Changes of serum albumin level and systemic inflammatory response in inoperable non-small cell lung cancer patients after chemotherapy

Abstract

Aim: 

Hypoalbuminemia and systemic inflammatory response (SIR) parameters are a key role in the prognosis of cancer patients. We aim to investigate the changes of serum albumin level and SIR after chemotherapy, in patients with inoperable non-small cell lung cancer (NSCLC). The hypothesis is that improved serum albumin level may be beneficial to the SIR parameters and will reduce chemotherapy-induced toxicity.

Patients and Methods: 

Forty-nine stage III b or stage IV inoperable NSCLC patients were divided into two groups, depending on whether albumin administration was given before chemotherapy. The Karnofsky performance score (KPS), nutritional status including body mass index (BMI), and serum albumin level were evaluated. SIR was evaluated by investigating the changes of the C-reactive protein (CRP), calculating the neutrophil lymphocyte ratio (NLR), and the platelet lymphocyte ratio (PLR), before and after chemotherapy. The chemotherapy-induced toxicity was also evaluated.

Results: 

In the group of patients without albumin administration before chemotherapy, the serum albumin level was significantly decreased (P < 0.05) and the CRP level was significantly increased than before (P < 0.05). Significant correlations were noted between hypoalbuminemia and CRP increase (r = 0.533 P < 0.05), between hypoalbuminemia and NLR ≥5 (r = 0.574 P < 0.01) after chemotherapy. Patients with hypoalbuminemia developed more severe chemotherapy-induced toxicity symptoms. In the group of patients with albumin administration before chemotherapy, there was no significant difference in serum albumin level before and after chemotherapy (P > 0.05), even though the patients may have been malnourished or diagnosed with pleural effusions. There were no significant changes in the SIR parameters.

Conclusion: 

Early assessment of the serum albumin level in patients with inoperable NSCLC and their improvement in the serum albumin level may suggest that there are beneficial effects after chemotherapy.

INTRODUCTION

Chemotherapy is an important anti-cancer treatment in patients with non-small cell lung cancer (NSCLC), while chemotherapy-induced toxicity continues to be a severe problem. Nutritional status plays a key role in cancer patients, especially hypoalbuminemia.[¹²] Systemic inflammatory response (SIR) parameters, weight loss, and hypoalbuminemia were associated with malnutrition of cancer patients. In addition, SIR is an important tumor-stage-independent predictor.[³] Elevated preoperative inflammatory markers could predict a poor survival rate in resected NSCLC.[⁴] In this study, 49 stage IIIb or stage IV inoperable NSCLC patients were divided into two groups, depending on whether albumin administration was given before chemotherapy. We aim to investigate the proposal that an improvement in serum albumin level may lead to an improvement in the SIR parameters and a reduction of chemotherapy-induced toxicity in patients with inoperable NSCLC.

PATIENTS AND METHODS

Eligibility criteria

All patients gave a written informed consent. We evaluated 49 patients from our hospital, who were diagnosed with inoperable NSCLC, from January 2010 to June 2013.

Inclusion criteria

The inclusion criteria were as follows: Patients who were diagnosed with stage IIIb or stage IV inoperable NSCLC, verified by histopathology or pleural effusion cytology. The patients were eligible to receive chemotherapy for two cycles. Exclusion criteria included patients who could not complete the cycles of chemotherapy, patients with signs of infection, acute inflammatory processes, or severe liver and kidney disorders. The patients were divided into two groups depending on whether albumin administration was given before chemotherapy. Group 1: Patients without albumin administration before chemotherapy (n = 44); Group 2: Patients with albumin administration before chemotherapy (n = 5); for patients in this group whose serum albumin level was lower than 30.0 g/L, Human Albumin (CSL Behring GmbH, Germany) 10.0 g/d was given intravenously for three days until the serum albumin level reached to over 35.0 g/L.

