The value of prognostic immune-inflammatory-nutritional score in predicting survival after surgery in stage I–III non-small cell lung cancer

Abstract

Background

Non-small cell lung cancer (NSCLC) remains one of the leading causes of cancer-related mortality worldwide. While traditional prognostic factors have mainly focused on tumor characteristics, recent evidence underscores the importance of immune response, inflammation, and nutritional status in determining patient outcomes. This study assesses the prognostic value of prognostic immune-inflammatory-nutritional (PIIN) score in predicting overall survival (OS) of NSCLC patients.

Methods

A retrospective analysis was conducted on the clinical data of 406 NSCLC patients who underwent surgical treatment. The optimal PIIN score cut-off value was established using receiver operating characteristic (ROC) curve analysis, dividing patients into high and low PIIN score groups. Both univariate and multivariate Cox regression analyses identified independent prognostic factors, which were used to construct a nomogram.

Results

The ideal PIIN score cut-off value was 24.2. Multivariate Cox regression analysis demonstrated that PIIN score [hazard ratio (HR): 2.116, 95% confidence interval (CI): 1.305–3.430, P=0.002], tumor-node-metastasis (TNM) stage (stage II: HR: 2.437, 95% CI: 1.223–4.855, P=0.01; stage III: HR: 6.753, 95% CI: 3.779–12.065, P<0.001), and forced expiratory volume in the first second (FEV₁) (HR: 2.335, 95% CI: 1.402–3.889, P=0.001) were independent prognostic factors. The concordance index (C-index) of the nomogram constructed based on independent risk factors was 0.838 (95% CI: 0.736–0.906). ROC analysis showed that the area under the curve (AUC) values for the nomogram’s prediction of 1-, 3-, and 5-year OS were 0.843, 0.831, and 0.825, respectively.

Conclusions

PIIN score was validated as an independent and reliable predictor of OS in stage I–III NSCLC patients after surgery. This score provides a valuable tool for individualized prognosis evaluation in clinical practice.

Highlight box.

Key findings

• The study found that the prognostic immune-inflammatory-nutritional (PIIN) score is a significant predictor of survival in stage I–III non-small cell lung cancer (NSCLC) patients following surgery.

What is known and what is new?

• The PIIN score, a novel composite biomarker integrating immune, inflammatory, and nutritional parameters, has demonstrated prognostic relevance in intrahepatic cholangiocarcinoma and pancreatic cancer. However, its prognostic significance in patients with NSCLC remains to be elucidated.

• This study is the first to investigate the prognostic significance of the PIIN score in patients with NSCLC undergoing radical surgery. The results suggest that the PIIN score can serve as a simple, cost-effective, and non-invasive biomarker for personalized prognostic evaluation in surgically treated NSCLC patients.

What is the implication, and what should change now?

• PIIN score can guide clinical decision-making by identifying high-risk patients for targeted interventions, such as enhanced perioperative care and immune-nutritional support. The study suggests broader adoption of the PIIN score and further research to explore its integration with other predictive factors for refined NSCLC prognosis prediction.

Introduction

Lung cancer remains a leading cause of cancer-related mortality globally, accounting for approximately 18% of all cancer deaths (1). Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases, and surgical intervention remains the primary treatment for patients with early-stage NSCLC (2). However, patient prognoses post-surgery can vary significantly (3,4). Presently, the main prognostic indicators for NSCLC include tumor-node-metastasis (TNM) stage, histological type, molecular characteristics, age, sex, ethnicity, and other clinical parameters (5,6). Nevertheless, there are limitations with these factors in accurately predicting overall survival (OS) in NSCLC patients. Therefore, more sensitive, and specific clinical indices for accurate prognosis prediction in NSCLC patients need to be identified.

Emerging evidence underscores the importance of immune function, nutritional status, and inflammatory processes in tumor biology and progression (7-10). Various blood-based biomarkers related to immunity and inflammation, such as the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and advanced lung cancer inflammation index (ALI), have been shown to be associated with NSCLC prognosis (11,12). Additionally, specific immune and nutritional indicators, such as the Geriatric Nutritional Risk Index (GNRI), Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score, have shown efficacy in predicting survival outcomes in cancer patients (13-15). However, none of the aforementioned indices fully capture the combined immune, nutritional, and inflammatory status.

