In NSCLC, Does Inflammation Predict Postsurgical Outcomes?
—Measures of systemic inflammation have been developed as prognostic indexes, but few studies have examined the association between these indexes and NSCLC postsurgical outcomes. Researchers in the U.K. attempted to set the record straight.
According to a new study, low preoperative scores on the advanced lung cancer inflammation index (ALI) were associated with reduced overall survival (OS) in patients who underwent surgery for primary non-small cell lung cancer (NSCLC).1
While many biomarkers and composite measures of systemic inflammation have been developed as prognostic indexes for outcomes in cancer, the use of these measures for prediction in NSCLC is not common in clinical practice.2
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Studies have also investigated the use of measures of systemic inflammation as components of pretreatment prognostic models for OS in NSCLC.3,4 “However, there is little published literature evaluating how these [measures of systemic inflammation] values could be used to inform clinical practice and examining whether the extent of inflammation at the time of surgery correlates with long-term outcomes,” wrote the U.K.-based authors of the new study.1
To address this gap, the investigators examined the associations between 6 different preoperative measures of systemic inflammation and outcomes in more than 5000 patients with NSCLC in the U.K.
How the study was designed
The study was a retrospective analysis of consecutive patients with primary NSCLC who had lung resection at Manchester University NHS Foundation Trust and Liverpool Heart and Chest Hospital between January 2012 and December 2018.1 Records containing laboratory and outcome data were obtained from the Northwest Clinical Outcomes Research Registry.
Six measures of systemic inflammation were analyzed:
- neutrophil-to-lymphocyte ratio (NLR)
- platelet-to-lymphocyte ratio (PLR)
- ALI, which is calculated as albumin/neutrophil-to-lymphocyte ratio x body mass index
- prognostic nutritional index (PNI), which is calculated as lymphocyte count x 0.005 + albumin
- systemic immune inflammation index (SII), which is calculated as platelet count x neutrophil count/lymphocyte count/10
- hemoglobin albumin lymphocyte platelet score (HALP), which is calculated as hemoglobin x albumin x lymphocyte count/platelet count
Data from the most recent blood test before surgery were used to calculate the measures of systemic inflammation, with imputation for missing data. OS was the primary outcome, and lower respiratory tract infection and postoperative atrial fibrillation were the secondary outcomes.
Patient characteristics in more detail
The study included 5029 patients, with a mean age of 68.6 (± 9.1) years. Almost half (n=2444) were male (48.6%). A total of 3002 patients (59.7%) had stage I disease, 1199 (23.8%) were classified as stage II, and 828 (16.5%) had stage III disease.
Most surgeries (n=3807) were thoracotomies (75.7%). Noncomplex lobectomy was performed in 3917 patients (77.9%), extended resection in 576 (11.5%), and sublobar resection in 536 (10.7%). The mean number of resected segments was 3.9 (± 1.8).
Survival was analyzed during a median follow-up of 33 months (interquartile range 19 to 53 months). A total of 185 patients (3.7%) died within 90 days after surgery. Lower respiratory tract infection was diagnosed in 555 patients (11.0%), and postoperative atrial fibrillation occurred in 365 (7.3%).
Several key associations are noted
The association of each measure of systemic inflammation with OS was determined by multivariable analysis, with adjustment for age, comorbidities, disease stage, functional status, extent of resection, and surgical approach. ALI (hazard ratio [HR] 1.000, 95% confidence interval [CI] 1.000 to 1.000; P = .049) and HALP (HR 1.001, 95% CI 1.000 to 1.002; P = .014) were associated with OS when analyzed as continuous variables. However, NLR, PLR, PNI, and SII were not associated with OS.
The investigators analyzed each measure of systemic inflammation as a dichotomous variable. By this analysis, ALI <366.43 was independently associated with reduced OS (HR 1.362, 95% CI 1.137 to 1.631; P < .001). The association was maintained after the investigators removed cases that were missing data. On the other hand, the HALP, NLR, PLR, PNI, and SII dichotomous variables were not associated with OS.
Links between each measure of systemic inflammation and OS for each disease stage were also analyzed. In patients with stage I disease, ALI <366.43 was associated with lower OS (HR 1.450, 95% CI 1.104 to 1.906; P = .008). ALI <366.43 was also associated with lower OS in patients with stage II disease (HR 1.502, 95% CI 1.070 to 2.107; P = .019) but not in patients with stage III disease (HR 1.146, 95% CI 0.805 to 1.630; P=.451). HALP, NLR, PLR, PNI, and SII were not associated with overall survival at any disease stage.
No measure of systemic inflammation was linked with postoperative atrial fibrillation by multivariable analysis. PLR was the only measure of systemic inflammation associated with a reduced risk of lower respiratory tract infection (HR 0.998, 95% CI 0.997 to 1.000; P = .029).
A step toward moving ALI to clinical practice?
Study limitations include the lack of information on genetic biomarkers, missing measurements that prevented the research team from testing other factors potentially associated with adverse outcomes, and the retrospective study design, which didn’t allow the investigators to distinguish cause and effect. Nevertheless, these results support those of previous smaller studies that found an association between low ALI and poorer OS in patients with NSCLC who underwent lung resection,5,6 as well as the findings from a meta-analysis of studies of patients with lung cancer.7
“The identification of ALI as associated with reduced overall survival means that patients with a high-risk ALI value could be targeted for additional preoperative interventions (such as prehabilitation) or more intensive postoperative surveillance with a lower threshold for offering adjuvant therapy in an attempt to improve survival,” the investigators wrote.1
In contrast to the associations between ALI and survival, only a slight association was found between a single measure of systemic inflammation and lower respiratory tract infection, and no association was noted between any of the 6 measures of systemic inflammation and postoperative atrial fibrillation. From these results, the investigators concluded that “the lack of clear association between [measures of systemic inflammation] and postoperative complications suggests that their role is primarily for prognostication, with little to contribute to perioperative risk stratification.”1
In the future, the investigators wrote, next steps should include following the changes in measures of systemic inflammation at various time points after surgery—for example, 90 days, 6 months, and 1 year—and their association with outcomes.
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