Treatment outcome and safety of durvalumab after concurrent chemoradiation in very elderly patients with unresectable stage III non-small cell lung cancer

Introduction

Background

Non-small cell lung cancer (NSCLC) accounts for roughly 85% of all lung cancer cases, and it is estimated that between 20% and 35% of these patients present with stage III disease at the time of diagnosis (1,2). Prior to the incorporation of durvalumab into the standard treatment paradigm for patients with unresectable stage III NSCLC, the conventional management—consisting of platinum-based concurrent chemoradiotherapy (CCRT) followed by observation—was associated with 5-year survival rates ranging from 15% to 32% (3,4).

The PACIFIC trial demonstrated that up to 12 months of consolidation therapy with durvalumab significantly prolonged both progression-free survival (PFS) and overall survival (OS) compared with placebo in patients with unresectable stage III NSCLC who had not exhibited disease progression following CCRT (5). At the most recent update, median PFS was 16.9 months with durvalumab versus 5.6 months with placebo and 5-year PFS rates were 33.1% versus 19.0%, respectively. The median OS was 47.5 months with durvalumab versus 29.1 months with placebo and 5-year OS rates were 42.9% versus 33.4%, respectively (6).

Rationale and knowledge gap

Lung cancer occurs more frequently in older adults compared to younger individuals, with the average age at diagnosis being 71 years. The highest proportion of lung cancer diagnosis occurs in individuals aged 65 to 74 years, accounting for 35.6% of cases, followed by those aged 75 to 84 years, who comprise 27.4% of diagnoses (7). However, patients aged 70 years or older were underrepresented in the PACIFIC trial, comprising only 158 out of 713 participants (22.2%) (5). Moreover, a post-hoc exploratory analysis of the PACIFIC trial, employing an age cutoff of 70 years, suggested that durvalumab conferred PFS and OS benefits regardless of patient age; nonetheless, the exploratory, post-hoc nature of this subgroup analysis, along with disparities in potentially prognostic baseline factors and subgroup sizes, impairs the robustness of the conclusions (8). Additional evidence supporting this finding is provided by real-world data from the PACIFIC-R study, which demonstrated that individuals aged 75 years and older experienced less favorable PFS outcomes than those younger than 75 years (9).

Data from real-world clinical settings on the use of durvalumab consolidation in elderly patients are scarce, although a few relevant studies have been published. A recent retrospective, multicenter investigation by Korean researchers evaluated the efficacy and safety of durvalumab consolidation therapy in older adults with unresectable stage III NSCLC. The analysis revealed comparable PFS and OS between patients aged 70 years and older and those under 70, although adverse events (AEs) were observed more frequently in the elderly cohort (10). Australian researchers conducted a retrospective, multicenter study evaluating durvalumab consolidation therapy in patients aged ≥70 years with unresectable stage III NSCLC. Outcomes in older patients, including PFS, OS, and AEs, were comparable to those in younger patients (11). A single-center retrospective study from Canada evaluated CCRT followed by durvalumab in older patients with unresectable stage III NSCLC, reporting comparable PFS, OS and safety between patients aged ≥70 and those <70 years (12).

Objective

Although all aforementioned real-world data across various regions have demonstrated relatively consistent outcomes using 70 years as the age cutoff, this threshold has not been universally established as the definition of ‘elderly’ and the average age at the time of lung cancer diagnosis continues to rise. Thus, it may be worthwhile to explore whether comparable outcomes persist with more advanced age thresholds. This study aimed to evaluate the efficacy and safety of durvalumab consolidation following CCRT in very elderly patients with unresectable stage III NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-926/rc).