The prognostic immune-inflammatory-nutritional (PIIN) score is a novel metric that integrates fibrinogen (FIB), NLR, SII, albumin-bilirubin (ALBI) score, and PNI. This score was originally designed to predict outcomes in patients with resectable intrahepatic cholangiocarcinoma (16). Subsequent study has indicated that the PIIN score is also significantly associated with the prognosis of pancreatic cancer (17). However, its applicability to NSCLC prognosis prediction remains uncertain.

This study included 406 patients with stage I–III NSCLC who underwent surgical treatment. Clinical data such as gender, age, body mass index (BMI), laboratory test results, operation time, and clinical stage were collected. Based on the laboratory findings, the PIIN score was calculated. Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors for overall survival OS in NSCLC patients. Additionally, a nomogram was developed to predict OS. We present this article in accordance with the TRIPOD reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1830/rc).

Methods

Patients

This retrospective study included 406 patients diagnosed with NSCLC who underwent lung resection procedures at our institution from November 2016 to December 2018. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Ethics approval (approval number: 2024-Ke-28) was obtained from the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University and individual consent for this retrospective analysis was waived. Inclusion criteria: (I) aged between 18 and 80 years; (II) pathological confirmation of NSCLC; (III) staged as stage I–III according to the 8th edition staging system of the American Joint Committee on Cancer (AJCC); (IV) no prior anti-cancer therapies before surgery; (V) no history of other malignancies. Exclusion criteria: (I) preoperative fever; (II) history of previous thoracic surgery; (III) presence of autoimmune, hematologic, or infectious diseases; (IV) incomplete clinical data or lack of follow-up information.

Data collection

Patient information was extracted from electronic medical records and included demographic data (gender, age, BMI), history of pulmonary diseases (bronchiectasis, asthma, bronchitis, chronic obstructive pulmonary disease), smoking history, pulmonary function indicators [forced expiratory volume in the first second (FEV₁) and forced expiratory volume in the first second/forced vital capacity (FEV₁/FVC)], and laboratory results obtained within 24 hours of admission. Additional data collected comprised surgical details (surgical approach, operation time), TNM stage, pathologic type, adjuvant therapy, postoperative complications, chest tube duration, and length of hospital stay.

Calculation of the PIIN score

The PIIN score was calculated using the following formula: PIIN=0.876×NLR + 0.0174×SII + 14.355×FIB + 2.209×ALBI − 0.386×PNI (16). The NLR was derived by neutrophil count/lymphocyte count. The SII as the platelet count×neutrophil count/lymphocyte count. The ALBI score as log10 bilirubin (µmol/L)×0.66 − albumin (g/L)×0.085. The PNI was computed as albumin (g/L) + 5×lymphocyte count.

Postoperative follow-up

Survival status was tracked through telephone calls or outpatient visits until death or July 2023. OS was defined as the interval from surgery until death or last follow-up. The median follow-up period was 62 months [interquartile range (IQR): 56–71 months], and a total of 93 death events were observed.

Statistical analysis

To compare continuous variables, an independent samples t-test or a Mann-Whitney U test was used, while categorical variables were assessed using the chi-square test or Fisher’s exact test. The optimal cutoff point for the PIIN score was determined using receiver operating characteristic (ROC) analysis, with the 5-year OS as the outcome measure. Survival curves were plotted using the Kaplan-Meier method. Independent prognostic factors for OS were identified through Cox regression modeling. A nomogram was developed to estimate long-term survival. Calibration curves were plotted to assess the concordance between predicted and observed survival times. A P value of less than 0.05 (two-tailed) was considered statistically significant. The analyses were conducted using SPSS (version 26.0), GraphPad Prism (version10.2), and R (version3.6.2).

