Prognostic value of lactate dehydrogenase to albumin ratio in first-line chemoimmunotherapy for locally advanced or metastatic non-small cell lung cancer

Introduction

Lung cancer is currently the most common malignancy and the leading cause of cancer-related death worldwide (1). Non-small cell lung cancer (NSCLC) accounts for about 85% of total cases. Due to the lack of typical symptoms in early stages, a large proportion of patients have already experienced distant metastasis upon initial diagnosis, losing the opportunity for surgical cure (2). In recent years, the development and approval of immune checkpoint inhibitors (ICIs), especially those targeting programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1), have significantly changed the treatment paradigm of advanced lung cancer. Several clinical trials have confirmed that the efficacy of chemoimmunotherapy is significantly better than chemotherapy alone for first-line treatment of advanced NSCLC and has become the preferred treatment modality in current clinical practice (3-6). At present, the expression of PD-L1 is a commonly used biomarker for predicting therapeutic efficacy. However, a pooled analysis has found that NSCLC with negative PD-L1 expression can also significantly benefit from chemoimmunotherapy (7). Correspondingly, a considerable portion of patients with high PD-L1 expression experienced short-term progression treated with pembrolizumab (8). Therefore, PD-L1 expression alone is insufficient and further identification of simple and effective biomarkers for predicting therapeutic efficacy and prognosis still holds significant value.

Lactate dehydrogenase (LDH) is a commonly used index in clinical practice. Its elevation is usually associated with several pathological conditions such as rhabdomyolysis, myocardial infarction, hepatic disorders, pulmonary embolism, renal disease or tumors (9). The level of serum LDH of tumor patients is closely related to the prognosis (10). Besides, tumor often leads to hypoalbuminemia due to the large amount of nutrients required for its growth (11). The lactate dehydrogenase to albumin ratio (LAR) which combines LDH and albumin (ALB) levels together has been developed in recent years. Theoretically, the level of LAR is positively correlated with the overall tumor burden and prognosis. In fact, studies have confirmed that preoperative LAR is closely related to the prognosis of bladder and colorectal cancer patients undergoing radical surgery (12,13). In addition, similar results are also obtained in advanced cancer. For instance, higher LAR levels have been demonstrated to be associated with poorer prognosis in advanced NSCLC treated with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) or gastric cancer patients treated with Nivolumab (14,15). However, its role in NSCLC treated with chemoimmunotherapy remains unexplored. Thus, the present study aimed to clarify the prognostic value of LAR in NSCLC patients treated with first-line chemoimmunotherapy and attempted to establish a prognostic prediction model based on LAR in clinical settings. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2577/rc).

Methods

Ethical statement

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethical Committee of Xuanwu Hospital, Capital Medical University (No. KS2024413). Written informed consent was obtained from all enrolled participants.

Patients

Consecutive patients with newly diagnosed locally advanced or metastatic NSCLC treated with anti-PD-1/-PD-L1 antibodies combined with platinum-based chemotherapy at Xuanwu Hospital, Capital Medical University between January 2021 and March 2024 were reviewed. The specific inclusion criteria were as follows: (I) age between 18 and 80 years old; (II) pathologically confirmed as locally advanced or metastatic NSCLC by transthoracic needle aspiration (TTNA), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), tumor cells found in pleural effusion or resection of metastatic lesions and were not suitable for radical surgery or radiotherapy; (III) have an Eastern Cooperative Oncology Group (ECOG) performance status of grade 0–1; (IV) excluding epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutations for patients with lung adenocarcinoma (LUAD); (V) have not received systematic anti-tumor treatment previously. We excluded patients if they met any of the following criteria: (I) have a history of other malignancy; (II) fail to complete treatment due to complications or adverse events; (III) have a history of acute hepatitis, pulmonary embolism, renal disease, myocardial infarction, rhabdomyolysis within 6 months prior to diagnosis; (IV) have incomplete clinicopathological data.

