|Year : 2014 | Volume
| Issue : 3 | Page : 681-685
Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy
Hong-Bing Shi1, Xiao-Dong Li1, Jing-Ting Jiang2, Wei-Qing Zhao1, Mei Ji2, Chang-Ping Wu1
1 Department of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
2 Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu Province, China
|Date of Web Publication||14-Oct-2014|
Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou 213003, Jiangsu Province
Source of Support: This work was funded by grants from the Major Bidding Project Changzhou Health Bureau (ZD200810) provided by Dr. Mei Ji, Conflict of Interest: None
Aim: The aim of this study was to determine the expression levels of serum ferritin (SF) and investigate the correlation between SF expression levels and clinical characteristics as well as the efficacy to platinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC) patients.
Materials and Methods: Electrochemiluminescence method was used to determine the expression levels of SF in the peripheral blood of 46 advanced NSCLC patients and 63 healthy subjects.
Results: The expression levels of SF in healthy subjects were significantly lower than those in patients with advanced NSCLC patients (t = −3.279,P = 0.001). There was a statistically significant difference between SF expression levels and distant metastasis, regional lymph node metastasis, respectively (P < 0.05). However, there was no correlation between SF expression levels and sex, age, eastern cooperative oncology group performance status, smoking history, pathological type, tumor location and tumor-node-metastasis stage (All P > 0.05). The overall response rate to platinum-based chemotherapy was 57.1% (12/21) in normal SF expression levels group, which was significantly higher than that was 28% (7/25) in high SF expression levels group (χ2 = 3.998,P = 0.046).
Conclusions: SF may be a valuable blood marker for predicting the tumor progression and the efficacy of platinum-based therapies for advanced NSCLC patients.
Keywords: Advanced non-small cell lung cancer, efficacy, prognosis, serum ferritin
|How to cite this article:|
Shi HB, Li XD, Jiang JT, Zhao WQ, Ji M, Wu CP. Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy. J Can Res Ther 2014;10:681-5
|How to cite this URL:|
Shi HB, Li XD, Jiang JT, Zhao WQ, Ji M, Wu CP. Serum ferritin is elevated in advanced non-small cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy. J Can Res Ther [serial online] 2014 [cited 2020 Jul 4];10:681-5. Available from: http://www.cancerjournal.net/text.asp?2014/10/3/681/139156
| > Introduction|| |
Primary lung cancer is the most common cancer in human. The predicted incidence of lung cancer is a million new cases all over the world every year, of which most (over 80%) have a diagnosis of non-small cell lung cancer (NSCLC). From 60% to 70% of advanced NSCLC patients is diagnosed for III-IV stage and only relieved by chemotherapy or radiotherapy. Some studies confirmed that platinum-based chemotherapy was the current first-line standards of care for Stage III-IV NSCLC, but the efficacy had only 25-30%, and 2-year survival rates was less than 15%. ,, Therefore, there is a crucial need to explore novel tumor markers for predicting the progression of advanced NSCLC as well as helping to establish treatment strategies.
Serum ferritin (SF), a glycoprotein consist an inorganic iron compounds and the primary intracellular iron-storage protein in both prokaryotes and eukaryotes, keeps iron in a soluble and non-toxic form. In humans, it acts as a buffer against iron deficiency and iron overload. To date, some studies have suggested that there was abundant SF in tumor cells, and increasing SF expression levels can help diagnose malignant tumors. ,,, However, the clinical significance of SF in advanced NSCLC has not been well investigated.
In this study, we examined SF expression levels in blood specimens from patients with advanced NSCLC and healthy subjects using the electrochemiluminescence method. Additionally, we investigated the correlations between SF expression levels and clinicopathological parameters as well as subsequently evaluated whether or not it can be used to predict the efficacy of platinum-based therapies in advanced NSCLC patients.
| > Materials and methods|| |
50 patients were chemo-naive staged III or IV NSCLC, and the diagnoses of advanced NSCLC were based on conventional clinical, radiographic and histopathologic or cytological criteria. Each NSCLC patients was classified on the basis of the tumor-node-metastasis (TNM) classification of the international union against cancer (2009, Edition 7 th ). In addition, 63 healthy subjects (33 men and 30 women; age range, 19-75 years old; average age, 50.63 years old) were selected as the control group. Before chemotherapy, all patients who aged over 18 years had an eastern cooperative oncology group (ECOG) performance status (PS) of 0-2 and adequate bone marrow reserve and organ function, such as blood routine (hemoglobin >9 g/dl, neutrophil count >1.5 × 10 9 /L, and platelet count ≥ 100 × 10 9 /L), hepatic function (bilirubin <1.5 times the normal upper limit, aspartate aminotransferase and alanine aminotransferas <2.5 times the normal upper limit) renal function (creatinine clearance rate >50 ml/s), and normal electrocardiogram. Patients who underwent symptomatic brain metastases and previous chemotherapy were excluded. Furthermore, none of subjects enrolled in this study was treated with iron or suffered from other cancers, inflammatory and other known disorders affecting ferritin metabolism. The protocol of this study was approved by the ethics committee of our hospital, and all specimens were collected from patients and healthy subjects provided written informed consent in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice Guidelines.
