Research Article |
Corresponding author: Tanya Zlatanova ( tanya_zlatanova@yahoo.com ) Academic editor: Georgi Momekov
© 2024 Tanya Zlatanova, Jeliazko Arabadjiev.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Zlatanova T, Arabadjiev J (2024) The prognostic role of markers of systemic inflammation in patients with metastatic lung cancer receiving immunotherapy: A comprehensive review of the literature. Pharmacia 71: 1-7. https://doi.org/10.3897/pharmacia.71.e115558
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Lung carcinoma stands as a prevalent malignancy characterized by a distressingly elevated fatality rate. Immunotherapy, administered either as a monotherapy or together with chemotherapy, represents the primary therapeutic approach for the majority of individuals grappling with advanced non-small cell lung cancer. The influence of systemic inflammation in fostering cancer dissemination and progression is a well-documented phenomenon. This literature review examines contemporary indices and scoring systems, which have emerged as informative indicators of systemic inflammation in recent years. These indices and scores are valuable prognostic and predictive elements in assessing treatment response among patients with metastatic lung cancer undergoing immunotherapeutic treatment.
markers of systemic inflammation, lung cancer, immunotherapy
Lung cancer holds the unfortunate distinction of being the leading global cause of cancer-related mortality. In 2020, as per GLOBOCAN data, it accounted for a staggering 1,796,144 deaths, representing 18% of all cancer-related fatalities (
Immunotherapy has emerged as the predominant treatment modality for NSCLC patients over the past decade, in line with recommendations from national and international treatment guidelines. In the majority of cases, patients with advanced and metastatic NSCLC currently receive first-line immunotherapy either as a monotherapy or in conjunction with chemotherapy. The critical necessity of identifying clearly defined prognostic factors cannot be understated. These factors serve the crucial purpose of guiding treatment decisions individually and setting priorities for preventive and therapeutic strategies, especially in light of the escalating costs associated with treatment. The identification of prognostic factors that are readily accessible and cost-effective is of paramount importance in clinical practice.
Prognostic factors are closely linked to the disease outcome, with overall survival being the most commonly employed parameter for comparative analysis. These factors are measured before treatment initiation and significantly impact prognosis, independent of the treatment administered (
In recent decades, with the introduction of novel drug classes for advanced NSCLC treatment, such as targeted therapies and immunotherapies, researchers have been actively exploring new prognostic factors linked to poor survival. Markers of systemic inflammation have emerged as potential prognostic factors, with several of them integrated into total scores and indices for comprehensive assessment. This literature review endeavors to provide a succinct summary of the key systemic inflammation biomarkers with the potential to serve as prognostic indicators for immunotherapy treatment in patients grappling with metastatic NSCLC.
In 2023, we undertook a bibliographic investigation to assess the indicators of systemic inflammation that have been explored as prospective prognostic determinants in managing lung carcinoma. Our study employed data from reputable sources, including PubMed and Google Scholar. It was conducted utilizing the following search terms: “markers of systemic inflammation,” “SII,” “ALI,” “Khorana score,” “lung cancer,” and “immunotherapy.” Our primary emphasis was on prognostic biomarkers that are straightforward to administer, facile to conduct, and suitable for integration into routine clinical practice.
Inflammation is linked to the initiation of tumor growth and the development of cancer, facilitating the proliferation, spread, and endurance of tumor cells through the activation of oncogenic signaling pathways. Tumor-promoting inflammation ensues when tumor cells induce the death of healthy cells, and this inflammation induced by tumors stands as a prominent hallmark of cancer (Hanahan and Weinberg 2011), as illustrated in Fig.
Biological Hallmarks of Cancer, Source: Adapted from Hallmarks of Cancer: The Next Generation, Hanahan D., Weinberg R.A. , Cell, Volume 144, ISSUE 5, P646-674, March 04, 2011, https://doi.org/10.1016/j.cell.2011.02.013.
The local immune response and the interplay between neoantigens, cytotoxic and regulatory T-cells, as well as suppressive factors, hold significant importance in the context of the inflammatory process (
Even prior to the introduction of immune checkpoint inhibitors into the lung cancer treatment landscape, certain biomarkers associated with the systemic inflammatory response and malnutrition, assessed before the commencement of systemic therapy, were recognized as independent prognostic factors in various oncological conditions, including lung cancer.
