Research ArticleClinical Studies

Systemic Inflammatory Score Predicts Response and Prognosis in Patients With Lung Cancer Treated With Immunotherapy

JUNICHI ZAITSU, YOSHINORI YAMASHITA, AKIRA ISHIKAWA, AKIHISA SAITO, ATSUSHI KAGIMOTO, TAKESHI MIMURA, TETSU HIRAKAWA, MINEYO MITO, KAZUHIDE FUKUHARA, TADASHI SENOO, KIKUO NAKANO, KAZUYA KURAOKA and KIYOMI TANIYAMA
Anticancer Research July 2021, 41 (7) 3673-3682; DOI: https://doi.org/10.21873/anticanres.15158

Abstract

Aim: This study aimed to investigate useful prognostic factors of immunotherapy in patients with lung cancer. Patients and Methods: We retrospectively observed 73 patients who underwent immunotherapy (nivolumab, pembrolizumab, and atezolizumab) for lung cancer. The systemic inflammatory score (SIS) was calculated as the sum of the following factors scored one point each: Hemoglobin <12.5 g/dl and serum albumin <3.6 g/dl, resulting in scores of 0-2. We examined the correlation between the SIS and initial tumor response and progression-free and overall survival with other existing markers, namely tumor programmed death-ligand 1 (PD-L1) expression level; neutrophil-to-lymphocyte ratio (NLR); modified Glasgow prognostic score; and prognostic nutritional index, etc. Results: SIS ≤1 was significantly associated with better initial tumor response. In multivariate analysis, PD-L1 expression ≥50% (p=0.010), SIS ≤1 (p=0.028) and NLR <5.6 (p=0.047) were significantly associated with longer progression-free survival, and SIS ≤1 (p=0.030) and NLR <5.6 (p=0.037) were associated with longer overall survival. Conclusion: SIS is a useful marker of the efficacy of immunotherapy that can be obtained via routine blood tests.

Key Words:

Lung cancer has the highest mortality rate worldwide of all cancer types (1, 2). In recent years, the emergence of molecular targeted drugs and immune checkpoint inhibitors (ICIs) has drastically changed the strategy for the treatment of advanced lung cancer. ICIs improve the overall survival (OS) of patients with lung cancer (3-5).

The expression level of programmed death-ligand 1 (PD-L1) in tumor cells is determined through immunohistochemistry (IHC). PD-L1 is a significant predictive marker of ICIs; however, it is not a sufficient indicator of the efficacy of immunotherapy. Several serum-based parameters related to systemic inflammation and nutritional status of patients have been studied as predictive or prognostic markers during immunotherapy, such as the neutrophil-to-lymphocyte ratio (NLR), modified Glasgow prognostic score (mGPS), and prognostic nutritional index (PNI) (6-8). However, the unified cutoff points for these metrics and other parameters that are more sensitive than these markers are controversial.

This study aimed to investigate factors of the efficacy of immunotherapy that are readily available via routine blood tests. We focused on the combination of hemoglobin (Hb) and serum albumin levels.

Patients and Methods

This retrospective study included consecutive patients with inoperable lung cancer who underwent monotherapy with ICIs, including nivolumab, pembrolizumab and atezolizumab, at the National Hospital Organization Kure Medical Center Chugoku Cancer Center between November 2016 and April 2020. Patients treated with durvalumab after chemoradiotherapy and those having concomitant use of chemoradiotherapy and pembrolizumab were excluded because other therapies made it difficult to determine the direct efficacy of ICIs.

Agreement was obtained from the patients for publication of their clinical information. This study was approved by the Ethical Committee of the Kure Medical Center Chugoku Cancer Center (2019-95).

Clinicopathological parameters. We investigated the following parameters before immunotherapy from electric medical records: Patient age, sex, clinical tumor stage, smoking history, treatment history, performance status, tumor histological subtype, programmed death-ligand 1 (PD-L1) expression level determined using IHC (monoclonal antibody, 22C3; Dako, Carpinteria, CA, USA), epidermal growth factor receptor (EGFR) mutation status, anaplastic large-cell lymphoma kinase (ALK) rearrangement status, and c-ros oncogene 1 (ROS1) mutation status.