Chemotherapy regimens

All patients received chemotherapy at the hospital, using gemcitabine (GEM) and cisplatin (DDP) combination chemotherapy for two cycles. Chemotherapy regimens: Gemcitabine 1600 mg IV, first and eighth days; Cisplatin 30 mg IV, first, second, and third days.

Study assessment

The Karnofsky performance score (KPS) was evaluated before and after chemotherapy. The nutrition status was evaluated by measuring the body mass index (BMI) and serum albumin level, BMI = weight (kg)/height squared (m²). BMI <20 kg/m² indicated that the subject was underweight; BMI <18.5 kg/m² suggested malnutrition. Serum albumin levels <35 g/L indicated malnutrition. The calculation data of absolute Neutrophil Lymphocyte Ratio (NLR) and Platelet Lymphocyte Ratio (PLR) was from the whole blood routine inspection results (including lymphocyte count), NLR = Neutrophils absolute count/Lymphocyte absolute count, and PLR = Platelet absolute count/Lymphocyte count. Venous blood samples were drawn from patients after an overnight fast. The blood biochemistry included C-reactive protein (CRP), and serum albumin level. All laboratory values were determined using routine automated analyzers. The occurrence of chemotherapy-induced toxicity was evaluated.

Statistical analyses

The SPSS 16.0 software was used for statistical analyses. Non-parametric analyses with the Kruskal-Wallis test and Mann-Whitney's test were used for KPS scores, with P values and a median value. Data were given as mean ± standard deviation. One-way analysis of variance (ANOVA) by the least significant difference (LSD) method was used to determine the differences of mean between more than two groups. The Paired-sample t-tests were used to compare the means before and after chemotherapy, in a single group of patients. Data were compared using the Pearson's correlation coefficients. Statistical significance was set at P < 0.05.

RESULTS

Demographics in the non-small cell lung cancer patients before chemotherapy

Among the 49 inoperable NSCLC patients, there were 30 males (61.22%) and 19 females (38.78%), the mean age was 68.48 ± 9.31 years (range 57~80 years), and 42 patients (85.71%) had a history of smoking. The median KPS was 70 (range 50~80) before chemotherapy, and after chemotherapy the median KPS decreased to 60 (range 40~80). There was no significant difference in KPS before and after chemotherapy (P > 0.05). Classified by the pathology, there were 25 cases of squamous carcinoma (51.02%), 20 cases of adenocarcinoma (40.82%), and four cases of carcinoma sareomatodes (8.16%) [Table 1].

Table 1: Demographics in NSCLC patients before chemotherapy

Changes in serum albumin level and systemic inflammatory response in non-small cell lung cancer patients without albumin administration before chemotherapy

Before chemotherapy, the serum albumin level was 36.31 ± 4.03 g/L, and after chemotherapy, the serum albumin level was significantly decreased to 32.51 ± 2.62 g/L (P < 0.05). Our results indicated that chemotherapy might have an effect on the serum albumin level.

Hypoalbuminemia and body mass index

There was no significant correlation between hypoalbuminemia and malnourishment (BMI <18.5 kg/m²) (P > 0.05). The mean BMI in this group of patients was 23.0 ± 3.7 kg/m². There were seven (15.90%) malnourished patients; five (11.36%) patients with malnourishment demonstrated hypoalbuminemia (albumin level ≤35 g/L) after chemotherapy. Among these five patients, three (6.82%) of them manifested severe gastrointestinal symptoms with albumin levels decreased to less than 30 g/L, after chemotherapy. When albumin administration (10 g/day, for three days) was given to the three patients, the chemotherapy toxic symptoms were significantly reduced. We suggest that for patients with malnourishment (BMI <18.5 kg/m²), more attention should be given to the serum albumin level after chemotherapy. The administration of albumin might alleviate chemotherapy-induced toxicity.

Hypoalbuminemia and pleural effusion

There were 30 patients (68.18%) with pleural effusions (n = 44). Eighteen patients (40.91%) developed hypoalbuminemia after chemotherapy, indicating that attention should be given to NSCLC patients with pleural effusion. These patients could be more susceptible to develop hypoalbuminemia after chemotherapy.

