|Ahead of print publication
Evaluation of the relationship between serum ghrelin levels and cancer cachexia in patients with locally advanced nonsmall-cell lung cancer treated with chemoradiotherapy
Pelin Uysal1, Cigdem Usul Afsar2, Volkan Sozer3, Berrin Inanc4, Fulya Agaoglu1, Zeynep Gural1, Nevin Yaman Fazlıoglu5, Caglar Cuhadaroglu6, Hafize Uzun7
1 Department of Chest Diseases, Faculty of Medicine, Atakent Hospital, Mehmet Ali Aydınlar University, Tekirdag, Turkey
2 Department of Medical Oncology, Faculty of Medicine, Bakırkoy Hospital, Mehmet Ali Aydınlar University, Tekirdag, Turkey
3 Department of Biochemistry, Yildiz Technical University, Tekirdag, Turkey
4 Department of Radiation Oncology, İstanbul Education and Research Hospital, Tekirdag, Turkey
5 Department of Chest Diseases, Faculty of Medicine, Tekirdag Namık Kemal University, Tekirdag, Turkey
6 Department of Chest Diseases, Faculty of Medicine, Altunizade Hospital, Mehmet Ali Aydınlar University, Tekirdag, Turkey
7 Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey
|Date of Submission||03-Jan-2019|
|Date of Decision||23-May-2019|
|Date of Acceptance||22-Aug-2019|
|Date of Web Publication||16-May-2020|
Department of Biochemistry, Cerrahpasa Faculty of Medicine, Istanbul University-Cerrahpasa, 34303 Cerrahpasa, Istanbul
Source of Support: None, Conflict of Interest: None
Background: Ghrelin plays a role in mechanisms related to cancer progression – including cell proliferation, invasion and migration, and resistance to apoptosis in the cell lines from several cancers. We investigated the role of ghrelin levels in cancer cachexia-anorexia in patients with locally advanced nonsmall-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT).
Materials and Methods: This study involved 84 NSCLC patients who had received concomitant CRT. Blood ghrelin levels were compared before and 3 months after CRT. Meanwhile, changes in body weight of the patients were also investigated with changes in ghrelin levels before and after CRT.
Results: Ghrelin levels were significantly decreased in line with changes in patients' weights in patients receiving CRT (P < 0.001). Serum albumin levels and inflammatory-nutritional index were significantly decreased after radiotherapy (RT) (3.01 ± 0.40 g/dL, 0.38 ± 0.20) when compared with its baseline levels (3.40 ± 0.55 g/dL,P < 0.001; 0.86 ± 0.71,P < 0.001, respectively). Serum C-reactive protein levels were significantly increased after CRT (7.49 ± 6.53 mg/L) when compared with its baseline levels (9.54 ± 3.80 mg/L,P = 0.038). After RT, ghrelin levels in patients were positively correlated with body mass index (r = 0.830,P < 0.001) and albumin (r = 0.758,P < 0.001).
Conclusion: Ghrelin may play a role in the pathogenesis of weight loss in NSCLC patients. Ghrelin seems to be implicated in cancer-related weight loss. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia in patients with NSCLC. Results of this study need further evaluation as regards to its potential role as an adjuvant diagnostic or prognostic marker.
Keywords: Cancer cachexia, chemoradiotherapy, ghrelin, locally advanced nonsmall cell lung cancer
|How to cite this URL:|
Uysal P, Afsar CU, Sozer V, Inanc B, Agaoglu F, Gural Z, Fazlıoglu NY, Cuhadaroglu C, Uzun H. Evaluation of the relationship between serum ghrelin levels and cancer cachexia in patients with locally advanced nonsmall-cell lung cancer treated with chemoradiotherapy. J Can Res Ther [Epub ahead of print] [cited 2020 Aug 10]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=284487
| > Introduction|| |
Lung cancer is the most common cancer in all over the world and cancer-related death in both sexes. Lung cancer is classified as small-cell lung cancer (SCLC) and non-SCLC (NSCLC) in terms of treatment and prognosis. NSCLC is responsible for 80%–85% of all cases. Other factors that determine the prognosis of the disease are the stage of the tumor, gender, age, and weight loss. Anorexia and cachexia due to tumor characteristics affect patients' mortality, morbidity, and quality of life. In the course of life-threatening diseases such as cancer, more than 6% weight loss accompanied by hypercatabolic condition in the last 6 months is defined as cachexia.