Data collection

All data were collected through the electronic medical record system of our institution. The following variables were obtained: age at diagnosis, sex, smoking history, body mass index [BMI, calculated as weight (in kg)/height² (in m²)] at diagnosis, baseline tumor staging, pathological type, expression of PD-L1, tumor Ki-67 index, baseline LAR, therapeutic regimen, progression-free survival (PFS).

Tumor staging was determined according to the ninth edition TNM classification of lung cancer (16). Expression of PD-L1 was evaluated using tumor proportion score (TPS) through immunohistochemistry (IHC). For laboratory indicators, all blood samples were drawn within 5 days before the biopsy procedure in a fasting status at 5’o clock in the morning and were transferred to the lab within two hours. Baseline LAR was calculated as the ratio of serum LDH (U/L) ALB (g/L). Patients were divided into high baseline LAR or low baseline LAR groups based on a 50% ratio.

The standard treatment regimen was PD-L1/PD-1 inhibitors combined with platinum-based dual drug chemotherapy, which was administered intravenously every 21 days for 4–6 cycles. The chemotherapy regimen for LUAD was pemetrexed combined with carboplatin, while that for lung squamous cell carcinoma (LUSC) was albumin-bound paclitaxel combined with carboplatin. Immunotherapy drugs included atezolizumab, tislelizumab, pembrolizumab, camrelizumab or sintilimab. A portion of patients continued to receive immune monotherapy or monochemotherapy combined with ICIs maintenance therapy after standard treatment. All patients received reassessment every 2 cycles during standard treatment, and every 3 months after completing standard treatment to evaluate efficacy. Tumor response was assessed by at least two senior oncologists based on response evaluation criteria in solid tumors (RECIST) version 1.1 (17). PFS was calculated as the time from diagnosis to first progression or death. The last follow-up date was October 31, 2024.

Statistical analysis

IBM SPSS (version 26.0) was used for statistical analyses. Continuous variables were provided as median [interquartile range (IQR)] if the distribution was nonnormal, and as mean ± standard deviation (SD) if the distribution was normal. Categorical variables were provided as numbers and percentages. Student t-test or Mann-Whitney U-test was used for comparing the differences between groups for continuous variables while χ² or Fisher’s exact test was used for categorical variables. The Kaplan-Meier curve was employed to demonstrate survival between different groups and log-rank test was applied to compare the statistical differences between the groups. Univariate and multivariate Cox analyses were conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated to identify independent indicators of PFS. A two-sided P value <0.05 was recognized as statistically significant among all analyses. Finally, R software (version 4.4.1) was applied to establish the nomogram based on independent prognostic factors and calculate the C-index.

Results

Clinicopathological features of patients with locally advanced or metastatic NSCLC treated with first-line chemoimmunotherapy

As shown in Figure 1, between January 2021 and March 2024, a total of 144 patients with locally advanced or metastatic NSCLC received first-line chemoimmunotherapy at our department. Thirty-four patients were excluded from the present study due to failure to complete at least 4 cycles of treatment because of adverse events, not undergoing at least once follow-up at our hospital after standard treatment or incomplete data. Ultimately, the remaining 110 patients were included in the present study. Then based on a 50% ratio, patients were divided into high baseline LAR or low baseline LAR groups. The specific characteristics of all enrolled patients and the comparison of patients between the two groups were shown in Table 1. The proportion of patients with stage IVB diseases was higher in high baseline LAR group than low baseline LAR group (P=0.04). In addition, patients with high baseline LAR had significantly shorter PFS than patients with low baseline LAR (P=0.02). Except for this, there were no statistically significant differences in age, sex, smoking history, BMI, pathological type, PD-L1 TPS and Ki-67 index between the two groups.

Figure 1 Patient selection flowchart for this study. LAR, lactate dehydrogenase to albumin ratio; NSCLC, non-small cell lung cancer.

