The primary tools recommended for assessing chemotherapy risk in elderly patients encompass the following: CARG chemotherapy risk assessment scale (17), CRASH (18), instrumental activities of daily living (IADL), activities of daily living (ADL), Charlson comorbidity index (CCI), cumulative illness rating scale-geriatric (CIRS-G), mini-mental state examination (MMSE), geriatric depression scale (GDS), geriatric screening tool-8 (G-8) and vulnerable elders survey-13 (VES-13), among others (8).

Of particular clinical significance, CARG and CRASH exhibit comprehensive coverage and robust clinical applicability. Moreover, they exhibit comparable predictive performance for chemotherapy resistance (19), positioning them as the most promising tools for optimizing chemotherapy regimens (6). Hurria et al. (17) initially introduced the CARG scale in a prospective cohort study involving 500 cancer patients aged 65 and older, with 29% diagnosed with lung cancer. The study found that patients classified as low risk, medium risk, or high risk based on the CARG scale had proportions of grade three to five chemotherapy-related AEs of 30%, 52%, and 83%, respectively (P < 0.001). Conversely, when risk grouping was based on KPS scores, no significant difference in the incidence of chemotherapy-related AEs was observed in each group (P = 0.19). Subsequent analysis involved calculating the area under the receiver operating characteristic (ROC) curve, revealing that the CARG outperformed KPS in predicting chemotherapy-related AEs (0.72 vs. 0.53). This has led to the speculation that the CARG scale possesses predictive capabilities regarding chemotherapy tolerance in elderly patients, a hypothesis substantiated by subsequent research (20). In 2012, Extermann et al. (18) proposed the CRASH scale for the first time. The scale was based on a introduced the CRASH scale, based on a prospective cohort study encompassing 562 cancer patients, including 518 evaluable cases, with an average age of 70 years or older (20% of whom were lung cancer patients). The study demonstrated that the CRASH scale could predict the incidence of hematological and non-hematological toxicity induced by chemotherapy drugs, suggesting its potential to forecast chemotherapy tolerance in elderly patients. CARG and CRASH are shown in Tables 1 – 3 , respectively.

The utility of CGA in guiding targeted and immunotherapy for elderly patients with advanced NSCLC remains an evolving field with no established assessment tool. A prospective observational cohort study by Gomes et al. (21) involved 140 elderly patients with cancer, of which 55% were diagnosed with NSCLC. The study categorized patients into elderly and young groups based on a 1:1 age ratio, with median ages of 75 and 62 years, respectively. The G-8 assessment was conducted before treatment in the elderly group, with a score of less than 15 indicating a positive result. Single-drug immune checkpoint inhibitors (ICIs) were administered as treatment. The study revealed that elderly patients with a positive G-8 assessment exhibited higher mortality and readmission rates, suggesting the G-8 score may play a role in predicting severe adverse events in frail elderly NSCLC patients. A recent review of screening assessment tools for elderly cancer patients (22) highlighted G-8 and VES-13 as the most commonly used assessment tools. G-8 demonstrated higher sensitivity, whereas VES-13 exhibited higher specificity, and both can be employed individually or in combination. However, it should be noted that these two assessment tools lack specificity for NSCLC, and there remains a dearth of high-quality research to validate their use.

However, CGA often requires multidisciplinary collaboration to accurately assess patients and is therefore very time-consuming, posing a significant barrier to its adoption in clinical practice (23). In the future, two approaches could be explored: First, the design of a more convenient evaluation tool, followed by large-scale prospective clinical trials to verify its effectiveness; second, the development of a calculator based on the current evaluation tool to facilitate the calculation of scores and assist in assessing pre-treatment risk.

The driver gene profiles of elderly patients exhibit certain characteristics, which, however, are not significantly different from those of younger patients. Targeted therapy offers distinct advantages, including minimal side effects, good tolerance, enhanced quality of life, and potential improvements in prognosis. Consequently, it is recommended that patients with non-squamous NSCLC and certain squamous cell carcinomas undergo routine screening for specific driver gene mutations, such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) fusion genes, ROS1 fusion genes, RET fusion genes, BRAF gene V600E mutation, MET gene exon 14 skipping mutation, and other pertinent driver genes. Targeted therapy is the primary treatment choice for elderly patients with advanced NSCLC who test positive for these driver mutations (8, 27).