Hypoalbuminemia and the changes of systemic inflammatory response parameters

The SIR parameters include CRP, NLR, and PLR in inoperable NSCLC patients, after chemotherapy. Statistical analysis in the group without albumin administration before chemotherapy demonstrates that a significant correlation is noted between hypoalbuminemia and an increase of CRP (r = 0.533 P < 0.05), suggesting that patients with hypoalbuminemia will have an increase of CRP level. Hypoalbuminemia is significantly correlated with NLR ≥5 (r = 0.574 P < 0.01), NLR ≥ 5 is significantly correlated with PLR ≥ 250 (r = 0.467 P < 0.05), and NLR ≥5 is significantly associated with the decrease in total white blood cells (r = 0.428 P < 0.05) after chemotherapy, while NLR ≥5 has no significant relationship with BMI, age or gender. This indicates that patients with hypoalbuminemia may possibly be accompanied with NLR ≥5 or a decrease in total white blood cells. No correlation was found between PLR ≥250 and age, gender, BMI, or hypoalbuminemia (P > 0.05), suggesting that NLR ≥5 is more predictive than PLR ≥250 in NSCLC patients, after chemotherapy.

Chemotherapy-induced toxicity

The observed chemotherapy-induced toxic symptoms included, 34 patients (77.27%) with alopecia, 27 patients (61.36%) with gastrointestinal symptoms (nausea, vomiting, and decreased appetite), 20 patients (45.45%) with anemia, 14 patients (31.82%) with lymphopenia, and 14 patients (31.82%) with leucopenia. Significant decreases were noted in the total white blood cells, absolute lymphocyte count, and total platelets in the blood components in NSCLC patients, after chemotherapy (P < 0.05). There were no significant changes in the hemoglobin level after chemotherapy in this group of patients (P > 0.05) [Table 2]. This indicated that the chemotherapy regimens used in our study could have had an influence on the number of total white blood cells, absolute lymphocyte count, and total platelets. Patients with hypoalbuminemia manifested more severe chemotherapy-induced toxicity than those with a normal serum albumin level.

Table 2: Changes of biomarkers and blood components in NSCLC patients without albumin administration before chemotherapy

Changes of serum albumin level and systemic inflammatory response in non-small cell lung cancer patients with albumin administration before chemotherapy

Relationship of improved albumin level and chemotherapy

All the patients in this group (n = 5) developed hypoalbuminemia (with an albumin level ≤30 g/L), with a mean BMI of 20.61 ± 3.90 kg/m²; three (60.00%) patients were with malnourishment (BMI <18.5 kg/m²) and three patients (60.00%) with pleural effusions. To investigate whether the improved serum albumin level may have been beneficial to NSCLC patients, human albumin was given to this group of patients before chemotherapy. The serum albumin level was elevated from 29.09 ± 0.62 g/L to 36.50 ± 1.11 g/L after albumin administration. Although the serum albumin level was lower after chemotherapy (35.22 ± 3.12 g/L), there was no significant difference in the serum albumin level before and after chemotherapy (P > 0.05). Our results indicated that the improved serum albumin level before chemotherapy may be effective to maintain the serum albumin level during chemotherapy, even though the patients may have malnourishment or pleural effusion.

The improved serum albumin level and changes in SIR parameters

There was no significant increase in the CRP level before and after chemotherapy in this group (P > 0.05). All patients had both NLR <5 and PLR <250 either before or after chemotherapy, this suggested that the improved serum albumin level may have some effect on the SIR parameters in this group.