Inflammatory and nutritional markers. We investigated the serum albumin level, C-reactive protein level, complete blood count, and body mass index (BMI) of all patients before immunotherapy. NLR is the ratio of absolute neutrophil and lymphocyte counts in peripheral blood. The platelet-to-monocyte ratio (PLR) was also calculated accordingly. The mGPS is based on assigning a score of one point for albumin <3.5 g/dl, and one point for C-reactive protein ≥1.0 mg/dl, leading to scores of 0-2. The PNI was calculated as 10×albumin (g/dl)+0.005×lymphocyte count (n/mm3), as reported by Onodera et al. (9).

The hemoglobin, albumin, lymphocyte, and platelet (HALP) score was calculated as Hb (g/l)×albumin (g/l)×lymphocyte (n/l)/platelet count (n/l). The cutoff values for NLR, PNI, and HALP were determined according to receiver operating characteristic analysis. The cut-off points for PLR and BMI were defined as >175 (10) and <18.5 kg/m2 (11), respectively, as reported previously in literature. Additionally, we calculated the systemic inflammatory score (SIS), which is a score based on assigning a score of one point for Hb <12.5 g/dl, and one point for albumin <3.6 g/dl, leading to scores of 0-2. The cutoff points of Hb and albumin levels were determined as reported by Lago et al. (10).

Evaluation of the therapeutic effect. Patients underwent computed tomography (CT) before and 4-12 weeks after immunotherapy. In cases of suspected brain metastasis, magnetic resonance imaging of the brain was performed accordingly in those patients. The initial efficacy of ICIs was determined according to the New Response Evaluation Criteria in Solid Tumors: the revised RECIST guidelines (RECIST 1.1) (12). Subsequently, we performed CT every 2-6 months and a brain magnetic resonance imaging every 6 months. We investigated progression-free survival (PFS) and OS from ICI initiation, as defined by RECIST 1.1. We divided the patients into two groups according to the initial tumor response, those with progressive disease (PD), and those with stable disease/complete response, and examined the clinical factors affecting the initial tumor response.

Statistical analysis. Statistical analyses were performed using JMP software version 13.0.0 (SAS Institute Inc., Cary, NC, USA). Continuous variables are presented as the mean±standard deviation. The normal distribution of these variables with the homogeneity of variance was compared using a t-test. The differences between two groups for categorical variables were compared using the chi-square test or Fisher’s exact test, according to the expected numbers for each category. PFS and OS were analyzed using the Kaplan-Meier method with the log-rank test. We used Cox proportional hazards regression models for univariate and multivariate analyses to calculate the hazard ratios (HRs) of the prognostic factors. Multivariate analysis was performed including factors which were significant in univariate analysis. We did not include hemoglobin and albumin as factors of multivariate analysis because of the multi-collinearity with SIS. Statistical significance was set at p<0.05.

Results

Clinical findings. In total, 95 patients underwent immunotherapy at our Institution. Three patients were subsequently administered durvalumab after chemoradiotherapy, and eight patients underwent concomitant chemotherapy and pembrolizumab. Among the remaining 84 patients, 10 were excluded owing to the loss of CT findings before or after immunotherapy. In addition, one patient was excluded because the observation of the clinical course for 9 months during the treatment was missing in this case. Finally, we included 73 patients (Figure 1) who were administered nivolumab (n=28), pembrolizumab (n=39), and atezolizumab monotherapy (n=8). Among them, one patient was treated with nivolumab and atezolizumab, and another patient was treated with pembrolizumab and atezolizumab during separate periods.

Figure 1.
Figure 1.

Flow diagram of patient selection process for inclusion in the present study.