ICIs have ushered in groundbreaking advancements in the treatment of advanced lung cancer, making them a focal point in the realm of lung cancer treatment. Subgroup analysis of KEYNOTE-024 study (49) revealed that among elderly patients with advanced NSCLC exhibiting high expression of programmed cell death ligand 1 (PD-L1) (TPS ≥50%) and lacking EGFR/ALK mutations, pembrolizumab was consistent with the overall population in extending OS and significantly outperformed chemotherapy (HR=0.64, 95% CI: 0.42-0.98). In a subgroup analysis of the EMPOWER Lung-01 study (50), elderly patients with advanced NSCLC and high PD-L1 expression experienced significant extensions in both OS and PFS when treated with cemiplimab compared to chemotherapy. A real-world study (51) involving 2049 patients who received ICIs demonstrated that elderly patients aged ≥75 years, after undergoing immune monotherapy, exhibited no significant difference in OS compared to patients aged 50-75 or <50 years. Both non-elderly and elderly patients benefited from PFS when platinum-based chemotherapy was combined with pembrolizumab in the Keynote-189 (52) and Keynote-407 (53), though the benefit was somewhat lower in elderly patients. In the IMpower 150 study (54), elderly patients aged ≥75 years did not experience a significant PFS benefit with atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP) compared to the bevacizumab plus carboplatin plus paclitaxel (BCP) group, while non-elderly patients showed significant benefits in a subgroup (65-75 years old: 9.7 vs 6.9 months, P<0.05; <65 years old: 8.0 vs 6.8 months, P<0.05). In the phase III randomized CheckMate-227 trial (55), nivolumab combined with ipilimumab offered a modest OS benefit to patients aged ≥75 and 65-74 years old compared to chemotherapy, but this benefit was less pronounced than in patients under 65. In the Check-Mate 9LA study (56), patients aged ≥75 years did not derive an OS benefit, while those under 75 experienced significant OS benefits. These results suggest that the diminished OS benefit in elderly patients under intensive combination therapy may be associated with lower tolerability. According to the FDA’s retrospective summary analysis (57), when PD-L1 expression is ≥50%, there is no difference in survival between chemotherapy combined with ICIs and ICIs alone in patients aged 65-74 years. Patients aged ≥75 years exhibited better survival outcomes with ICIs than with chemotherapy combined with ICIs. For patients with PD-L1 expression of 1-49%, chemotherapy combined with ICIs was superior to ICIs alone in patients under 75 years old, but there was no difference in survival between these two treatment strategies in patients aged ≥75 years.

A meta-analysis (58) of patients receiving nivolumab for advanced renal cell carcinoma, melanoma, and NSCLC demonstrated that the incidence of all-grade AEs was similar in elderly and non-elderly patients, but elderly patients had a higher incidence of ≥grade three AEs (71.7% vs. 58.4%). Conversely, in a pooled analysis (59) encompassing the CheckMate-057, KEYNOTE-010, OAK, and POPLAR studies, the incidence of grade three to four immune-related AEs in individuals aged ≥75 years was lower than in each age group under 75 years (23% vs. 47%, 49%), and the incidence of AEs leading to treatment discontinuation was similar (5% vs. 7%, 7%). These findings suggest that older age does not increase the number of immune-related AEs leading to treatment termination and may even reduce it.