Results

Baseline characteristics

This study analyzed 406 NSCLC patients, with a median age of 61 years (IQR: 55–66 years). Females accounted for 52.2% of the cohort, and males for 47.8%. A smoking history was recorded in 37.4% of patients, while 10.8% had existing respiratory conditions. Adenocarcinoma was the most common pathologic type, making up 80.0% of cases. Among the patients, 67.7% were classified as stage I according to the TNM staging system, 12.1% as stage II, and 20.2% as stage III. 37.4% of patients received adjuvant therapy after surgery. Complications after surgery were noted in 24.1% of the patients. Detailed baseline characteristics can be found in Table 1.

Table 1. Patient characteristics.

Characteristics	All (n=406)
Age, years	61 [55–66]
Gender
Male	194 (47.8)
Female	212 (52.2)
BMI, kg/m2	23.85 [21.99–26.12]
Smoking history	152 (37.4)
Respiratory diseases	44 (10.8)
FIB, g/L	2.85 [2.42–3.30]
NLR	2.00 [1.41–2.58]
SII	437 [309–638]
ALBI	−2.87±0.32
PNI	51.3±4.6
PIIN	23.6 [17.6–34.1]
FEV1, %
<80	69 (17.0)
≥80	337 (83.0)
FEV1/FVC, %
<70	103 (25.4)
≥70	303 (74.6)
Pathologic type
Adenocarcinoma	325 (80.0)
Non-adenocarcinoma	81 (20.0)
TNM stage
I	275 (67.7)
II	49 (12.1)
III	82 (20.2)
Surgical approach
Lobe	371 (91.4)
Seg/Wed	35 (8.6)
Adjuvant therapy	152 (37.4)
Operation time, min	155 [135–195]
Chest tube duration, days	4 [3–6]
Length of hospital stay, days	12 [10–14]
Postoperative complications	98 (24.1)

Data are presented as median [IQR], mean ± SD or n (%). ALBI, albumin-bilirubin score; BMI, body mass index; FIB, fibrinogen; FEV₁, forced expiratory volume in the first second; FEV₁/FVC, forced expiratory volume in the first second/forced vital capacity; IQR, interquartile range; NLR, neutrophil-lymphocyte ratio; SII, systemic immune-inflammation index; PNI, prognostic nutritional index; PIIN, prognostic immune-inflammatory-nutritional score; Lobe, lobectomy; Seg, segmentectomy; Wed, wedge resection.

Correlation between PIIN score and clinical features

The correlation between PIIN score, its individual components, and long-term prognosis was assessed using ROC curves. By analyzing the area under the curve (AUC) for the six indicators, we found that the PIIN score exhibited significant statistical differences compared to NLR (P=0.007), SII (P=0.006), ALBI (P=0.04), and PNI (P=0.05). Although no significant statistical difference was observed between the PIIN score and FIB (P=0.15), the AUC of the PIIN score was higher (Table S1, Figure 1). Based on the ROC curve analysis, the optimal cutoff value for the PIIN score was determined to be 24.2. Based on this threshold, patients were categorized into low (PIIN ≤24.2, n=210) and high (PIIN >24.2, n=196) PIIN groups for further analysis of clinical characteristics, presented in Table 2. Statistically significant differences were observed between these groups concerning gender distribution (P=0.01), smoking history (P=0.005), FEV₁ (P=0.04), FEV₁/FVC (P=0.01), pathologic type (P<0.001), TNM stage (P<0.001), and the utilization of postoperative adjuvant therapy (P<0.001). Additionally, the high PIIN group exhibited a significantly longer length of hospital stay (P=0.001) and longer chest tube duration (P=0.01).

Figure 1.

Analysis of ROC curves for the PIIN score and its components. ALBI, albumin-bilirubin score; AUC, area under the curve; FIB, fibrinogen; NLR, neutrophil-to-lymphocyte ratio; PNI, prognostic nutritional index; PIIN, prognostic immune-inflammatory-nutritional score; ROC, receiver operating characteristic; SII, systemic immune-inflammation index.

Table 2. Relationship between PIIN score and clinical characteristics of NSCLC patients.