Patients were treated with one of the following platinum-based combination chemotherapy: cisplatin, 75 mg/m 2 or carboplatin, AUC 5.0 on day 1; The conjunctive chemotherapy included the combination of platinum with taxanes (pralitaxel, 175 mg/m 2 or docetaxel, 75 mg/m 2 on day 1), gemcitabine (1000 mg/m 2 on days 1 and 8), or pemetrexed disodium (500 mg/m 2 on day 1). All drugs were given by intravenous drip. All combination chemotherapy took 21 days as a cycle, and the therapeutic efficacy was evaluated after two cycles for treatment by computed tomography scan. The response to treatment was evaluated in accordance with response evaluation criteria in solid tumors Committee: complete remission (CR), partial remission (PR), stable disease (SD), and progress disease. The overall response rate (ORR) was defined as the sum of CR and PR rates.
Serum samples collection and analyses
In all patients, a 5-ml venous blood samples was collected in a plain vial at diagnosis prior to treatment. Similarly, control blood samples were also obtained from 63 healthy subjects. Collected samples were kept at room temperature for a minimum of 30 min (and a maximum of 60 min), and serum samples were obtained after centrifugation at 4000 rpm at 4°C for 10 min from peripheral venous blood and immediately stored at −80°C until use. The expression levels of SF in blood specimens from patients with advanced NSCLC and healthy subjects were assayed using electrochemiluminescence method, and the reagent kit was purchased from Roche Co., Ltd. (Germany). According to the manufacturer's instructions, the normal range of the SF was identified at 15-200 ng/mL for men and 12-150 ng/mL for women. Subsequently, patients were divided into two groups with normal (15-200 ng/mL in men and 12-150 ng/mL in women) and high (>200 ng/mL in men and >150 ng/mL in women) SF expression levels groups.
All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 16.0 software (Chicago, Inc., USA). Quantitative and qualitative data were expressed as means ± SD or rate, respectively. Student's t-test and χ2 -test were used to compare the difference for means or rates between two or more than two groups. A P < 0.05 was considered statistically significant.
| > Results|| |
0 Patient characteristics
A total of 50 patients with advanced NSCLC patients were recruited for the study in our hospital from July 2010 to March 2012. Four patients were excluded as 3 patients suffered from unacceptable toxicity after the first cycle and refused further chemotherapy; the other 1 was unsuccessfully followed up. Therefore, the final analyses included 46 eligible patients (32 men and 14 women; age range, 30-76 years old; average age, 59.85 years old). Characteristics of patients and healthy subjects are listed in [Table 1].
|Table 1: Baseline characteristics of advanced NSCLC patients and healthy subjects |
Click here to view
Comparison of the SF levels of advanced NSCLC patients and healthy controls
We measured the expression levels of SF in blood samples from 46 patients with advanced NSCLC and 63 healthy subjects by the electrochemiluminescence method. In 46 advanced NSCLC patients, the mean level of SF was 280.38 ± 182.62 ng/ml in men and 163.76 ± 99.27 ng/ml in women. Additionally, the expression levels of SF were significantly higher in patients with advanced NSCLC (244.89 ± 169.60 ng/ml) than those in healthy subjects (145.04 ± 141.77 ng/mL) (t = −3.279, P = 0.001) [Figure 1].
|Figure 1: Comparison of the serum ferritin (SF) expression levels in patients with advanced non-small cell lung cancer (NSCLC) and healthy subjects. The expression levels of SF in patients with advanced NSCLC (244.89 ± 169.60 ng/ml) were significantly higher than that in healthy subjects (145.04 ± 141.77 ng/ml) (t=−3.279, P=0.001)|
Click here to view
Correlation between SF levels and clinicopathological factors in advanced NSCLC patients
Because SF expression levels of advanced NSCLC patients were higher than that of healthy subjects, we decided to determine whether SF expression levels correlate with any clinicopathological parameters. As shown in [Table 2], single factor analysis demonstrated that there was no significant difference between the SF expression levels of advanced NSCLC patients and sex, age, ECOG PS, smoking history, pathological type, tumor location and TNM stage (All P > 0.05).