Lung cancer and gastrointestinal system (GIS) cancers are two types of tumors which are the most common causes of cancer cachexia. Cancer cachexia which is one of the most frequent effects of malignancies may be responsible for more than 20% of cancer-related deaths and is associated with poor prognosis. Cancer cachexia is a complex, multifactorial metabolic condition involving weight loss and anorexia secondary to increased skeletal muscle and fat loss. The development of cachexia in a patient with cancer decreases the tolerance to treatment, consumes hope due to depressive mood, and decreases treatment response. Negative effects on treatment response and decrease in survival lead to deterioration of quality of life.
Ghrelin is a hormone which is called endogenous growth hormone-associated peptide, is released from the gastric mucosa, and has roles in regulating energy balance and nutrient uptake because it has a strong growth hormone-releasing effect independent of hypothalamus., Ghrelin levels are found to be increased in cachexia and anorexia but decreased in obesity. In literature, there are studies investigating the relationship between blood ghrelin levels and tumor cachexia in cancer patients., However, the number of studies performed in patients with lung cancer treated with chemoradiotherapy (CRT) is almost negligible. It is a known fact that tolerability of radiotherapy (RT) is difficult in these patients. In some studies, it has been reported that plasma ghrelin levels are increased and ghrelin levels are positively correlated with tumor necrosis factor-α and negatively correlated with body mass index (BMI) in patients with lung cancer and congestive heart failure., Anamorelin (ghrelin analog) has been used in oncology to treat cachexia in some types of tumors.,,
We planned this study to investigate the role of ghrelin levels in cancer cachexia-anorexia in patients with locally advanced NSCLC treated with CRT.
| > Materials and Methods|| |
The study was designed prospectively. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study. The study was approved by the Ethics Committee of Mehmet Ali Aydınlar University Medical Faculty, and written informed consent was obtained from each patient (ATADEK-2017/14). Detailed history was taken from all participants and physical examinations were performed.
The serum samples of the lung cancer patients who were referred to Acibadem Mehmet Ali Aydınlar University Medical Faculty, Department of Medical Oncology and Radiation Oncology, from May 2018 to November 2018 were obtained. All patients had histologically confirmed lung cancer diagnosis and had not received chemotherapy (CTx) or CRT within 6 months. The staging was determined according to the American Joint Committee on Cancer and International Union against Cancer staging systems. Stage IIIA and IIIB patients were included in the study, and all had taken curative CRT. Patients with morbid obesity, who had another malignancy, and who had surgery within 6 months were excluded.
The pretreatment evaluation included assessment of detailed clinical history and physical examination with a series of biochemistry tests. Those with Eastern Cooperative Oncology Group performance status 1 or less and appropriate blood chemistry tests received CTx which included different combinations of paclitaxel, cisplatin, carboplatin, vinblastine, etoposide, and pemetrexed with concurrent RT. The most commonly given dose for definitive RT was 60–70 Gy in 2 Gy fractions. Response to treatment was determined according to the revised RECIST criteria version 1.1 by the investigators and classified as follows: complete response, partial response (PR), stable disease (SD), or progressive disease (PD). Follow-up programs of lung cancer patients consisted of clinical, laboratory, and imaging techniques such as computed tomography (CT) scan or positron emission tomography/CT depending on which imaging methods were used at baseline and performed at 12-week intervals. Patients with either PR or SD were classified as responders, and patients with PD were considered as nonresponders.
Sample collection and preparation
For all persons, clinical parameters including routine biochemical parameters were measured using the standard protocols. Blood samples taken from patients were collected in ethylenediaminetetraacetic acid-containing tubes and in dry tubes without anticoagulants. Blood samples were taken in tubes after overnight fasting before RT, in the 5th week of RT (acute effects of RT were observed), and at 3 months after RT to investigate the chronic effects of RT. Serum and plasma parts were separated immediately and stored at −80°C until analysis.