Characteristics	Low PIIN (≤24.2) (n=210)	High PIIN (>24.2) (n=196)	P value
Age, years	60 [54–65]	61 [56–67]	0.07
Gender
Male	88 (41.9)	106 (54.1)	0.01*
Female	122 (58.1)	90 (45.9)
BMI, kg/m2	23.85 [22.04–26.40]	23.85 [21.90–25.71]	0.37
Smoking history	65 (31.0)	87 (44.4)	0.005*
Respiratory diseases	23 (11.0)	21 (21.2)	0.94
FEV1, %			0.04*
<80	28 (13.3)	41 (20.9)
≥80	182 (86.7)	155 (79.1)
FEV1/FVC, %			0.01*
<70	42 (20.0)	61 (31.1)
≥70	168 (80.0)	135 (68.9)
Pathologic type			<0.001*
Adenocarcinoma	192 (91.4)	133 (67.9)
Non-adenocarcinoma	18 (8.6)	63 (32.1)
TNM stage			<0.001*
I	171 (81.4)	104 (53.1)
II	13 (6.2)	36 (18.4)
III	26 (12.4)	56 (28.6)
Surgical approach			0.31
Lobe	189 (90.0)	182 (92.9)
Seg/Wed	21 (10.0)	14 (7.1)
Adjuvant therapy	58 (27.6)	94 (48.0)	<0.001*
Operation time, min	150 [130–195]	165 [140–195]	0.22
Chest tube duration, days	4 [3–5]	4 [3–6]	0.01*
Length of hospital stay, days	12 [10–14]	13 [10–15]	0.001*
Postoperative complication	43 (20.5)	55 (28.1)	0.07

Data are presented as median [IQR] or n (%). *, the value of P<0.05, which is statistically significant. BMI, body mass index; FEV₁, forced expiratory volume in the first second; FEV₁/FVC, forced expiratory volume in the first second/forced vital capacity; Lobe, lobectomy; NSCLC, non-small cell lung cancer; PIIN, prognostic immune-inflammatory-nutritional score; IQR, interquartile range; Seg, segmentectomy; Wed, wedge resection.

Univariate and multivariate cox regression analyses

Univariate Cox regression analysis identified several factors as associated with poorer OS, including gender (P<0.001), smoking history (P<0.001), PIIN score (P<0.001), FEV₁ (P<0.001), FEV₁/FVC (P=0.005), pathologic type (P<0.001), TNM stage (P<0.001), and adjuvant therapy (P<0.001). In the multivariate analysis, after adjusting for confounders, PIIN score [hazard ratio (HR): 2.116, 95% confidence interval (CI): 1.305–3.430, P=0.002], TNM stage (stage II: HR: 2.437, 95% CI: 1.223–4.855, P=0.01; stage III: HR: 6.753, 95% CI: 3.779–12.065, P<0.001), and FEV₁ (HR: 2.335, 95% CI: 1.402–3.889, P=0.001) were identified as independent risk factors for OS (Table 3). In addition, Kaplan-Meier survival curves demonstrating PIIN score and TNM stage are shown in Figure 2, revealing significantly reduced survival rates in patients with high PIIN scores as well as those classified as TNM stage II and III (P<0.001).

Table 3. Univariate and multivariate analysis of overall survival in NSCLC patients.