Methods

Study design and participants

This retrospective cohort study, conducted at four medical centers in Republic of Korea, included patients over 18 years of age with unresectable stage III NSCLC who received platinum-based CCRT. All patients received definitive thoracic radiotherapy targeting the primary tumor and regional lymph nodes as part of concurrent chemoradiation therapy. Without evidence of disease progression, they proceeded to at least one cycle of durvalumab between 2020 and 2023. Clinical staging was determined according to the 8th edition of the American Joint Committee on Cancer TNM classification (13) and treatment response was evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, criteria (14). Collected data included patient demographics (age, sex, body mass index, smoking status); clinical characteristics such as Eastern Cooperative Oncology Group (ECOG) score, comorbidities, tumor histology, clinical stage; and molecular profiling results, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, and programmed death-ligand 1 (PD-L1) SP263 expression. Additionally, information on treatment modality, survival outcomes, and AEs was gathered. Death dates were ascertained from electronic medical records (EMRs) when death occurred at the participating hospitals. For deaths outside the centers, we verified death via the Korean National Health Insurance Service (NHIS) subscriber-eligibility database and set the date of death to one day before the eligibility-termination date. The cause of death was available for in-hospital deaths; for deaths outside these hospitals, cause of death was not available from NHIS and was recorded as unknown.

Outcomes

The investigated endpoints of this study were PFS, OS and AEs. Patients were stratified by age into two groups: those under 75 years and those aged 75 years or older. In addition, further subgroup analyses were conducted using alternative age thresholds of 70 and 65 years. Furthermore, comparisons were made between the historical control group (patients treated between 2008 and 2019 who did not receive durvalumab, as it was not reimbursed in Republic of Korea until April 1, 2020) and those who received durvalumab. These comparisons were conducted for the overall patient population as well as separately for patients aged ≥75 years and those aged <75 years.

PFS was defined as the interval from the start of treatment to either documented disease progression or death from any cause, whichever occurred first (15). OS was defined as the duration from treatment initiation to death from any cause (15). Treatment-related AEs were evaluated by the attending physicians and classified in accordance with the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. (16). Patients were followed from the index date—defined as the initiation of treatment—until the occurrence of death or the end of the study period (December 6, 2024), whichever occurred earlier.

Statistical analysis

Baseline variables, AEs, and survival outcomes were compared across age groups using chi-square or Fisher’s exact tests for categorical data, and t-tests or Mann-Whitney U tests for continuous measures. Survival outcomes were estimated using Kaplan-Meier survival analysis, with group comparisons assessed through the log-rank test. As most patients were ever-smokers, male, had no interstitial lung disease (ILD), were PD-L1 positive (≥1%), and EGFR wild-type, these variables were excluded from further analysis due to insufficient variability. Covariates with a univariate association at a significance level of P<0.10 were considered for inclusion in the multivariable regression models for each outcome. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated using a multivariable Cox proportional hazards regression model. All analyses were performed in R software (version 4.3.3; R Foundation, Vienna, Austria), with P<0.05 considered statistically significant.

Ethics

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by Hallym University Dongtan Sacred Heart Hospital (No. 2022-11-002), Hallym University Sacred Heart Hospital (No. 2023-11-012), Hallym University Kangnam Sacred Heart Hospital (No. 2023-12-004), and Hallym University Chuncheon Sacred Heart Hospital (No. 2023-12-001). Individual consent for this retrospective analysis was waived.