The complete blood count (CBC) is a standard test conducted in all lung cancer patients before initiating systemic therapy. Specific CBC parameters, such as platelets, neutrophils, and lymphocytes, which serve as markers of systemic inflammatory response, play a pivotal role in the immune response against tumor cells. Platelets have been demonstrated to significantly influence metastasis by inducing epithelial-mesenchymal transition, increasing vascular permeability, affecting tumor angiogenesis, and shielding circulating tumor cells from natural killer (NK) cell activity (
Furthermore, various simple formulas have been developed using combinations of the aforementioned hematological parameters, including the neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR) calculated as ANC/(WBC concentration – ANC), lymphocyteto-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR). These parameters have been subject to investigation as potential predictive factors (
The neutrophil-to-lymphocyte ratio (NLR) stands as one of the most extensively investigated prognostic indicators. Originating prior to the advent of immunotherapy as a therapeutic modality, NLR has demonstrated its utility in identifying unfavorable prognoses in patients with breast cancer, colorectal cancer, gastric cancer, hepatocellular carcinoma, and lung cancer (
In Bulgaria, a multicenter retrospective study involving 119 patients delved into the predictive and prognostic role of the neutrophil-to-lymphocyte ratio in individuals with advanced non-small cell lung cancer (NSCLC) who underwent pembrolizumab immunotherapy as a secondline treatment (
In another investigation conducted by Romano et al., the prognostic significance of NLR was corroborated in patients with NSCLC and elevated PD-L1 expression who were administered first-line pembrolizumab immunotherapy (
The systemic immune inflammation index (SII) is a parameter that has garnered substantial attention as a prognostic marker for survival across various tumor types, including hepatocellular carcinoma, gastric cancer, germ cell tumors, prostate cancer, and lung cancer (
An in-depth subgroup analysis, part of a meta-analysis conducted by Yang et al., encompassing 7,657 patients with diverse oncological conditions, concluded that an SII exceeding a predefined threshold reliably predicted poorer survival outcomes in patients with hepatocellular carcinoma, gastric cancer, esophageal squamous cell carcinoma, urinary neoplasms, small-cell lung cancer, and non-small cell lung cancer (
Over recent years, a growing body of evidence has underscored the role of SII as a prognostic index in lung cancer patients, a trend supported by data from various meta-analyses conducted primarily in China, Japan, and the USA. One such systematic review and meta-analysis by Zhang et al. summarized results from 2,786 lung cancer patients across seven clinical studies (
A meta-analysis and systematic review by Hang et al., published in 2022, incorporated 8,877 patients with non-small cell lung cancer (NSCLC) and affirmed the role of SII as a promising prognostic biomarker for guiding appropriate NSCLC therapy (
The predictive value of SII for the effectiveness of nivolumab immunotherapy as a secondline or further-line treatment was explored by Liu et al. (
In a retrospective study based on real-world data from two hospitals in China, the aim was to identify predictive clinical and hematological markers for the occurrence of immune-related adverse effects (
An exploration of associations between various markers of systemic inflammation and outcomes in metastatic NSCLC patients receiving first-line immune checkpoint inhibitors yielded inconsistent evidence in a single-site retrospective study (
Lastly, a retrospective study tracked dynamic changes in markers of systemic inflammation and nutritional indices in patients with advanced NSCLC at Shanghai Pulmonary Hospital in China who underwent first-line combination therapy with a PD-1 inhibitor and chemotherapy (
The Advanced Lung Cancer Inflammation Index (ALI) is another promising biomarker designed to predict the likelihood of a response to immune checkpoint inhibitors. ALI encompasses indicators of systemic inflammation within the host and reflects the influence of cancer-related cachexia. It comprises the following components: body mass index (BMI) measured in kg/m2, serum albumin levels in g/dL, and the neutrophil-to-lymphocyte ratio (NLR).
The role of ALI was examined in a retrospective study involving patients with stage IV lung cancer in Greece and Germany (
In conclusion, the authors noted that ALI serves as a robust prognostic and predictive biomarker for patients with advanced NSCLC who are treated with PD-L1 inhibitors alone but not when used in conjunction with chemotherapy. Its association with treatment outcomes appears to be more pronounced than that of other commonly used parameters, like NLR, PLL1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. In patients with high expression of PD-L1≥50%, an ALI score exceeding 18 could aid in the selection of patients for whom chemotherapy is not necessary as an adjunct to immunotherapy (
The Khorana Score (KS) represents the initially validated algorithm designed for the risk stratification of cancer patients about their susceptibility to venous thromboembolism (VTE) (
A retrospective investigation carried out by Bjornhart et al. examined the potential of the Khorana Score as a biomarker for patients with non-small cell lung cancer (NSCLC) undergoing immunotherapy (
In recent years, researchers have turned their attention to simultaneously investigating the impact of systemic inflammation and nutritional status on the treatment outcomes of individuals with metastatic non-small cell lung cancer (NSCLC). Numerous indices and scoring systems have been created and examined in this context, including the Prognostic Nutritional Index (PNI), Lung Immune Prognostic Index (LIPI), Lung Immuno-oncology Prognostic Score-3 (LIPS-3), Lung Immuno-oncology Prognostic Score-4 (LIPS-4), EPSILoN, Glasgow Prognostic Score (GPS), modified Glasgow Prognostic Score (mGPS), Holtzman Score, Scottish Inflammatory Prognostic Score (SIPS), Gustave Roussy Immune Score (GRIm), Royal Marsden Hospital Prognostic Score (RMH), Aarhus Composite Biomarker score (ACBS), and more. A retrospective analysis of data from a clinical site in Belgium compared most of these indices and scores, revealing a prognostic role but not a predictive one in patients with metastatic NSCLC who commenced first-line chemotherapy, immunotherapy, or a combination of both (
As immunotherapy gains greater prominence in managing metastatic NSCLC, the demand for effective prognostic and predictive biomarkers to gauge treatment response has become increasingly critical. Systemic inflammation is a pivotal feature in cancer, as it facilitates tumor progression and metastasis. Over the past few decades, numerous indices and scoring systems have emerged, considering the influence of systemic inflammation and a patient’s nutritional status. These indices have predominantly demonstrated their prognostic value and, to a lesser extent, their predictive potential. Conducting comprehensive international prospective studies to ascertain the most suitable and practical indices and scores for assessing systemic inflammation in routine clinical practice is imperative. This, in turn, will aid in determining the most appropriate initial therapy for patients with advanced lung cancer.