
Author(s) :
Alexandru Necula 1,2 , Andrei Belu3, Claudia Cristina Burz1,3
1 “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
2 Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
3 “Prof. Dr. Ion Chiricuta” Institute of Oncology, Cluj-Napoca, Romania
Corresponding author: Alexandru Necula, Email: alexnecula10@gmail.com
Publication History: Received - 1 Feb 2024, Revised - 27 May 2024, Accepted - 27 July 2024, Published Online - 27 July 2024.
Copyright: © 2024 The author(s). Published by Casa Cărții de Știință.
User License: Creative Commons Attribution – NonCommercial (CC BY-NC)
Highlights
- High lymphocyte levels tend to lead to a more favorable response in patients who received Cetuximab-based therapy for unresectable mCRC.
- High neutrophil and platelet levels are associated with a worse prognosis.
- Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio represent promising predictive biomarkers for mCRC.
Abstract
Background: Our retrospective single-center study aimed to assess the value of the inflammatory biomarkers in predicting the response to 5-fluorouracil/folinic acid-based chemotherapy and Anti-EGFR monoclonal antibodies (Cetuximab) in stage IV unresectable metastatic colorectal cancer (mCRC) patients
Material & Methods: We conducted a retrospective study on a series of 38 consecutively patients with stage IV mCRC patients who received first-line therapy (FOLFOX/FOLFIRI Doublet Chemotherapy + Cetuximab) between 2014 and 2023. Inclusion criteria encompassed KRAS wild-type status, left-sided colorectal cancer, and availability of response assessment on CT scan up to 3 months after starting the treatment. Chemotherapy response was assessed using RECIST 1.1 criteria. NLR (Neutrophil-to-Lymphocyte Ratio) , and PLR (Platelet-to-Lymphocyte Ratio) were measured a day prior to first day of therapy and a ROC curve analysis was performed to find the cutoff values able to predict among responders (complete or partial response )and non-responders (stable and progressive disease)
Results: ROC curve analysis showed cutoff values for NLR of 1.54 and for PLR of 95.90. High lymphocyte levels tend to lead to a more favorable response, while high neutrophil and platelet levels associate with a worse prognosis.
Conclusion: Our study highlights the role of NLR and PLR as predictive biomarkers in Cetuximab-based therapy for unresectable mCRC, providing valuable insights for clinicians in therapeutic decision-making.
1. Introduction
Colorectal cancer (CRC) is a significant global health problem, ranking third in incidence and second in cancer-related deaths according to the GLOBOCAN 2020 statistics [1,2]. In 2020 alone, CRC accounted for nearly one in ten new cancer diagnoses, with over 1.9 million cases reported worldwide. Over the last two decades, there has been an increase in CRC cases among young adults, particularly in Western countries where a modern lifestyle predominates. This trend has made CRC the leading cause of increase in young adults mortality in developed countries [1,4]. There is a strong correlation between a country’s human development index (HDI) and the incidence of colorectal cancer. This association is largely due to shifts towards highly processed diets, excessive body fat, and lifestyle factors [1]. Romania, which has recently adopted a Western lifestyle and in recent years has a high HDI, reports CRC as the leading cause of new cancer cases in both sexes combined (12.9%) and ranks second in cancer-related mortality (12.4%), emphasizing the seriousness of the issue (1-3).
The systemic inflammatory response is a well-recognized factor closely linked to cancer development and progression, relevant in several cancer types including colorectal cancer (CRC) [5,6]. Numerous studies have also indicated that prolonged, low-dose use of non-steroidal anti-inflammatory drugs significantly lowers the overall risk of developing CRC, underscoring their potential in chemoprevention within different populations (9,10,28). Inflammation can be triggered by various causes, from infections to environmental carcinogens, and is believed to play a critical role in the oncogenesis of CRC. Secondary inflammation that originates from the tumor itself also promotes tumor proliferation and facilitates metastatic spread (5,11).
1.1. Circulating Inflammatory Biomarkers
At present CT scan is the standard tool for evaluating the response to systemic therapies in colorectal cancer (CRC), and, although tumor biomarkers may be useful in some cases, currently there is no standard method recommended for monitoring treatment response to systemic therapy. A variety of biomarkers are currently under scrutiny, from circulating white blood cells (WBC) and platelets to tumor-infiltrating lymphocytes (TILs), surface receptors, circulating tumor DNA (ctDNA) and other indicators. In our study, we analyzed Neutrophil-to-Lymphocyte Ratio (NLR) and the Platelet-to-Lymphocyte Ratio (PLR), as predictive biomarkers for treatment response.
Different subtypes of white blood cells (WBCs) are present in the tumor microenvironment and systemic circulation and impact tumor behavior in distinct, sometimes opposite ways [12,17]. Elevated levels of circulating lymphocytes have been associated with favorable responses to systemic therapy in CRC and other cancers. In contrast, increased levels of neutrophils and platelets have been shown to support tumor progression and metastasis [17].
Both NLR and PLR have been acknowledged as biomarkers correlated to systemic inflammation and their ability to predict responses to systemic therapies has been demonstrated across various cancer types, including gastric, esophageal, breast, and colorectal[13-16, 20-22]. However, at present their use is considered experimental as there are no standard values that can be recommended in clinical practice [13-22]. Notably, most research on NLR and PLR in colorectal CRC has primarily concentrated on metastatic CRC (mCRC) in the context of post-resection systemic therapy [13-16]. Our study aims to extend this research by exploring the predictive value of NLR and PLR, specifically in the treatment response of unresectable mCRC.