Kaplan-Meier survival curve analysis

Firstly, we followed the abovementioned grouping method to plot Kaplan-Meier curve for all enrolled patients based on baseline LAR. As shown in Figure 2, compared with PFS of low baseline LAR patients, that of patients in high LAR group was significantly worse (HR =5.43, P<0.001). Subsequently, we conducted subgroup analysis on patients with different pathological types. We divided patients with squamous NSCLC and non-squamous NSCLC into high baseline LAR and low baseline LAR groups based on a 50% ratio, respectively. As shown in Figure 3, regardless of the pathological subtype, the PFS of high baseline LAR patients was significantly shorter than that of low baseline LAR patients (P<0.01). Finally, we conducted subgroup analysis on patients of different stages. Similarly, we divided patients with stage III/IVA or IVB NSCLC into high baseline LAR and low baseline LAR groups based on a 50% ratio, respectively. As shown in Figure 4, regardless of stage, the PFS of high baseline LAR patients was significantly worse than that of low baseline LAR patients (P<0.01).

Figure 2 The Kaplan-Meier curve demonstrates the PFS data for different baseline LAR patients in all enrolled patients. LAR, lactate dehydrogenase to albumin ratio; PFS, progression-free survival.

Figure 3 The Kaplan-Meier curve displays the PFS data for different baseline LAR patients in different pathological type subgroups. LAR, lactate dehydrogenase to albumin ratio; NSCLC, non-small cell lung cancer; PFS, progression-free survival.

Figure 4 The Kaplan-Meier curve shows the PFS data for different baseline LAR patients in different tumor staging subgroups. LAR, lactate dehydrogenase to albumin ratio; PFS, progression-free survival.

Identifying independent indicators for PFS and constructing the nomogram

Firstly, univariate COX hazard analysis was performed and predictors of P value<0.05 were included in the multivariate analysis. As shown in Table 2, age, PD-L1 TPS and baseline LAR were recognized as risk factors in univariate analysis. Consequently, age (HR: 0.965, 95% CI: 0.934–0.997, P=0.03), PD-L1 TPS (P=0.001) and baseline LAR (HR: 1.532, 95% CI: 1.346–1.745, P<0.001) were all identified as independent predictors of PFS through multivariate analysis (Table 3). Finally, a nomogram incorporating these predictors was developed to intuitively show the results (Figure 5). The C-index of the model was 0.801 (95% CI: 0.747–0.855).

Figure 5 A nomogram to predict PFS for patients with locally advanced or metastatic NSCLC treated with first-line chemoimmunotherapy. The value of each variable was given a score on the point scale axis. A total score could be easily calculated by adding every single score together. Locate it on the total points axis, then draw a line straight down to get the probability of PFS at each time point. LAR, lactate dehydrogenase to albumin ratio; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death ligand 1; PFS, progression-free survival; TPS, tumor proportion score.

Discussion

In the current study, we explored the prognostic value of LAR in locally advanced or metastatic NSCLC treated with first-line therapy of anti-PD-1/PD-L1 antibodies combined with platinum-based chemotherapy. We found that higher age, higher PD-L1 TPS and lower baseline were closely related to longer PFS of patients and we constructed a nomogram accordingly to quantitatively predict PFS for each patient. Our findings provide an easy method for prognosis prediction and early identification of patients who may experience short-term progression.