Results

Patient characteristics

Among the 46 patients with unresectable stage III NSCLC who received durvalumab between 2020 and 2024 at four hospitals, 13 were classified as older adults (≥75 years) and 33 as younger individuals (<75 years) (Table 1). The median age was 68 years, and most patients were men (97.8%) and had a history of smoking (97.8%). Pack-year history was comparable between the elderly and younger groups. Most patients had a good performance status (ECOG PS 0 or 1), with no significant difference observed between the two age groups. The prevalence of comorbid conditions such as chronic obstructive pulmonary disease (COPD), ILD, ischemic heart disease, and cerebrovascular accidents was similar between the two age groups. Additionally, no statistically significant differences were observed in clinical stage, tumor histology, EGFR or ALK mutation status, PD-L1 expression levels, best response to CCRT. The majority of patients (95.7%) received weekly paclitaxel in combination with a platinum-based agent. Among the platinum agents, cisplatin was used more frequently (87.0%) than carboplatin (13.0%), with no significant difference observed between age groups. Additionally, variables such as the number of chemotherapy cycles, total radiotherapy dose, CCRT completion rates, treatment discontinuation due to AEs, and mortality during CCRT were comparable between groups. However, dose reductions occurred more often in the elderly cohort than in the younger group (30.8% vs. 6.1%, P=0.045). When stratified by both the 70-year and 65-year age thresholds, only pack-years differed significantly between the groups (50 vs. 37 pack-years, P=0.02; 46 vs. 36 pack-years, P=0.01, respectively) (Tables S1,S2). In the comparison between the historical control group and patients who received durvalumab, the durvalumab group had a higher prevalence of COPD (20.8% vs. 56.5%, P<0.001) and received a lower total radiotherapy dose {63.0 [interquartile range (IQR), 60.0–66.0] vs. 60.0 (IQR, 60.0–60.0), P<0.001}; however, other baseline characteristics were generally comparable. A similar trend was observed in the subgroup of patients aged ≥75 years, where the durvalumab group received a lower total radiotherapy dose [66.0 (IQR, 63.0–66.0) vs. 60.0 (IQR, 60.0–60.0), P<0.001], while other characteristics were largely similar between the groups (Tables S3,S4).

Durvalumab treatment patterns and first subsequent treatment

The median interval between completion of CCRT and initiation of durvalumab was 22 days with no significant difference between the elderly group (≥75 years: 23 days) and the younger group (<75 years: 22 days) (Table 2). The median number of durvalumab cycles and the proportion of treatment discontinuation showed no significant differences between elderly and younger patients. For first-line subsequent therapy after durvalumab, most patients received cytotoxic chemotherapy (83.3%), with similar proportions in both age groups (≥75 years: 80.0% vs. <75 years: 85.7%; P=0.68). Salvage surgery was performed in one patient aged ≥75 years, and radiotherapy was given to one younger patient. When analyzed using both the 70-year and 65-year age cutoffs, no significant differences were observed between the groups in the interval between completion of CCRT and initiation of durvalumab, the number of durvalumab cycles administered, reasons for durvalumab discontinuation, or the choice of first-line subsequent therapy after durvalumab (Tables S5,S6).

Survival outcomes

The median PFS for all patients was 24 months [95% CI: 16–not evaluable (NE) months; Figure 1A]. In patients <75 years of age, the median PFS was 29 months (95% CI: 20–NE months) compared to 14 months (95% CI: 8–NE months) in patients ≥75 years of age (P=0.03, Figure 1B). In patients <75 years old, three-year PFS was 42.3% (95% CI: 27.3–65.5%) compared with 15.0% (95% CI: 2.7–83.1%) in patients ≥75 years old (P=0.03, Figure 1B). The median OS was not reached (95% CI: 40–NE months; Figure 1C). In patients <75 years of age, the median OS was not reached (95% CI: 49–NE months) compared to 40 months (95% CI: 27–NE months) in patients ≥75 years of age (P=0.16, Figure 1D). In patients <75 years old, three-year OS was 75.2% (95% CI: 60.6–93.3%) compared with 57.7% (95% CI: 30.4–100%) in patients ≥75 years old (P=0.16, Figure 1D). As no variables showed significant associations with PFS or OS in the univariable analyses, multivariable Cox proportional hazards analysis was not conducted (Tables 3,4).

Figure 1 Kaplan-Meier curves depicting PFS and OS among patients treated with durvalumab. (A) PFS in the overall cohort. (B) PFS stratified by age group (≥75 vs. <75 years). (C) OS in the overall cohort. (D) OS stratified by age group (≥75 vs. <75 years). CI, confidence interval; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression-free survival.

When stratified by the 70-year age threshold, the median PFS was 29 months (95% CI: 17–NE months) in patients aged <70 years and 16 months (95% CI: 8–NE months) in those aged ≥70 years, with no statistically significant difference between the groups (P=0.17; Figure S1A). Based on the 70-year age cutoff, patients younger than 70 years had a median OS that was not reached (95% CI: 49–NE months), while those aged 70 years or older had a median OS of 40 months (95% CI: 27–NE months). This difference was not statistically significant (P=0.32; Figure S1B), likely due to the small sample size.