Routine biochemical parameters were measured by the autoanalyzer (Hitachi Modular System, Roche Diagnostic, USA). Serum C-reactive protein (CRP) levels were measured by a nephelometric method (Immage 800 Beckman Coulter). Complete blood count parameters were obtained with automatic hematology analyzer (Siemens-Sysmex, Germany).
Inflammatory-nutritional index (INI) in patients was conducted to the laboratory for the measurement of serum albumin and CRP and subsequent calculation of the INI.
Measurement of plasma ghrelin (total) levels
Plasma ghrelin levels were measured by a commercially available competitive enzyme-linked immunoassay kit (Enzyme-Linked Immunosorbent Assay, Organon Teknika, Durham NC, USA). The coefficients of intra- and inter-assay variation were 5.1% (n = 20) and 6.0% (n = 20), respectively.
Statistical analysis was performed using the SPSS 20.0 (SPSS Inc., Chicago, IL, USA). All data were first checked for normality. Normally distributed continuous variables were presented as mean ± standard deviation and analyzed by one-way analysis of variance followed by Tukey's multiple comparison tests. The paired-sample t-tests were used to compare the means before and after CTx, in a single group of patients. Pearson's and Spearman's correlations were used for numerical and nominal data, respectively. Differences were considered statistically significant when the P < 0.05.
| > Results|| |
Characteristics of the 84 patients included NSCLC are shown in [Table 1]. Patients' stages were as follows; Stage IIIA (36%) and Stage IIIB (64%). Squamous histology was 41%, adenocarcinoma was 45%, and other was 14%. CTx and RT were given concurrently to 84 patients (100%), of whom 46 (55%) received cisplatin-based CTx and 38 (45%) received carboplatin-based CTx. Concurrent CT regimens were cisplatin 50 mg/m2 on days 1, 8, 29, and 36 with etoposide 50 mg/m2 on days 1–5 and 29–33; paclitaxel 50 mg/m2week ly with carboplatin AUC2 and for nonsquamous tumors only cisplatin 75 mg/m2 on day 1 with pemetrexed 500 mg/m2 on day 1 every 21 days for three cycles. All patients (n = 84; 100%) received a total radiation dose of at least 60 Gy (range 50–66 Gy) in 2.0 Gy daily fractions.
|Table 1: General characteristics and treatment modalities of nonsmall-cell lung cancer patients|
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Blood biochemical changes before and 3 months after CRT in patients with locally advanced NSCLC are shown in [Table 2]. Ghrelin levels (42.90 ± 10.55) after completion of CRT were lower than baseline ghrelin levels (63.10 ± 10.22) before the start of CRT in patients with locally advanced NSCLC. Neutrophil levels were not found to be significantly different between pre-CRT and 3 months after CRT. Serum albumin and INI levels were significantly decreased in after RT (3.01 ± 0.40 g/dL, 0.38 ± 0.20) when compared with its baseline levels (3.40 ± 0.55 g/dL, P < 0.001; 0.86 ± 0.71, P < 0.001, respectively). Serum CRP levels were significantly increased in after CRT (7.49 ± 6.53 mg/L) when compared with its baseline levels (9.54 ± 3.80 mg/L, P = 0.038).
|Table 2: Blood tests changes in preradiotherapy and 3 months after radiotherapy in nonsmall-cell lung cancer patients (n=84)|
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After CRT, ghrelin levels in patients were positively correlated with BMI (r = 0.830, P < 0.001) and albumin (r = 0.758, P < 0.001). After CRT, ghrelin levels were positively correlated with INI (r = 0.408, P < 0.001) and weak negatively correlated with CRP (for each comparison (r = 0.244, P < 0.01). Ghrelin levels were negatively correlated with the extent of weight changes (r = −0.33, P < 0.01).
| > Discussion|| |
Lung cancer is the most frequent cause of cancer-related deaths worldwide. Cancer cachexia is a multilayered syndrome which is a result of interaction between tumor cells and the host. Different cellular and soluble mediators are activated as a result of this interaction, and they trigger many metabolic and nutritional alterations.