|Table 2: Correlation between SF expression levels and patient's clinicopathologic factors |
Click here to view
Most patients (n = 20, 43.5%) had SF expression levels within the normal range, whereas 26 patients (56.5%) had higher values. The rate of high SF expression levels specimens was increasing while the degree of lymph node metastasis was higher and higher, and there were significant differences between any two groups of N1 (3/12, 25%), N2 (13/20, 65%) and N3 group (10/14, 71.4%) (F = 6.703, P = 0.035). In addition, the rate of high SF expression levels specimens for patients with distant metastasis was also significantly higher than for patients without distant metastasis (64.3% vs. 22.2%, χ2 = 4.852, P = 0.028) [Table 2].
Relationship SF levels with the efficacy of platinum-based chemotherapy for advanced NSCLC
In 46 advanced NSCLC patients, we compared the ORR between the normal and high SF expression levels groups according to the result of computed tomography scanning after patients received two cycles to platinum-based chemotherapy. Our study showed that the ORR was 57.1% (12/21) in normal SF expression levels group, which was significantly higher than that was 28% (7/25) in high SF expression levels group (χ2 = 3.998, P = 0.046) [Table 3].
|Table 3: Contrast of the efficacy to platinum-based chemotherapy for advanced NSCLC patients in normal and high SF expression levels group |
Click here to view
| > Discussion|| |
Ferritin is a 24-subunit protein that is composed of two types of subunits, termed H and L, which is a protein of crucial importance for human iron metabolism, which can be synthesised in most cells of the human body. , In healthy subjects, nearly all ferritin in plasma is produced by cells being engaged in iron recycling and iron storage, i.e. primarily hepatocytes and cells belonging to the reticuloendothelial system, ,, and the SF concentration reflects mobilizable body iron stores, being predominantly located in the liver, spleen and bone marrow. Under normal conditions, the ferritin is fewer and stable in serum. ,, However, SF is nonspecifically elevated in some conditions, including chronic disease, inflammation, and malignancy. , It has been reported that SF expression levels are higher in many malignancies, such as renal cancer,  colorectal cancer,  lung cancer,  prostatic cancer,  and so on. Similar to these findings, our results suggested that the SF expression levels of healthy subjects were obviously lower than that of patients with advanced NSCLC. Therefore, the elevated SF expression levels may be a common phenomenon in cancer patients.
The presence of high SF expression levels in cancer patients may be related to a multifactorial mechanism, such as enhanced growth and proliferation with increased necrosis and lysis of tumor cells and release of ferritin, malignant tumors cause ferric ions accumulating in cells of the reticuloendothelial system, resulting in ferritin synthesis.  Additionally, malignant tumors impacting the clearing ability of ferritin of liver cells and mediators of inflammation may result in increasing SF levels. ,,,
Singh  measured the expression levels of SF in 32 patients with untreated renal cell carcinoma and 32 normal controls, and found that the mean concentration of SF in cancer patients was significantly higher than that in healthy controls. In addition, the higher expression levels of SF were associated with advanced cancer stages and grades. Lorenzi  analyzed that the relationship between preoperative SF levels and clinicopathological parameters of patients with colorectal cancer. They found that patients with metastases had higher SF expression levels (but not significantly) compared to the group without secondary lesions. Kakari et al.  reported significantly higher SF expression levels in patients with extensive than with limited disease in patients with SCLC. Our data shown that the rate of high SF expression levels specimens was increasing while the degree of lymph node metastasis was higher and higher, and there were significant differences between any two groups of N1 (3/12, 25%), N2 (13/20, 65%) and N3 group (10/14, 71.4%) (F = 6.703, P = 0.035). In addition, the rate of high SF expression levels specimens was significantly higher in patients with distant metastasis than in those without distant metastasis (64.3% vs. 22.2%, χ2 = 4.852, P = 0.028). Collectively, these data support the idea that the assessment of SF expression in peripheral blood of advanced NSCLC patients might be helpful for predicting the tumor progression.
Several studies , showed that SF expression levels were associated with the survival of patients with advanced colorectal cancer and lung cancer. However, No previous study has tested the relationship SF expression levels with the efficacy of platinum-based chemotherapy for advanced NSCLC. The study showed that the ORR was 57.1% (12/21) in normal SF expression levels group, which was significantly higher than that of 28% (7/25) in high SF expression levels group (χ2 = 3.998, P = 0.046). Nevertheless, the findings need to be investigated further in a larger number of patients, in order to assess the value of this relationship.
