.72; p=0.027), stable or progressive disease after CCRT (HR, 0.42; 95% CI, 0.27 to 0.65; p < 0.001), and discontinuation of maintenance ICI owing to adverse events (HR, 1.89; 95% CI, 1.08 to 3.33; p=0.027). The results of the univariate and multivariate analyses for OS and PFS are summarized in Table 3
Prognostic factors for overall survival and progression-free survival
The patterns of failure according to pre-RT sarcopenia are summarized in S4 Table. Locoregional failure was more frequent than distant failure in both groups (sarcopenia group, 83.3% vs. non-sarcopenia group, 79.5%); however, the difference was not statistically significant (p=0.683). Distant failure was also statistically insignificant between the two groups (p=0.820).
Discussion
The results of this study indicated that in patients with stage III NSCLC receiving standard treatment, lymphocyte recovery after definitive CCRT was significantly improved in patients without pre-RT sarcopenia compared to those with pre-RT sarcopenia. The independent risk factors associated with grade 3 or higher lymphopenia during CCRT included a larger PTV, pre-RT sarcopenia, and lower baseline ALC. Given the significant difference observed in baseline ALC between patients with and without pre-RT sarcopenia, PSM was used to adjust for this variable. Even after adjusting for baseline ALC, patients with pre-RT sarcopenia exhibited poorer lymphocyte recovery and a significantly higher incidence of grade 3 or higher lymphopenia during CCRT. In addition, patients who experienced severe lymphopenia during CCRT exhibited significantly lower lymphocyte counts (even after lymphocyte recovery following CCRT) than those who did not experience severe lymphopenia during CCRT. Regarding survival outcomes, pre-RT sarcopenia significantly worsened OS and PFS, as indicated by the Kaplan-Meier curve; however, it emerged as a significant prognostic factor solely for OS in the multivariate analysis. In contrast, grade 3 or higher lymphopenia during CCRT was identified as a significant prognostic factor exclusively for PFS in both the Kaplan-Meier curve and multivariate analysis. Factors such as dose reduction, delay or omission of CCRT, poor tumor response to CCRT, and discontinuation of maintenance ICI were also poor prognostic factors for both OS and PFS.
The status of the host immune system plays a crucial role in determining the effectiveness of ICIs. In patients with NSCLC, lymphopenia during ICI is associated with a poor prognosis [8,19]. Specifically, in stage III NSCLC, approximately four-fifths of patients experience RT-induced lymphopenia after definitive CCRT [20]. Recent studies have indicated that this RT-induced lymphopenia, which occurs before maintenance ICI, also influences prognosis. For instance, Friedes et al. [21] conducted a retrospective analysis involving 78 patients who received maintenance ICI after definitive CCRT for NSCLC and found that patients with RT-induced severe lymphopenia had worse PFS compared to those without. Similarly, Jing et al. [22] reported retrospective results from a comparison of 192 patients who received only definitive CCRT and 117 patients who received maintenance ICI after definitive CCRT. In both groups, RT-induced severe lymphopenia was identified as a poor prognostic factor for survival, and in the event of RT-induced severe lymphopenia, maintenance ICI did not lead to improved survival. Similarly, our study revealed that patients with RT-induced grade 3 or higher lymphopenia exhibited significantly poorer PFS. Severe lymphopenia was one of the significant prognostic factors for PFS identified in the multivariate analysis. Furthermore, baseline ALC was not associated with OS or disease-free survival. However, patients with a low baseline ALC were significantly more likely to develop RT-induced grade 3 or higher lymphopenia. Therefore, patients with a low baseline ALC require special attention for ALC management.
In this study, a larger PTV was identified as a risk factor for RT-induced lymphopenia. Larger PTVs are more likely to result in lymphopenia [20,22] because a greater number of lymphocytes are exposed to radiation with increasing PTV size. Similarly, considering that the heart contains a substantial blood volume, the radiation dose to the heart is reportedly associated with lymphopenia [23,24]. Dosimetric parameters, such as mean heart dose or mean lung dose, were not identified as significant factors in our study. However, in the N2-3 category (mediastinal lymph node metastasis), more lymphopenia may be induced because of greater radiation exposure to the heart or major vessels, as the mediastinum is also included in the RT field.