Patient backgrounds are shown in Table I. The average patient age at immunotherapy was 70.9±9.4 years. Fifty-two patients were men. There were six and 47 patients who were diagnosed with clinical stage IIIB and IV, respectively, according to the eighth edition of the Union for International Cancer Control (UICC) staging system (13); the remaining 20 patients had recurrence of cancer after surgical resection or radical chemoradiotherapy. The number of squamous cell carcinomas, adenocarcinomas, and other subtypes was 27, 36, and 10, respectively. Other subtypes included small-cell carcinoma combined with a squamous cell carcinoma and adenocarcinoma component, atypical carcinoid tumor, six sarcomatoid (suspicious of pleomorphic) carcinomas, and large-cell carcinoma. One patient had poorly differentiated non-small-cell carcinoma; however, confirmation of the histological type was challenging. PD-L1 was expressed in most tumors (76.7%). EGFR mutation status was negative in most cases assessed (62/69). None of the patients had ALK rearrangement (n=67) or ROS1 mutations (n=51). The mean BMI was 22.9±3.5 kg/m2, and only eight patients had a BMI of <18.5 kg/m2 at immunotherapy.

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Table I.

The clinical background of the study patients (N=73).

Clinicopathological parameters associated with initial tumor response. There were 23 PR-CR, 12 SD, and 38 PD cases. The correlation between tumor response and clinicopathological parameters is shown in Table II. PD-L1 expression ≥50%, SIS ≤1, Hb ≥12.5 g/dl, HALP ≥32.9, and RDW <47.7 fl were associated with better initial tumor response. Other nutritional and inflammatory markers, namely PNI ≥43, albumin ≥3.6 g/dl, NLR <5.6, and mGPS ≤1, were also significantly associated with better initial tumor response. Patient age, sex, clinical stage, smoking history, BMI, PLR, performance status, tumor histological type, and EGFR mutation status were not associated with the initial tumor response.

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Table II.

Initial response to immune checkpoint inhibitors pembrolizumab and nivolumab according to clinicopathological parameters.

Clinicopathological parameters associated with PFS and OS. The curves of PFS and OS according to SIS (n=68) are shown in Figure 2, those of patients treated with pembrolizumab (n=38) and nivolumab (n=26) are shown in Figure 3. PFS of patients with SIS of 2 was under a fifth of that of patients with SIS ≤1 [median (95% confidence intervaI) of 43 (21-63) versus 230 (76-296) days, p<0.001]. OS was similarly significantly shorter at a median (95% confidence intervaI) of 174 (98-328) versus 1,064 (516-,153) days, p<0.001.

Figure 2.
Figure 2.

Kaplan-Meier analysis of progression-free (A), and overall (B) survival of patients who underwent therapy with immune checkpoint inhibitors according to their systemic inflammatory score (SIS) (n=68). Patients with SIS of 2 had significantly shorter PFS [median (95% confidence intervaI) of 43 (21-63) versus 230 (76-296) days, p<0.001]. Their OS was similarly significantly shorter at a median (95% confidence intervaI) of 174 (98-328) versus 1,064 (516-1,153) days, p<0.001.

Figure 3.
Figure 3.

Kaplan-Meier analysis of progression-free (upper panel), and overall (lower panel) survival of patients who underwent therapy with pembrolizumab (n=38) (A) and nivolumab (n=26) (B). Patients treated with pembrolizumab who had an SIS of 2 had significantly shorter PFS [median (95% confidence intervaI) of 43 (12-158) versus 271 (97-375) days, p=0.003]. Their OS was similarly significantly shorter at a median (95% confidence intervaI) of 156 (20-362) versus 1,064 (418-1,153) days, p<0.001. Patients treated with nivolumab with SIS ≥1 had similarly short median PFS and OS [53 (32-63) days (p<0.001) and 288 (182-376) days (p=0.001), respectively, versus not reached].

Univariate and multivariate analyses of PFS and OS are shown in Table III. In univariate analysis, PD-L1 expression ≥50%, SIS ≤1, HALP ≥32.9, PNI >43, mGPS ≤1, and NLR <5.6 were associated with a significantly longer PFS. In multivariate analysis, PD-L1 expression ≥50%, SIS ≤1 and NLR <5.6 were significantly associated with longer PFS. SIS≤1 was also associated with significantly longer OS in univariate analysis. In multivariate analysis, SIS ≤1 and NLR <5.6 was associated with a significantly longer OS.