Using a 65-year age cutoff for stratification, median PFS was 23 months (95% CI: 9–NE months) in patients <65 years and 24 months (95% CI: 14–NE) in those ≥65 years, without a statistically significant difference (P=0.84; Figure S2A). In patients <65 years of age, the median OS was not reached (95% CI: NE–NE months) compared to 49 months (95% CI: 40–NE months) in patients ≥65 years of age (P=0.51, Figure S2B), with no statistically significant difference likely due to the small sample size.

When comparing the historical control group with patients who received durvalumab, the durvalumab group showed significantly improved PFS (P=0.02) and OS (P<0.001) in the overall population, consistent with the findings of the PACIFIC trial (5) (Figure S3). Among patients aged ≥75 years, consistent with the main results of the present study, there was no significant difference in PFS (P=0.051), while OS was significantly better in the durvalumab group (P=0.01) (Figures S4,S5).

AEs during CCRT

Overall, 21 patients (45%) experienced at least one AE during CCRT, while only 6 patients (13%) developed grade 3–4 toxicity (Table 5). The most common AEs during CCRT overall included esophagitis (13%, n=6) and radiation pneumonitis (10.9%, n=5). There were no notable differences in toxicity profiles between older and younger patients. When patients were stratified by 70- and 65-year age cutoffs, no statistically significant differences in toxicity profiles were identified between the older and younger groups (Tables S7,S8).

AEs during durvalumab consolidation

A total of 19 patients (41%) experienced at least one AE during durvalumab consolidation, while only one patient (2%) developed grade 3–4 toxicity (Table 6). Radiation pneumonitis was the most frequently observed AEs, occurring in 26.1% of patients (n=12), and was also the only reported grade ≥3 toxicity (2.2%, n=1). No significant differences in toxicity profiles were observed between the older and younger patient groups. AEs resulted in treatment discontinuation in 17.3% of patients (n=8), all of which were related to pulmonary toxicity (Table 2). The incidence and severity of radiation pneumonitis following CCRT were also evaluated. Overall, 26.1% of patients (12 of 46) experienced radiation pneumonitis of any grade, with no statistically significant difference observed between the age groups stratified by the 75-year threshold (46.2% vs. 18.2%; P=0.07) (Table 6). Immune-related adverse events (irAEs) occurred in 39.1% of patients (n=18), with 6.5% (n=3) classified as grade ≥3 (Table 7). The most frequently reported irAE was pneumonitis, observed in 17.4% of patients. When stratified by both the 70-year and 65-year age thresholds, there were no statistically significant differences in the incidence of AEs or irAEs between the age groups (Tables S9-S12).

Discussion

In this study, among patients aged ≥75 years with unresectable stage III NSCLC, durvalumab after CCRT was associated with shorter PFS and comparable AE profiles (any-grade and grade ≥3) relative to younger patients. OS appeared similar; however, given the small sample size, these findings should be interpreted with caution. When stratified by both the 70-year and 65-year age thresholds, there were no statistically significant differences in PFS, OS and AEs between the age groups. These findings are consistent with previous studies using the age cutoff of 70 years, which also reported comparable survival outcomes between older and younger patient groups (10-12). To the best of our knowledge, this is the first real-world study to specifically evaluate clinical outcomes in very elderly patients with unresectable stage III NSCLC treated with CCRT followed by durvalumab consolidation.