Glycolysis is one of the crucial processes that fulfill the basic energy demands for cells. LDH is a key enzyme in the process, responsible for catalyzing the conversion of pyruvate to lactate and this process usually takes place in the cytoplasm (9). However, when cells are damaged by inflammation, ischemia or tumor burden, LDH will be released into the circulation, leading to an increase in the concentration of LDH. Therefore, the level of serum LDH may be a good indicator for evaluating general tumor burden. In fact, several studies have explored the relationship between level of LDH and advanced tumor prognosis or response to treatment and high levels of LDH are usually associated with poor prognosis or therapeutic efficacy (18-20). In addition, even if not directly related to the increase in serum LDH concentration, high expression of LDHA (encoding LDH) in tumor cells has been shown to be closely associated with epithelial mesenchymal transition (EMT), angiogenesis, tissue acidosis and immune escape, leading to poor prognosis (21). On the other hand, systemic malnutrition caused by tumor consumption is known to be strongly associated with tumor progression and prognosis and serum ALB level is a commonly used index to reflect the general nutritional status of the body (11). Tang et al. found that low serum ALB levels predict higher cancer mortality (22). In terms of therapeutic efficacy, Pu et al. confirmed that increased ALB level could significantly improve survival in advanced NSCLC patients treated with immunotherapy (23). Therefore, patients with higher levels of LDH and lower levels of ALB, which means that an obviously increase in LAR may indicate higher tumor burden and poorer therapeutic efficacy. And here, we have indeed achieved good predictive performance by combining the two indicators.

PD-L1 expression testing by IHC is currently the standard biomarker for identifying individuals who are most likely to benefit from immunotherapy and cases with high PD-L1 TPS usually have better therapeutic efficacy and prognosis (24). Similar results were also obtained in the present study. Patients with PD-L1 expression ≥50% tended to have longer PFS, while patients with negative PD-L1 expression tended to have shorter PFS.

Another indicator that we attempted to explore the correlation to prognosis is tumor Ki-67 index. Ki-67 index is a biomarker which can reflect tumor proliferation activity and has been shown to be associated with the prognosis in various tumors (25-27). We suppose that it may be due to the inconsistent sampling including primary tumors, distant metastases or lymph nodes, leading to the negative results for demonstrating the association between Ki-67 index and PFS.

Another independent predictor for PFS identified in our research is age and it is not entirely consistent with previous studies. The study conducted by Taro Hirabayashi and colleagues found no obvious correlation between age and PFS of patients with advanced NSCLC treated with first-line chemoimmunotherapy (28). And Chen et al.’s results were similar to ours. They found that under 51 years old was an independent predictor of poorer PFS in NSCLC patients receiving immunotherapy (29). We further explored the correlation between patients’ age and Ki-67 values and found a negative correlation (Spearman’s R =−0.26, P=0.0071, Figure S1). Therefore, we speculate that higher tumor proliferation rates may be a contributing factor to the shorter PFS in younger patients. Besides, the slower metabolism of older patients may limit the rapid growth of tumors. However, the value of age in prognosis prediction still needs further exploration.

Despite the findings, there are several limitations that should be noted in our study. First of all, it was a retrospective study with a relatively small sample size and short follow-up period. A proportion of patients did not undergo a long-term follow-up in our hospital after completing treatment. Next, we did not conduct further follow-up on overall survival (OS) and only used PFS as the endpoint of the study due to the relatively short follow-up time. In addition, although significant survival differences exist between ECOG 0 and 1 patients at diagnosis, we didn’t perform a separate analysis based on ECOG score. Besides, as mentioned earlier, diagnosis was made through various methods such as primary lesions, metastatic lesions or pleural effusion, which might lead to inaccurate assessment of PD-L1 expression or Ki-67 index. Finally, the first-line treatment regimen was determined by the attending physician based on factors such as the patients’ financial situation and preference of physician. Therefore, bias caused by inconsistent treatment may have occurred.

Conclusions

In summary, the present study revealed that baseline LAR is a useful prognostic predictor of PFS in patients with locally advanced or metastatic NSCLC treated with first-line combination therapy of ICIs and platinum-based chemotherapy. Patients with higher baseline LAR tend to have shorter PFS. Evaluating baseline LAR in addition to age and PD-L1 expression in clinical settings may enable the quantitative prediction of the prognosis of each patient. Future studies are warranted to validate our results.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2577/rc

Data Sharing Statement: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2577/dss

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2577/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2024-2577/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. This study was approved by the Ethical Committee of Xuanwu Hospital, Capital Medical University (No. KS2024413). Written informed consent was obtained from all enrolled participants.

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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