1.2. Anti-EGFR Therapy in mCRC
In 2004, the FDA approved Cetuximab as a result of positive randomized clinical trials that demonstrated its efficacy compared to best supportive care [24]. In the following years, Cetuximab was combined with fluorouracil-based chemotherapy, demonstrating superior outcomes compared to individual therapies [26,27]. The discovery of KRAS and BRAF mutations has further improved the response rates to Anti-EGFR therapies combined with FOLFOX/FOLFIRI chemotherapy. This advancement led to its endorsement as a first-line treatment specifically for patients with KRAS wild-type and BRAF wild-type subgroups [26,27].
2. Material and Methods
A retrospective, single-center study was conducted on 38 consecutive patients diagnosed with unresectable stage IV mCRC at our center. These patients received first-line therapy, which consisted of either FOLFOX or FOLFIRI combination chemotherapy in combination with Cetuximab, following the most recent ESMO and ASCO guidelines [29,30]. The inclusion criteria included pathologically confirmed CRC, KRAS wild-type status, left-sided colorectal cancer, and the availability of CT scans to assess treatment response. Additionally, peripheral blood counts were recorded at the initiation of therapy, and the NLR and PLR were measured one day prior to treatment administration.
Chemotherapy regimen efficacy was evaluated using CT scans conducted no later than three months after initiating treatment. Patients were then classified into three categories: Response (R), Stable Disease (SD), and Progressive Disease (PD), in accordance with RECIST 1.1 criteria. For our statistical analysis, we employed ROC curve analysis to identify a cut-off value that could differentiate the patient that responded to the treatment from those with stable or progressing disease [33].
GraphPad Prism® 9.0.1 was used for statistical analysis.
3. Results
To differentiate between a positive treatment response more accurately and either stable or progressive disease, ROC curve analysis were performed for both NLR and the PLR. This analysis identified a cutoff value of 1.54 for NLR and 95.90 for PLR. The corresponding areas under the curve (AUC) were 0.65 for NLR and 0.61 for PLR, respectively [Figure 1, Figure 2].
Figure 1. ROC Curve analysis for NLR cut-off value between R group patients and the rest of SD and PD group patients ( AUC= area under curve, Se= sensibility, Sp= specificity)
Figure 2. ROC Curve analysis for PLR cut-off value between R group patients and the rest of SD and PD group patients ( AUC= area under curve, Se= sensibility, Sp= specificity)
4. Discussion
In concordance with prior published literature, our study dsemonstarted the association of higher NLR and PLR with poorer prognoses in patients treated with Cetuximab. Conversely, elevated circulating lymphocyte levels (low NLR and PLR) correlated with a more favorable response to treatment. Interestingly, the cutoff values found—1.54 for NLR and 95.90 for PLR—are significantly lower than those typically reported in the literature, which range between 3-5 for NLR and 150-160 for PLR [11,13-20]. We plan to further investigate possible factors related to this discrepancy.
This study has clear limitations. First, due to the retrospective, single-center design a selection bias may have been introduced. Another bias may have been introduced by having different radiologists reading the CTs. Patients with infections or hematological disorders that could affect WBC and platelet levels were excluded, but other unaccounted variables may have influenced the blood counts.
5. Conclusions
Our study confirms the potential utility of NLR and PLR as biomarkers, aligning with existing literature that supports their use in guiding clinical decisions regarding Cetuximab-based systemic therapy for unresectable mCRC. While the use of these biomarkers does not provide definitive accuracy in predicting treatment response and is currently considered experimental, their cost and ease of implementation may warrant a closer investigation of their benefit through a large prospective randomized study. Notably, the significance of these biomarkers may be particularly relevant to specific patient populations ie left sided mCRC, underscoring the need for further research in this area.
Abbreviations
mCRC: Metastatic Colorectal Cancer, EGFR: Epidermal Growth Factor Receptor, FOLFOX: Combination Chemotherapy Regimen (5-Fluorouracil, Leucovorin, Oxaliplatin), FOLFIRI: Combination Chemotherapy Regimen (5-Fluorouracil, Leucovorin, Irinotecan), ChT: Chemotherapy, NLR: Neutrophil-to-Lymphocyte Ratio, PLR: Platelet-to-Lymphocyte Ratio, CT: Computed Tomography, RECIST 1.1: Response Evaluation Criteria in Solid Tumors version 1.1, ROC: Receiver Operating Characteristic, AUC: Area Under the Curve , ESMO: European Society for Medical Oncology, ASCO: American Society of Clinical Oncology, FDA: U.S. Food and Drug Administration, HDI: Human Development Index, WBC : white blood cells
Statements
Authors’ contributions: A.N., C-C.B., A.B. conceived and planned the analysis; A.N., C-C.B. contributed to the interpretation of the results; A.N., A.B. – performed data collection and statistical analysis; A.N. took the lead in writing the manuscript; C-C.B., A.N. made the final approval.
Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.
Conflict of interests: The authors declare no conflict of interest.
Funding Sources: None
Statement of Ethics: No study has been carried on human or animal samples. Only patient data was used in the statistical analysis and database formation process, which was approved by an Ethics Committee.
Acknowledgments
Institute of Oncology “Prof dr. Ion Chiricuta” Cluj-Napoca
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A) Trend of the median values of NLR in the three patient response groups
B) Trend of the median values of PLR in the three patient response groups