Subgroup analyses from both the PACIFIC trial and the PACIFIC-R study indicated a tendency toward worse survival outcomes in older patients, which is consistent with the findings of the present study (8,9). In a post-hoc exploratory analysis of the PACIFIC trial, durvalumab improved PFS and OS among patients aged ≥70 years [PFS: HR =0.62 (95% CI: 0.41–0.95); OS: HR =0.78 (95% CI: 0.50–1.22)] and <70 years [PFS: HR =0.53 (95% CI: 0.42–0.67); OS: HR =0.66 (95% CI: 0.51–0.87)] (8). The multinational observational PACIFIC-R study, which assessed the real-world effectiveness of durvalumab, found that PFS was comparable between patients aged <70 years and those aged 70–75 years (median, 22.8 vs. 22.4 months), while it was relatively shorter in patients older than 75 years (median, 19.2 months) (9). However, both studies demonstrated numerical but not statistically significant differences in outcomes between age groups (8,9). In a post-hoc exploratory analysis of the PACIFIC trial, the authors reported imbalances in potentially prognostic baseline factors (e.g., Asian ethnicity, pre-existing COPD, and pre-existing cardiovascular disorders) and subgroup sizes, which limited the ability to draw robust conclusions (8). In contrast, the present study found no significant differences in baseline characteristics between the groups stratified by the 75-year age threshold, except for dose reduction. Such conditions may contribute to a more reliable and meaningful statistical analysis. Therefore, it is noteworthy that the present study found significantly poorer PFS in patients aged ≥75 years compared to those aged <75 years.

Although current guidelines recommend durvalumab after CCRT regardless of patient age, the results of this study could be misinterpreted as suggesting that durvalumab may be less effective or even unnecessary in very elderly patients (17,18). To address this concern, we established a historical control group and compared outcomes in both the overall cohort and among patients aged ≥75 years. This analysis demonstrated that the addition of durvalumab did not result in inferior PFS compared to patients who did not receive durvalumab. However, this finding should be interpreted with caution due to the limited sample size.

The potential mechanisms underlying these findings can be explained by several hypotheses. First, immune senescence may play a critical role. Although not yet clinically proven, age-related factors may play a role in modulating the effectiveness of immunotherapy. In fact, the activity of immune checkpoint inhibitors (ICIs) could be affected by age-associated changes in immune system function. Specifically, alterations in the ratio of lean to adipose tissue within lymphoid organs and bone marrow contribute to reduced production and activation of T and B lymphocytes (19). This phenomenon has been associated with an increased risk of cancer development and progression (20), as well as a diminished response to ICIs through the upregulation of immune-suppressive pathways, as demonstrated in several in vivo models (21,22). One study reported that an increased proportion of senescent T cells correlated with inferior treatment outcomes in patients treated with ICIs compared to those receiving platinum-based chemotherapy (23). The burden of senescent T cells may represent biological age and impact the clinical effectiveness of ICIs. Second, inflammaging may also contribute. The process of aging is associated with increased secretion of pro-inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-1 beta (IL-1β) by innate immune cells, including macrophages and fibroblasts. This increase in circulating cytokine levels contributes to the development of a chronic, low-grade inflammatory state (24). This pro-inflammatory environment fosters carcinogenesis by promoting genomic instability, angiogenesis, and immune evasion mechanisms (25,26). Furthermore, inflammaging may impact the efficacy of ICIs. A previous study demonstrated that TNF blockade enhanced the antitumor efficacy of ICIs and reduced irAEs (27). Moreover, studies have shown that patients treated with a combination of ICIs and celecoxib experienced improved therapeutic outcomes (28). Third, hyperprogressive disease (HPD) and primary resistance to ICIs may contribute to poorer outcomes in elderly patients. In the study by Champiat et al. (29), older age was associated with a higher incidence of HPD. Patients who developed HPD were significantly older than those who did not, with 19% of individuals aged over 65 years experiencing HPD compared to only 5% among those younger than 64 years. These findings suggest that elderly patients may derive less benefit from ICIs therapy compared to their younger counterparts. The biological basis of this phenomenon remains largely unclear, highlighting a critical area for future investigation in cancer translational research.

In our study, while PFS showed a statistically significant difference based on the 75-year age cutoff, OS appeared to diverge but did not reach statistical significance. Among the deceased patients, cause of death could be identified in only 11 cases through EMR review, all of which were attributable to lung cancer, whereas the cause of death in the remaining 35 cases could not be determined. Although the possibility of non-lung cancer-related deaths in the <75 years group cannot be completely ruled out, the lack of statistical significance in OS is more likely attributable to the small sample size and the limited number of events. These limitations further underscore the challenge of interpreting OS differences in a small cohort.