Although the real-world study included a heterogeneous population of patients treated with different types of PD-(L)1 inhibitors, these patients received different treatment regimens (60), and direct comparisons between the study results and clinical trials are not reasonable (61). However, real-world studies have reached conclusions similar to clinical studies, namely that old age is not a substitute for clinical frailty, nor is age a limiting condition for immunotherapy (12, 13, 23, 60, 62–75). Many studies have shown that older patients exhibit similar efficacy and safety in immunotherapy as the general population. A real-world study comparing the effectiveness of pembrolizumab, nivolumab, and atezolizumab found objective response rates (ORR) and disease control rates (DCR) of 22.4%, 8.2%, and 4.3% (p = 0.004) and 59.2%, 55.7%, and 30.0% (p = 0.001), respectively. Although there was no difference in OS between the three groups (12.6 months vs. 8.4 months vs. 7.7 months, p = 0.334), pembrolizumab had the longest OS. In the PD-L1 ≥ 50% subgroup, pembrolizumab showed a statistically significant OS advantage compared to atezolizumab (pembrolizumab vs. atezolizumab, p = 0.023; nivolumab vs. atezolizumab, p = 0.153; pembrolizumab vs. nivolumab, p = 0.406) (61).

In conclusion, it is recommended that elderly patients with advanced NSCLC who exhibit high PD-L1 expression should be treated with ICIs monotherapy as the first-line approach. While ICIs combination therapy demonstrates a beneficial trend in patients under 75 years old, there is insufficient evidence to support its use in patients aged ≥75 years.

The third generation of non-platinum chemotherapy drugs comprises agents such as vinorelbine, gemcitabine, paclitaxel, docetaxel, and pemetrexed. Previous studies have extensively examined the survival outcomes and safety profile of chemotherapy in elderly lung cancer patients. For elderly patients with advanced NSCLC who lack targeted driver gene mutations and exhibit low PD-L1 expression, platinum-containing doublet combination therapy is the recommended first-line treatment option for those who are suitable (76). However, this approach can be associated with greater AEs, making it unsuitable for elderly patients or individuals in poor health. The ELVIS study (77) investigated 191 elderly patients aged 70 years and above with advanced NSCLC. Results revealed that, when compared to the best supportive care (BSC) group alone, the vinorelbine combined with BSC group significantly prolonged the median survival time (MST) (28 weeks vs. 21 weeks), improved the 1-year survival rate (32% vs. 14%), and enhanced the quality of life (QOL). A meta-analysis (78) that included data from 10 studies involving a total of 2,510 elderly patients with advanced NSCLC demonstrated that the response and survival rates were superior in the platinum-containing doublet chemotherapy group compared to single-agent therapy. However, it’s worth noting that the incidence of grade 3/4 adverse events such as anemia, thrombocytopenia, and neurological toxicity was higher in the doublet chemotherapy group.

A real-world study involving 474 consecutive elderly patients (≥70 years of age) diagnosed with stage IIIB-IV NSCLC found that a platinum-based dual-drug regimen (OR 2.23, 95% CI 1.02-4.87, p<0.04) was an independent risk factor for hospitalization. The use of a platinum-based dual-drug regimen was associated with a higher risk of hospitalization and conferred no survival benefit compared to a third-generation single-drug chemotherapeutic regimen (79).

In summary, when considering treatment options for elderly patients, it is crucial to conduct a comprehensive assessment of their overall health and ability to tolerate double-drug chemotherapy. This approach is recommended as the first-line treatment for elderly patients without driver gene mutations and with low PD-L1 expression.

Anti-angiogenic therapeutic drugs, whether administered alone or in combination with chemotherapy, EGFR-TKIs, or immune checkpoint inhibitors, have demonstrated significant efficacy (8). The ALTER0303 study (80) revealed that anlotinib exhibited notable benefits for elderly patients, exhibiting superior PFS (HR=0.22, 95% CI: 0.07-0.64) and OS (HR=0.34, 95% CI: 0.12-0.94), particularly among those aged ≥70 years. Conversely, the POINTBREAK study (81) showed that while the combination of chemotherapy with anti-angiogenic drugs extended PFS compared to chemotherapy alone (6.0 months vs. 5.6 months), there was no significant difference in OS. The ARIES study (82) reported that combining bevacizumab with chemotherapy in elderly patients did not result in different PFS and adverse event profiles when compared to their non-elderly counterparts, although OS was slightly shorter. In the NEJ026 study (83), elderly patients with EGFR fusion gene-positive NSCLC, both those < 75 and ≥75 years old, experienced PFS benefits from erlotinib combined with bevacizumab. Similarly, the ACTIVE study (84) demonstrated improved PFS in the elderly subgroup when apatinib was combined with gefitinib (HR=0.9 vs. 0.67). Studies like those referenced (82, 85, 86) indicate that the adverse event grading for bevacizumab combined with chemotherapy mostly remained below grade two, with no statistical difference in the incidence of grade three and higher adverse events between elderly and non-elderly patients. This suggests that the safety profile of anti-angiogenic treatment is comparable for both elderly and non-elderly lung cancer patients.