Skeletal muscle releases myokines such as interleukin (IL)-6, IL-7, and IL-15, which regulate the immune system [25]. However, sarcopenia can impair immunological protection through various mechanisms. Among these myokines, IL-7 is most strongly associated with lymphocytes. IL-7 is a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus. However, it is also classified as a myokine owing to its expression and secretion by skeletal muscle cells [6]. IL-7 plays an important role in the development and maintenance of immature lymphocytes [26], and exogenously injected IL-7 during radiation-induced lymphopenia has been demonstrated to aid in restoring lymphocyte counts [27]. Consequently, sarcopenia may result in impaired IL-7 signaling, leading to defective maintenance and development of T- and B-lymphocytes. In our study, lymphocyte recovery was inhibited in patients with pre-RT sarcopenia, and grade 3 or higher RT-induced lymphopenia occurred frequently. In addition, given the significant difference in baseline ALC between the pre-RT sarcopenia and non-sarcopenia groups, PSM was conducted to assess the isolated effect of pre-RT sarcopenia on lymphocyte count. The results indicated that pre-RT sarcopenia alone significantly affected lymphocyte recovery, which may be attributable to impaired IL-7 signaling.
Pretreatment sarcopenia not only indirectly affects prognosis by inducing lymphopenia but also directly affects survival. In previous studies, we demonstrated an association between pretreatment sarcopenia and poor survival outcomes in various solid cancers [2,3,28]; notably, similar results have been observed for NSCLC. A meta-analysis revealed that sarcopenia serves as an independent predictor of reduced OS (but not disease-free survival) in both stage I-II and stage III-IV NSCLC [29]. Additionally, a systematic review examining the clinical impact of sarcopenia on patients with NSCLC who received ICI found that pre-immunotherapy sarcopenia was significantly associated with worse OS (HR, 1.61; 95% CI, 1.24 to 2.10) and PFS (HR, 1.98; 95% CI, 1.32 to 2.97) [30]. In our study, pre-RT sarcopenia was identified as a significant prognostic factor for OS, consistent with the findings of previous studies. Although treatment outcomes in the overall patient cohort were similar to those observed in the PACIFIC trial [31], patients without pre-RT sarcopenia exhibited a significantly better prognosis. This improvement is likely attributable to a combination of factors, including the direct impact of sarcopenia on survival, the influence of sarcopenia-induced lymphopenia, and reduced treatment compliance associated with sarcopenia or lymphopenia. Therefore, providing intensive nutritional support to patients with stage III NSCLC who have pre-RT sarcopenia may improve prognosis.
For PFS, pre-RT sarcopenia emerged as a significant prognostic factor in the univariate analysis; however, it was not significant in the multivariate analysis. In contrast, the multivariate analysis identified severe lymphopenia during CCRT as a significant prognostic factor. This outcome may be attributed to the observation that, in the event of severe lymphopenia during CCRT, lymphocyte counts often remain low even after CCRT, leading to persistent hematologic toxicity. Several studies, including previous research conducted at our institution, have reported that sustained lymphopenia after CCRT affects prognosis, including PFS [22,32-34]. Additionally, sustained lymphopenia may influence overall health conditions that could affect treatment or clinical management after CCRT, ultimately having a significant impact on PFS. Thus, for PFS, sustained lymphopenia associated with severe lymphopenia during CCRT appears to have a more fundamental impact than pre-RT sarcopenia. This may explain the differing outcomes of pre-RT sarcopenia between OS and PFS in the multivariate analysis.
In our study, radiation pneumonitis occurred in 33.8% of patients after CCRT, a rate similar to the 33.9% reported in the PACIFIC trial and the 36.3% observed in the PACIFIC-KR trial involving Korean patients [7,35]. Severe radiation pneumonitis (grade 3 or higher) was observed in 4.0% of patients enrolled in our study, compared to the 3.4% and 1.9% observed in the PACIFIC and PACIFIC-KR trials, respectively. In the PACIFIC trial, the discontinuation rate of maintenance ICI owing to adverse events was 15.4%, with 40.9% of these discontinuations attributed to radiation pneumonitis. Similarly, in the SPOTLIGHT trial, the discontinuation rate owing to adverse events was 9.0%, with 76.7% of these discontinuations caused by radiation pneumonitis [36]. In our study, 13.9% of all patients discontinued maintenance ICI owing to adverse events, with 66.7% of these discontinuations caused by radiation pneumonitis, highlighting its role as a major cause, consistent with the findings from previous studies. Additionally, our analysis indicated that the discontinuation of maintenance ICI was an independent prognostic factor associated with poor outcomes, although radiation pneumonitis was not a significant factor in the multivariate analysis. These results suggest that, while radiation pneumonitis and maintenance ICI discontinuation are interrelated, the latter has a more substantial impact on prognosis. Therefore, managing radiation pneumonitis is crucial for ensuring the continuation of maintenance ICI and improving prognosis.