Our study reveals that there exists a clinically relationship between the expression levels of SF and the tumor progression as well as the efficacy of platinum-based therapies for advanced NSCLC patients. However, it is necessary to perform progressive studies with larger samples for the internal mechanisms.
| > Acknowledgments|| |
This work was funded by grants from the Major Bidding Project Changzhou Health Bureau (ZD200810) provided by Dr. Mei Ji.
| > References|| |
Hirsh V, Glaspy J, Mainwaring P, Manegold C, Ramlau R, Eid JE. Phase II study of two dose schedules of C.E.R.A. (Continuous Erythropoietin Receptor Activator) in anemic patients with advanced non-small cell lung cancer (NSCLC) receiving chemotherapy. Trials 2007;8:8.
Matakidou A, El Galta R, Rudd MF, Webb EL, Bridle H, Eisen T, et al
. Prognostic significance of folate metabolism polymorphisms for lung cancer. Br J Cancer 2007;97:247-52.
Yildirim A, Meral M, Kaynar H, Polat H, Ucar EY. Relationship between serum levels of some acute-phase proteins and stage of disease and performance status in patients with lung cancer. Med Sci Monit 2007;13:CR195-200.
Wang W, Knovich MA, Coffman LG, Torti FM, Torti SV. Serum ferritin: Past, present and future. Biochim Biophys Acta 2010;1800:760-9.
Milman N, Pedersen LM. The serum ferritin concentration is a significant prognostic indicator of survival in primary lung cancer. Oncol Rep 2002;9:193-8.
Singh KJ, Singh SK, Suri A, Vijjan V, Goswami AK, Khullar M. Serum ferritin in renal cell carcinoma: Effect of tumor size, volume grade, and stage. Indian J Cancer 2005;42:197-200.
Oremek GM, Sauer-Eppel H, Bruzdziak TH. Value of tumour and inflammatory markers in lung cancer. Anticancer Res 2007;27:1911-5.
Munro HN, Linder MC. Ferritin: Structure, biosynthesis, and role in iron metabolism. Physiol Rev 1978;58:317-96.
Worwood, M.Serum ferritin. In: Jacobs A, Worwood M, editors. Iron in Biochemistry and Medicine II. London: Academic Press; 1980. p. 204-44.
Finch CA, Huebers HA, Cazzola M, Bergamaschi G, Belloti V, Storage iron. In: Albertini A, Arosio P, Chiancone E, Drysdale J, editors. Amsterdam: Elsevier Science; 1984. p. 3-21.
Walters GO, Miller FM, Worwood M. Serum ferritin concentration and iron stores in normal subjects. J Clin Pathol 1973;26:770-2.
Milman N, Pedersen NS, Visfeldt J. Serum ferritin in healthy Danes: Relation to marrow haemosiderin iron stores. Dan Med Bull 1983;30:115-20.
Bosch-Barrera J, Montero A, López-Picazo JM, García-Foncillas J, Ferrer M, Yuste JR, et al
. Adult onset Still's disease after first cycle of pemetrexed and gemcitabine for non-small cell lung cancer. Lung Cancer 2009;64:124-6.
Lorenzi M, Lorenzi B, Vernillo R. Serum ferritin in colorectal cancer patients and its prognostic evaluation. Int J Biol Markers 2006;21:235-41.
Kuvibidila SR, Gauthier T, Rayford W. Serum ferritin levels and transferrin saturation in men with prostate cancer. J Natl Med Assoc 2004;96:641-9.
Ulbrich EJ, Lebrecht A, Schneider I, Ludwig E, Koelbl H, Hefler LA. Serum parameters of iron metabolism in patients with breast cancer. Anticancer Res 2003;23:5107-9.
Rambod M, Kovesdy CP, Kalantar-Zadeh K. Combined high serum ferritin and low iron saturation in hemodialysis patients: The role of inflammation. Clin J Am Soc Nephrol 2008;3:1691-701.
Manousou P, Kalambokis G, Grillo F, Watkins J, Xirouchakis E, Pleguezuelo M, et al
. Serum ferritin is a discriminant marker for both fibrosis and inflammation in histologically proven non-alcoholic fatty liver disease patients. Liver Int 2011;31:730-9.
Kakari S, Stringou E, Toumbis M, Ferderigos AS, Poulaki E, Chondros K, et al
. Five tumor markers in lung cancer: Significance of total and "lipid"- bound sialic acid. Anticancer Res 1991;11:2107-10.
[Table 1], [Table 2], [Table 3]