Regarding treatment safety, no significant differences in AEs were observed between the older and younger groups when stratified by 65-, 70-, and 75-year age thresholds. However, other studies analyzing outcomes based on a 70-year age cutoff have reported either a higher incidence of AEs in older patients (10) or similar toxicity profiles between age groups (11,12). The observed variability in AEs across studies emphasizes the necessity of additional research to clarify these discrepancies.

The concept of frailty, characterized by increased vulnerability to illness or death under stress, is becoming an increasingly important consideration in the management of elderly patients. Frailty was observed in 45% of patients with lung cancer, and frail individuals exhibited a threefold higher mortality rate compared to their non-frail counterparts (30). Implementing comprehensive geriatric screening, assessment, and targeted interventions has been shown to reduce treatment-related toxicity and enhance both quality of life and the overall delivery of healthcare in older patients (31,32). Although our study did not include a formal geriatric assessment, evaluating the ability of very elderly patients with lung cancer to tolerate treatment prior to initiating durvalumab consolidation after CCRT may be beneficial. Moreover, such evaluation processes could be streamlined and standardized to ensure they can be efficiently incorporated into routine clinical practice with minimal additional burden.

The present study has some limitations. First, as a retrospective observational study, its findings may not be fully generalizable to the broader patient population. However, while most previous studies have used a 70-year age cutoff, we analyzed outcomes based on a 75-year threshold. This approach provides more clinically relevant insights to support treatment decision-making for very elderly lung cancer patients, who represent an increasingly important and challenging group in real-world practice. Second, the possibility of selection bias exists, as our cohort included only patients who successfully completed CCRT and proceeded to durvalumab. As a result, the study population likely consisted predominantly of older patients with good treatment tolerance. Nonetheless, considering the outcomes observed in patients aged ≥75 years in our study, a more deliberate and individualized treatment decision may be warranted in very older patients. Third, the relatively small sample size may have limited the statistical power of our analyses. This constraint should be taken into account when interpreting the findings. Still, this study adds meaningful data on a population often underrepresented in clinical trials. We plan to validate these findings in a larger, multi-center dataset to improve statistical power and confirm the robustness and generalizability of our results. Fourth, the cause of death was unavailable for many patients, limiting attribution of toxicity-related deaths and descriptive cause-of-death analyses. However, death dates were reliably ascertained via EMRs (in-hospital) and the NHIS subscriber-eligibility database (for out-of-hospital deaths). Fifth, we did not systematically perform comprehensive geriatric assessment. Thus, key geriatric domains were not formally captured, which may limit risk stratification and confound age-based comparisons. Future work will incorporate comprehensive geriatric assessment to better inform treatment selection and interpret outcomes in very elderly patients.

Conclusions

In conclusion, in patients aged ≥75 years with unresectable stage III NSCLC, durvalumab after CCRT was associated with shorter PFS and comparable AE profiles to younger patients. While OS appeared similar, the limited sample size precludes firm conclusions. Comprehensive geriatric assessment may help guide treatment decisions for very elderly patients with unresectable stage III NSCLC. Further large-scale, prospective studies are needed to optimize treatment approaches specifically for very elderly patients.

Acknowledgments

This abstract was presented at the 2024 American Thoracic Society (ATS) International Congress in San Diego, USA.

The authors are grateful to the professors at each hospital who helped recruit subjects and clinical data.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-926/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-926/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-926/prf

Funding: This research was supported by Hallym University Research Fund, 2022 (No. HURF-2022-50).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-926/coif). The authors have no conflicts of interest to declare.

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. The study was approved by Hallym University Dongtan Sacred Heart Hospital (No. 2022-11-002), Hallym University Sacred Heart Hospital (No. 2023-11-012), Hallym University Kangnam Sacred Heart Hospital (No. 2023-12-004), and Hallym University Chuncheon Sacred Heart Hospital (No. 2023-12-001). Individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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