Regarding tumor response after CCRT, the PACIFIC and PACIFIC-KR trials reported an objective response rate of 50.6% and 51.0%, respectively, both statistically similar to the 51.7% observed in our study [7,35]. Additionally, our findings indicated that objective response was significantly associated with survival outcomes, consistent with the findings of other studies that have demonstrated a correlation between clinical response after CCRT and prognosis [37]. In our study, patients with pre-RT sarcopenia exhibited poorer tumor response after CCRT, likely because of their generally worse health conditions, which often resulted in more frequent dose reductions, delays, or omissions in the scheduled concurrent chemotherapy. Additionally, survival analysis revealed that adjustments in concurrent chemotherapy dosing significantly impacted prognosis.
This study had several limitations owing to its retrospective nature. First, not all variables and potential confounders could be assessed. For example, impaired IL-7 signaling may contribute to RT-induced lymphopenia; however, our analysis relied solely on the results of routine blood examinations. Second, toxicity and quality of life assessments could not be implemented owing to inaccuracies in the medical records. Finally, the exclusion of patients who did not complete the scheduled RT, owing to a lack of medical records following treatment, made it challenging to analyze intention-to-treat outcomes.
Despite these limitations, this study analyzed a homogenous group of patients who underwent consistent examinations, treatments, and routine clinical follow-up at our institution. Additionally, PSM was employed to minimize selection bias related to other clinical factors when analyzing the impact of sarcopenia on lymphopenia. Furthermore, this study represents the largest investigation of the prognostic significance of pretreatment sarcopenia in patients with stage III NSCLC who received definitive CCRT followed by ICI therapy. In addition, to the best of our knowledge, this study is one of the few investigations that have clinically assessed the relationship between sarcopenia and lymphopenia.
In conclusion, the findings of this study demonstrate that pre-RT sarcopenia is associated with poor survival outcomes and reduced lymphocyte recovery after definitive CCRT in patients with stage III NSCLC. Additionally, the deterioration in general health conditions owing to pre-RT sarcopenia led to concurrent chemotherapy dose adjustments, which negatively affected tumor response after CCRT and, ultimately, prognosis. Furthermore, CCRT-induced lymphopenia not only contributed to poor prognosis but may have also impaired the therapeutic efficacy of subsequent maintenance ICI, resulting in worse treatment outcomes. The discontinuation of maintenance ICI owing to adverse events, such as radiation pneumonitis, was also identified as an independent and clinically significant prognostic factor. Early interventions, such as exercise therapy and nutritional support, may help reducing muscle wasting, thereby preventing lymphopenia during CCRT and improving lymphocyte recovery after CCRT. Moreover, careful monitoring and proactive management of ALC and radiation pneumonitis can improve the treatment outcome of patients with stage III NSCLC receiving maintenance ICI therapy.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
This study was approved by the Severance Hospital institutional review board (No. 3-2023-0261), and the requirement for informed consent was waived because of its retrospective design. The study procedures were in accordance with the principles outlined in the Helsinki Declaration of 1975, as revised in 2000.
Author Contributions
Conceived and designed the analysis: Cho Y.
Collected the data: Lee J.
Contributed data or analysis tools: Kim KH, Lee CG, Cho J, Yoon HI, Kim J.
Performed the analysis: Lee J.
Wrote the paper: Cho Y, Lee J.
Conflict of Interest
Conflict of interest relevant to this article was not reported.
Funding
This study was supported by a faculty research grant of Yonsei University College of Medicine for (6-2020-0225) and by National Research Foundation of Korea Grant funded by the Korean Government (NRF-2021R1A2C1007191).