Variables	Univariable Cox regression			Multivariable Cox regression
	HR (95% CI)	P value		HR (95% CI)	P value
Age, years
<60	1.000
≥60	1.077 (0.712–1.629)	0.73
Gender
Male	1.000			1.000
Female	0.411 (0.267–0.632)	<0.001*		0.661 (0.348–1.258)	0.21
BMI, kg/m2
<23.85	1.000
≥23.85	0.840 (0.559–1.263)	0.40
Smoking history
No	1.000			1.000
Yes	2.063 (1.373–3.101)	<0.001*		1.117 (0.636–1.961)	0.70
Respiratory diseases
No	1.000			1.000
Yes	0.752 (0.364–1.552)	0.44		0.776 (0.358–1.685)	0.52
PIIN
≤24.2	1.000			1.000
>24.2	3.287 (2.089–5.172)	<0.001*		2.116 (1.305–3.430)	0.002*
FEV1, %
≥80	1.000			1.000
<80	3.149 (2.058–4.819)	<0.001*		2.335 (1.402–3.889)	0.001*
FEV1/FVC, %
≥70	1.000			1.000
<70	1.831 (1.201–2.793)	0.005*		0.814 (0.499–1.327)	0.41
Pathologic type
Adenocarcinoma	1.000			1.000
Non-adenocarcinoma	2.567 (1.677–3.929)	<0.001*		0.792 (0.468–1.341)	0.39
TNM stage
I	1.000			1.000
II	3.916 (2.133–7.190)	<0.001*		2.437 (1.223–4.855)	0.01*
III	8.878 (5.533–14.243)	<0.001*		6.753 (3.779–12.065)	<0.001*
Surgical approach
Seg/Wed	1.000
Lobe	1.286 (0.561–2.946)	0.55
Adjuvant therapy
No	1.000			1.000
Yes	3.321 (2.177–5.067)	<0.001*		1.093 (0.655–1.822)	0.73
Postoperative complication
No	1.000
Yes	1.385 (0.889–2.156)	0.15

*, the value of P<0.05, which is statistically significant. BMI, body mass index; NSCLC, non-small cell lung cancer; FEV₁, forced expiratory volume in the first second; FEV₁/FVC, forced expiratory volume in the first second/forced vital capacity; Lobe, lobectomy; PIIN, prognostic immune-inflammatory-nutritional score; Seg, segmentectomy; Wed, wedge resection.

Figure 2.

Kaplan-Meier survival curves for patients with different PIIN levels and TNM stage. (A) Kaplan-Meier survival curves for patients with different PIIN levels. (B) Kaplan-Meier survival curves for patients with TNM stage. PIIN, prognostic immune-inflammatory-nutritional score; TNM stage, tumor-node-metastasis stage.

Nomogram development and validation

A nomogram was constructed using the independent prognostic factors identified by the Cox regression analysis to predict long-term survival in NSCLC patients (Figure 3). The calibration curves demonstrated strong concordance between the nomogram’s predicted outcomes and the observed survival rates (Figure 4). The predictive power of the model was assessed using the concordance index (C-index), which was 0.838 (0.736–0.906). Additionally, ROC curves for predicting 1-, 3-, and 5-year OS yielded AUC values of 0.843, 0.831, 0.825, respectively (Figure 5), emphasizing the nomogram’s accuracy in predicting survival outcomes for NSCLC patients.

Figure 3.

Nomogram and calibration curves for predicting OS of NSCLC patients. FEV₁, forced expiratory volume in the first second; NSCLC, non-small cell lung cancer; OS, overall survival; PIIN, prognostic immune-inflammatory-nutritional score; TNM stage, tumor-node-metastasis stage.

Figure 4.

Calibration curves for predictive models estimating survival at 1-, 3-, and 5-year.

Figure 5.

ROC curves of the nomogram for NSCLC patients undergoing pulmonary resection. AUC, area under the curve; NSCLC, non-small cell lung cancer; ROC, receiver operating characteristic.

Discussion

In this study, we are the first to provide evidence demonstrating the prognostic significance of PIIN score in patients with NSCLC who underwent surgical treatment. Our findings demonstrate that the preoperative PIIN score is independently associated with the prognosis of NSCLC patients, consistent with previous research on PIIN’s prognostic capabilities in other tumor types, including intrahepatic cholangiocarcinoma and pancreatic cancer (16,17). Unlike standard blood biomarkers, PIIN score integrates FIB, NLR, SII, ALBI, and PNI, covering critical aspects such as immune response, inflammatory state, and nutritional status, making it a potent tool for evaluating personalized prognosis in NSCLC patients.

Inflammation and immune dysregulation are well-established drivers of tumor development and progression in NSCLC (18,19). Lymphocytes, for instance, key players in the innate immune system, exert cytotoxic effects and induce apoptosis in tumor cells, thereby inhibiting cancer cell growth, invasion, and metastasis (20-23). Conversely, neutrophils support tumor growth by secreting cytokines that promote a pro-tumorigenic environment and by suppressing lymphocyte-mediated anti-tumor responses (24,25). Moreover, in hypoxic conditions, the chemokine CXCL6 activates tumor-associated neutrophils, enhancing cell proliferation and invasion (26). The NLR and SII, which include levels of neutrophils and lymphocytes in the body, reflect the dynamic balance between pro-carcinogenic inflammation and anti-tumor immune activity, and have been shown to be associated with poor prognosis in NSCLC (27-29).