In a real-world study that retrospectively collected electronic medical records of NSCLC patients receiving Endostar combined with chemotherapy, 554 and 571 patients were assigned to ≤60 years of non-elderly patients and >60 years of elderly patients, respectively, and performed propensity score matching. Results showed no significant difference in efficacy between the two groups, and the adverse reactions were tolerable (87). Another study retrospectively enrolled 83 elderly patients (>65 years of age) with NSCLC who had previously received at least two lines of systemic therapy and whose disease had progressed. The ORR was 7.2% (95% CI = 2.7-15.1%) and the DCR was 78.3% (95% CI = 67.9-86.6%), consistent with the ALTER0303 clinical trial. This study found that the third-line efficacy of anlotinib monotherapy in the treatment of elderly patients with advanced NSCLC was satisfactory, and the safety was tolerable (88).

It is important to note that elderly patients often present with underlying cardiovascular and cerebrovascular conditions, and the risk of these conditions may increase with the use of anti-angiogenic drugs. Therefore, treatment decisions should not be based solely on age and should be approached with caution and vigilant monitoring.

For patients with unresectable stage III NSCLC, the guidelines recommend concurrent chemoradiotherapy (cCRT) with subsequent durvalumab treatment for one year (76). Subgroup analysis of the PACIFIC study (89, 90) compared patients who received cCRT followed by durvalumab with those who received cCRT followed by a placebo. In the elderly subgroup aged ≥65 years, there was a prolonged PFS (HR=0.74, 95% CI: 0.54-1.01) and a 5-year OS (HR=0.79, 95% CI: 0.60-1.05), although the differences were not statistically significant. A retrospective study conducted using real-world data from the Netherlands (91) involved 2,942 patients with stage III NSCLC who underwent radical chemoradiotherapy (CRT). The study categorized patients into two groups: cCRT and sequential chemoradiotherapy (seqCRT). The median ages for these groups were 66 and 69 years, respectively. The study found that age itself was not a risk factor for acute toxicity or 3-month mortality after a three-month follow-up. However, it was noted that patients treated with cCRT, those with a higher TNM stage (IIIC) and poorer baseline health status had significantly higher three-month toxicity.

A retrospective analysis was conducted in patients with unresectable lung cancer who received treatment. Although older patients who received synchronous CRT had better OS (median OS: 40.9 months vs. 24.4 months), this difference was not statistically significant in the multivariate analysis (P = 0.09), suggesting that the treatment outcome in the elderly remained unsatisfactory and that the effect of multimodal therapy on elderly patients was limited (92). Two other studies found no association between age 70 and factors such as grade 3-4 CRT or Durvalumab toxicity, reduced chemotherapy dose, delay or cessation of treatment, progression, or death. These findings reinforce the current guideline recommendation that cCRT is associated with optimal outcomes in unresectable locally advanced NSCLC, even in older patients (93, 94).

In summary, there is currently insufficient evidence to make strong recommendations regarding the use of radiotherapy and chemotherapy in elderly patients with stage III NSCLC.

The current guidelines (76) do not provide a surgical strategy for elderly patients with advanced NSCLC, and the suitability of surgical interventions for such patients remains undetermined. Kirk et al. (95) conducted a retrospective study to investigate the safety of lobectomy in NSCLC patients aged 80 years or older. They found that surgical morbidity and mortality were not increased in this age group; however, it’s important to note that the proportion of patients in this age category was low (4.9%). Additionally, these patients underwent rigorous screening and had low rates of smoking and pre-existing respiratory, cardiovascular, and neurological diseases. These factors could potentially introduce biases into the conclusions. As a result, more prospective research evidence is necessary to establish whether elderly patients with advanced NSCLC can benefit from surgical interventions.