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Table III.

Clinicopathological parameters affecting the progression-free and overall survival of patients treated with immunotherapy.

Among the 39 and 28 patients treated with pembrolizumab and nivolumab, respectively, SIS of ≤1 and 0 were correlated with significantly longer PFS in univariate and multivariate analyses and significantly longer OS in univariate analysis (Tables IV and V).

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Table IV.

Clinicopathological parameters affecting the progression-free and overall survival of patients treated with pembrolizumab (N=39).

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Table V.

Clinicopathological parameters affecting the progression-free and overall survival of patients treated with nivolumab (N=28).

We were unable to evaluate patients treated with atezolizumab as the number of these patients was too small for statistical analysis, and seven out of the eight patients were diagnosed with PD at their initial evaluation. Two patients treated with atezolizumab and another patient treated with PD-L1 antibody during separate periods were determined to have PD at the initial response to both ICIs.

Discussion

In recent years, many clinicopathological factors have been studied as predictive and prognostic factors of immunotherapy in patients with lung cancer. PD-L1 expression levels in tumor cells determined by IHC, tumor-infiltrating lymphocytes, and tumor mutational burden have been considered predictors of ICI efficacy (14). However, these markers have several limitations, such as tumor heterogeneity. Universal markers, in addition to tumor PD-L1 expression level, are controversial, and there is hope in terms of finding other sensitive parameters. Albumin is a negative acute-phase protein, and hypoalbuminemia is associated with malnutrition and systemic inflammation. It is an important risk factor for poor prognosis in patients with lung cancer (15, 16). Chronic inflammation causes cancer progression through reactive oxygen/nitrogen species (17). Several serum markers of nutritional or systemic inflammatory status, NLR (6), mGPS (7, 8), and PNI (8) have been reported as predictive and prognostic markers of immunotherapy.

In the present study, we reported that SIS at immunotherapy was significantly associated with initial response, PFS, and OS after immunotherapy. SIS can be readily and inexpensively obtained via blood tests performed during routine medical care. Therefore, we focused on the importance and significance of albumin and Hb levels in immunotherapy.

We found that several parameters related to erythrocyte series were also significantly associated with initial tumor response, PFS, and OS at immunotherapy in our cases. RDW is a biomarker of erythrocyte homeostasis, and its elevation in patients with cancer reflects inflammation, malnutrition, and oxidative stress (18). It has also been reported as a prognostic and predictive marker for patients treated with anti-PD-1 blockade agents (19). HALP is a marker of systemic inflammatory status and a prognostic marker of gastrointestinal, pancreatic, prostatic, and urinary bladder cancer (20) and small-cell carcinoma of the lung (21). The association between the HALP score and the efficacy of immunotherapy is unknown. SIS appears to be a more sensitive marker of efficacy than existing ones.

These results shed light on new useful biomarkers, including erythrocyte series as a predictor of ICIs. We consider anemia to be another important factor that affects the efficacy of ICI efficacy. Anemia is caused by several pathogenic mechanisms. Malnutrition, including iron, zinc, and vitamin deficiency, is considerable on account of anemia (22). Anemia also occurs in chronic systemic inflammation through iron-restricted erythropoiesis due to increased hepcidin levels and suppression of erythropoiesis caused by cytokines (23). However, it is unclear whether anemia directly affects ICI efficacy. Zhang et al. reported that patients with non-small cell lung cancer with pretreatment Hb level <11.0 g/dl showed a poorer PFS and OS after ICI monotherapy and combination therapy or anti-angiogenic agents (24). Our cases confirmed their argument of the importance of anemia as a prognostic marker of immunotherapy. In head and neck squamous cell carcinoma, severe anemia (Hb level <11.0 g/dl) correlated with low tumor oxygenation and resistance to radiotherapy (25). Tumor hypoxia is considered to change the tumor microenvironment to an immunosuppressive status (26). In non-small cell lung cancer, pathological vessels cause tumor hypoxia, which leads to macrophage reprogramming to an immunosuppressive M2 phenotype (27) and recruitment of immunosuppressive regulatory T-cells through the induction of chemokines (28). Anti-angiogenic therapy alleviates hypoxia and improves the immunosuppressive tumor microenvironment (29). Anemia may therefore affect tumor hypoxia and support an immunosuppressive tumor microenvironment and therapeutic resistance to ICIs.