Ghrelin has been characterized as a ligand of the growth hormone secretagogue receptor (GHSR), and it is a multifunctional peptide and plays a role in the regulation of energy balance, gastric acid release, appetite, insulin secretion, gastric motility, and the turnover of gastric and intestinal mucosa. Cancer is a multiplex disease in which different and many pathways are activated. Several critical factors are involved in cancer including proliferation, apoptosis, metastasis, angiogenesis, and drug resistance.
Although there is growing evidence that indicates the function of ghrelin in regulating a number of processes related to cancer progression, its primary role is not understood yet. Many cancer studies have observed expression of ghrelin and its receptor (GHSR1a, 1b, or both) in renal cell carcinoma, pancreatic cancer, breast cancer, gonadal cancer, gastric cancer, colorectal cancer, prostate cancer, thyroid cancer, lung cancer, ovarian cancer, and oral cancer.,,,, Ghrelin promotes growth of adipose tissue by activation of lipogenic pathways and can influence regulation of skeletal muscle mass by stimulation of insulin-like growth factor 1 production.
Ghrelin levels after completion of CRT were lower than baseline ghrelin levels before the start of CRT in patients with locally advanced NSCLC. Ghrelin has a protective factor against the toxic effects of chemotherapeutic agents. Therefore, ghrelin levels may be reduced. If we investigate the relationship between ghrelin and lung cancer, it has been found that ghrelin promotes human NSCLC cell proliferation through PI3K/Akt/mTOR/P70S6K and ERK signaling pathways. Anamorelin (a ghrelin analog) is found to be an important molecule which significantly increases lean body mass, and it is studied in patients with advanced NSCLC.,
Although there is evidence of anorexia and ghrelin relationship in literature, there are only limited data about RT effect, cancer anorexia-cachexia, and ghrelin relationship. For head and neck carcinomas, ghrelin is found to be an important peptide for the prevention of radiation-induced oral mucositis.,, Other cancer which is explored for ghrelin, appetite, and RT interaction is gastrointestinal cancer. In one study, it has been found that initiation of ghrelin analog in patients receiving CRT with GIS malignancies can both prevent weight loss by increasing appetite and decrease severity of inflammation.
Serum albumin level is commonly used to assess nutritional status. Malnutrition is related with hypoalbuminemia, and both are common in patients with NSCLC. In the current study, serum albumin levels after RT were lower than the baseline albumin levels before the initiation of therapy in patients with NSCLC. Albumin levels were related to the development of RT-induced toxicity. Arrieta et al. showed that CTx-induced toxicity in NSCLC patients treated with paclitaxel and cisplatin was associated with malnutrition and hypoalbuminemia. Wang et al. suggested that improvement and early assessment of the serum albumin level in patients with inoperable NSCLC may be beneficial effects after CTx. In the present study, ghrelin levels in patients with NSCLC were positively correlated with albumin. Our and other studies, showed that early nutritional assessment and support treatment might confer beneficial effects.
Systemic inflammation, which plays an important role in cachexia genesis and progression, should be evaluated, considering that it implies worsening in prognosis., Ghrelin levels in patients with NSCLC were positively correlated with INI in the current study. The present study showed that risk INI is a simple scoring system based on routine, cheap, and easily available laboratory tests.
In our study, we found that ghrelin levels decrease during CRT in lung cancer patients who have a positive correlation with the decrease of patients' weights and albumin levels. Cancer cachexia is closely linked to patients with NSCLC. RT is an inflammatory process which can decrease the appetite of patients and results in weight loss and cachexia. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia. There are many effects in the body as anabolic effects of ghrelin but need further investigation. This is an interesting finding, and it should be lightened with other studies.
| > Conclusion|| |
Ghrelin may play a role in the pathogenesis of weight loss in NSCLC patients. Ghrelin, cancer, and RT all together have a role in tumor-related anorexia-cachexia in patients with NSCLC. Results of this study need further evaluation as regards to its potential role as an adjuvant diagnostic or prognostic marker.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]