FIB is another component of the PIIN score and has also become a key biomarker associated with poor prognosis in patients with NSCLC. Mitsui et al. identified high preoperative fibrinogen levels as a predictor of poor prognosis in stage I NSCLC (30). Another study suggested the F-NLR score (combining FIB and NLR) as a promising prognostic tool for resectable NSCLC (31). The increased fibrinogen’s association with poor prognosis might be due to its role in protecting tumor cells from natural killer (NK) cell-mediated cytotoxicity by forming dense fibrin layers around the tumor cells (32).

Malnutrition is a common issue in NSCLC patients, significantly affecting treatment response and prognosis (33-35). Albumin, a marker of overall nutritional status, plays a role in removing pro-inflammatory stimuli and mitigating inflammatory responses (36,37). Additionally, albumin influences immune regulation and reduces oxidative stress. Low albumin levels indicate poor tolerance to cancer progression and clinical interventions (38,39). The ALBI score, which assesses liver function and nutritional status by considering albumin and bilirubin levels, has been associated with the prognosis of various cancers, including hepatocellular carcinoma, pancreatic head cancer, and lung cancer (40-42). The PNI, a straightforward yet effective measure of nutritional status, has been linked to lower survival rates in cancer patients (43-45). The integration of these nutritional parameters within the PIIN score allows for a more holistic evaluation of a patient’s overall health, providing prognostic insight beyond what is achievable with purely inflammatory markers.

Given the complex inflammatory and nutritional variances among NSCLC patients, our findings demonstrate that the PIIN score, a composite clinical index of NLR, SII, FIB, ALBI, and PNI, exhibited the highest AUC value compared to any single index. Furthermore, we developed a reliable prognostic tool for forecasting overall survival in NSCLC patients using the PIIN score, presented as a nomogram. The performance of this nomogram was evaluated using the C-index. The C-index value for patients with NSCLC was 0.838 (0.736–0.906). ROC curves generated for 1-, 3-, and 5-year survival rates demonstrated the model’s discriminatory power, with AUC values of 0.843, 0.831, and 0.825, respectively, underscoring the model’s robustness in predicting survival outcomes.

Beyond its prognostic utility, the PIIN score could serve as a guide for therapeutic decision-making. Patients with high PIIN scores, indicative of heightened inflammation, poor nutritional status, and compromised immune function, may benefit from more aggressive perioperative management, including prehabilitation programs focused on improving nutrition and immune function. In addition, such patients might be candidates for novel immunomodulatory therapies, given the strong influence of inflammation and immune responses on NSCLC progression.

We acknowledge several limitations in our study. Being a single-center retrospective analysis, our findings may be subject to selection bias, and the results may not be generalizable to broader populations. To verify and refine these results, larger, multi-center prospective studies are necessary. Additionally, our focus was on NSCLC patients in stages I-III who underwent surgery, limiting the applicability of our findings to those with advanced stages or alternative treatment modalities. Moreover, while the PIIN score effectively integrates immune, inflammatory, and nutritional markers, future research could explore the addition of molecular and genetic markers to further refine and individualize prognosis prediction models for NSCLC patients.

Conclusions

In conclusion, our study illustrates that PIIN score serves as an independent prognostic marker for long-term outcomes in patients with stage I-III NSCLC. The use of PIIN score offers clinicians a comprehensive and precise tool for assessing patient prognosis, aiding in the optimization of treatment strategies.

Supplementary

The article’s supplementary files as

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 the Ethics Committee of Beijing Chaoyang Hospital, Capital Medical University (approval number: 2024-Ke-28) and individual consent for this retrospective analysis was waived.

Data Sharing Statement

Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1830/dss

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DOI: 10.21037/jtd-24-1830