The improved serum albumin level and chemotherapy-induced toxicity

The observed chemotherapy-induced toxic symptoms were seen in the following cases - three patients (60.00%) developed alopecia; one patient (20.00%) had nausea and decreased appetite; two patients (40.00%) had lymphopenia; and three patients (60.00%) were with leucopenia. Significant decreases were noted in the total white blood cells, absolute lymphocyte count, and total platelets in the blood components (P < 0.05), while there was no significant change in the hemoglobin level after chemotherapy (P > 0.05) [Table 3]. This indicates that the improvement in serum albumin level can reduce chemotherapy-induced toxicity to some extent, but not overwhelm it.

Table 3: Changes of biomarkers and blood components in NSCLC patients with albumin administration before chemotherapy

DISCUSSION

Serum albumin has been described as an independent prognosticator of survival rate and an independent indicator for prognosis in cancer patients.[⁵⁶⁷] A systematic review of 29 epidemiological studies on the relationship between serum albumin and cancer survival rates showed that pretreatment with serum albumin is a predictor of cancer survival rates. It is also provides a useful prognostic meaning in cancer.[⁸] Of the 10 studies reviewed on lung cancer, all except one found higher serum albumin levels to be associated with a better survival rate.[⁹] Therefore, there is great significance in exploring the hypothesis that the improved serum albumin level might be beneficial to NSCLC patients.

We showed that the serum albumin level was significantly decreased after chemotherapy, especially in patients with malnourishment and malignant pleural effusion. In addition, we demonstrated that the improved serum albumin level by albumin administration before chemotherapy, could effectively maintain the serum albumin level after chemotherapy. Patients with hypoalbuminemia developed a more severe case of chemotherapy-induced toxicity symptoms. Serum albumin is the most abundant plasma protein and an important circulating carrier. Regimens consist of cisplatin, which is one of the most commonly used in first-line chemotherapy. Chemotherapy-induced toxicity is associated with anti-cancer agents. These anti-cancer agents can be transported by binding them with plasma proteins, mainly albumin; the latter is significant for its pharmacokinetic behavior. It also extensively binds to tissue proteins and its removal is primarily carried out by hepatic metabolism.[¹⁰¹¹¹²] Serum albumin also has the potential to antagonize multiple reperfusion injury mechanisms.[¹³¹⁴] We have demonstrated, in previous study, that albumin could have an impact on the stroke-related pathogenic factor (vascular endothelial growth factor (VEGF) for the formation of brain edema and reduce brain edema in its progression to an acute stage of cerebral ischemia.[¹⁵] Albumin may play the same role in NSCLC patients with pleural effusions in a pathological mechanism, elevating the serum albumin level may increase the plasma colloid osmotic pressure, prevent introvascular leakage, and reduce pleural effusion.

Significant correlations were noted between hypoalbuminemia and an increased level of CRP and between hypoalbuminemia and NLR ≥5, after chemotherapy. However, in this study, after improving the serum albumin level by albumin administration, no significant change was detected in the SIR parameters. SIR is commonly discovered with an elevated level of CRP. NLR and PLR have also been shown to have a prognostic value in cancer patients.[¹⁶¹⁷] The prognostic value of NLR has been established in bladder cancer.[¹⁸¹⁹] Elevated preoperative NLR and CRP can predict poor survival rate in resected NSCLC.[⁴] We have taken NLR ≥5 or PLR ≥250 as the SIR evaluation boundary value,[²⁰] and demonstrated that hypoalbuminemia is significantly associated with NLR ≥5, consistent with other reports.[²¹²²] We indicated that NLR ≥5 is more predictive than PLR ≥250. SIR is associated with poor prognosis in lung cancer. The development of SIR may be related to neuroendocrine metabolism, interleukin synthesis or acute phase protein production.[²³²⁴] We suggested that the improved serum albumin level may be related to the suppression of inflammation and SIR parameters. Also it may be related to their innate immune system and may be beneficial to inoperable NSCLC patients, after chemotherapy.

ACKNOWLEDGMENTS

This study is supported by the Tianjin Science and Technology Council Grant of China (No. 09JCYBJC11700), the Tianjin Educational and Scientific Grant (No. 20050107), and the Natural Science Foundation of China (NSFC, No. 81273009).