In patients with cancer, anemia can occur as a symptom of cachexia (30) and is associated with an impaired immune response (31). The mGPS has been reported as a useful parameter for predicting cachexia (32). One of the characteristics of SIS is that it semi-quantitatively reflects multiple risk factors. It is possible that SIS reflects an aspect of cancer cachexia. Therefore, we are considering whether it might be a good marker for developing personalized treatment strategies for each patient. For example, if a patient’s SIS prior to immunotherapy is high, the therapeutic effect of ICI might be expected to be poor, even if the tumor PD-L1 expression is high. In this case, other therapeutic modalities should be considered prior to immunotherapy, considering their balance with side-effects.

Our study has several limitations. Firstly, it was a retrospective study performed at a single institution. Secondly, the number of patients was too small to confirm the relationship between SIS, cachexia and immunosuppression. Thirdly, the normal value of Hb level differed by age and sex, although these factors were not associated with ICI efficacy in our cases. Finally, the etiology of anemia in each patient was not determined. Further prospective studies are hence required to clarify these issues.

In conclusion, the efficacy of ICIs was found to be associated with tumor PD-L1 expression, NLR, PNI, mGPS, albumin, Hb, HALP, RDW, and SIS. These data can be easily obtained via blood tests performed during routine medical care. Among them, Hb, HALP, RDW, and SIS are characteristically related to the erythrocyte series. In particular, SIS was a more useful factor for the efficacy of ICIs compared to existing serum-based parameters. Further studies are needed to clarify the relationship between Hb and albumin levels and the efficacy of ICIs.

Acknowledgements

The Authors are grateful to all the patients who participated in this study. The Authors thank the staff of the Department of Pathology and the Institution for Clinical Research of Kure Medical Center and Chugoku Cancer Center for their technical assistance. We would like to thank Editage (www.editage.com) for English language editing.

Footnotes

  • Author’s Contributions

    Junichi Zaitsu: Formal analysis, investigation, data curation, writing - original draft. Yoshinori Yamashita: Conceptualization, methodology, writing – review and editing. Akira Ishikawa: Resources. Akihisa Saito: Resources. Atsushi Kagimoto: Resources. Takeshi Mimura: Resources. Tetsu Hirakawa: Resources. Mineyo Mito: Resources. Kazuhide Fukuhara: Resources. Tadashi Senoo: Resources. Kikuo Nakano: Resources. Kazuya Kuraoka: Resources, writing – review and editing. Kiyomi Taniyama: Resources, writing – review and editing.

  • Conflicts of Interest

    The Authors have no conflicts of interest to declare in relation to this study.

  • Received May 12, 2021.
  • Revision received June 8, 2021.
  • Accepted June 15, 2021.

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Systemic Inflammatory Score Predicts Response and Prognosis in Patients With Lung Cancer Treated With Immunotherapy
JUNICHI ZAITSU, YOSHINORI YAMASHITA, AKIRA ISHIKAWA, AKIHISA SAITO, ATSUSHI KAGIMOTO, TAKESHI MIMURA, TETSU HIRAKAWA, MINEYO MITO, KAZUHIDE FUKUHARA, TADASHI SENOO, KIKUO NAKANO, KAZUYA KURAOKA, KIYOMI TANIYAMA
Anticancer Research Jul 2021, 41 (7) 3673-3682; DOI: 10.21873/anticanres.15158
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