Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 9  |  Page : 336-340

Clinical evaluation of potential usefulness of serum lactate dehydrogenase level in follow-up of small cell lung cancer


Department of Respiratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Jian-An Huang
Department of Respiratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.168994

Rights and Permissions
 > Abstract 

Background: Lactate formation is upregulated in tumor cells by lactate dehydrogenase (LDH). High serum LDH level is linked to many malignancies with poorer survival, but tumor LDH has not been well investigated in small cell lung cancer (SCLC).
Patients and Methods: The study was performed in 120 cases of SCLC confirmed by pathological examination. The evaluation of treatment response to chemotherapy was based on response evaluation criteria in solid tumors criteria. The serum LDH levels were determined at diagnosis and follow-up visits. The distribution and differences in LDH change and the chemotherapeutic response rate was evaluated by using χ 2 tests. Receiver operating characteristic curves were calculated to select the cut-off level of an increase in LDH indicating significant progression. The correlation of time of serum LDH normalization, time-to-progression (TTP), and overall survival (OS) were analyzed by Pearson correlation. Influence of increasing LDH on survival was calculated using the Kaplan–Meier method.
Results: At diagnosis, significant differences in LDH levels were found between the groups with limited or extensive. In contrast to the limited-stage group, the extensive-stage group showed significantly decreased the level of LDH after the first-line chemotherapy. In patients whose diseases progressed, LDH levels were significantly higher in the last 1-month period preceding progression compared with the level at the progression. In the follow-up, we found that prolonging periods of serum LDH normalization were co-related to TTP and OS significantly. An increase in LDH by at least 51.5 U/L was found to be associated to a significantly higher probability of disease progression, and patients with initial increased LDH had a significantly reduced probability of survival.
Conclusions: LDH is validated for its potential usefulness as markers for monitoring treatment response in SCLC and also suitable for discriminating between disease and disease-free periods.

Keywords: Evaluation, lactate dehydrogenase, small cell lung cancer, stage


How to cite this article:
Chen C, Zhu YH, Huang JA. Clinical evaluation of potential usefulness of serum lactate dehydrogenase level in follow-up of small cell lung cancer. J Can Res Ther 2018;14, Suppl S2:336-40

How to cite this URL:
Chen C, Zhu YH, Huang JA. Clinical evaluation of potential usefulness of serum lactate dehydrogenase level in follow-up of small cell lung cancer. J Can Res Ther [serial online] 2018 [cited 2019 Jul 21];14:336-40. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/336/235351


 > Introduction Top


Small cell lung cancer (SCLC) accounts for approximate 15–20% of all lung cancer cases with two-third of patients presenting with extensive disease. Although SCLC is considered a chemotherapy-responsive disease, recognition of disease progression is an important decision point concerning intensive therapies.[1],[2] Accordingly, sensitive and reliable makers will provide useful information for treatment strategy of SCLC. Although neuron-specific enolase (NSE) has been preferentially used as a tumor marker of SCLC, clinical experiences have revealed several disadvantages of NSE including low positive rates in patients with SCLC and relatively high positive rates in patients with advanced non-SCLC (NSCLC).[3] Therefore, a more sensitive and specific disease progression marker of SCLC patients has been required.

Here, we have identif ied lactate dehydrogenase (LDH) as a suitable follow-up parameter. In a subgroup of patients, the decrease in LDH was accompanied by therapy response. In the follow-up, we found that in progressive SCLC patients, the LDH level will be increased compared to that of the remissive period, and an increase in LDH may predict disease progression. Importantly, a high LDH at diagnosis was found to be associated with decreased probability of survival.


 > Patients and Methods Top


Patients

During the period from 2007 to 2013, a total of 120 patients with SCLC were treated. A total of 61 cases were diagnosed as extensive-stage SCLC. All patients underwent medical histories-taking and physical examination including documentation of concomitant medications, performance status, history of smoking, laboratory tests (complete blood count, biochemistry profile, and urinalysis), and computed tomography scans of chest before the start of chemotherapy. Subjects with autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus), chronic infections (e.g., human immunodeficiency virus infection, tuberculosis), anticoagulant and antithrombotic drug use, or those who had received immunosuppressive treatment were excluded. The study was approved by Ethics Committee.

Treatment and evaluation

Ninety-three patients were assigned to treatment (cisplatin [75 mg/m 2] on days 1 to 2 or carboplatin [area under the curve 4.0–5.0] on day 1 and etoposide [75 mg/m 2] on days 1 to 5). The dose was adjusted as follows: The dose would be decreased 20% in one of the following events: (1) Absolute neutrophil count <1.5 × 109/L for 4 days or more, (2) thrombocytopenia associated with bleeding episode, (3) grade 3 or higher nonhematological toxicity including alopecia, nausea, and vomiting. Treatment cycles were repeated every 3–4 weeks with a maximum of six cycles administered. Some patients also received second-line chemotherapy, thoracic radiotherapy, and whole brain irradiation.

Tumor assessments were carried out once every two cycles by the response evaluation criteria in solid tumors criteria including complete response (CR), partial response (PR), stable disease (SD), and progressive disease. Tumor measurements were also made during follow-up.

Serial determinations of lactate dehydrogenase levels

The serum LDH levels (125–225 U/L) were determined at diagnosis and routine follow-up visits. For calculations, LDH levels from 1-month period were used for statistical calculations. To determine the statistical significance of the increase in LDH in patients with documented progression, the last 1-month period before progression were compared with real-time of progression. For control purpose, we also compared LDH levels in patients who did not show a progression. The time of serum LDH normalization, time-to-progression (TTP), and overall survival (OS) were calculated.

Statistical analysis

Statistical analysis was performed with SPSS statistical software (SPSS Inc., Chicago, IL). The distribution and differences in LDH change and response rate were evaluated by using χ 2 tests. Receiver operating characteristic (ROC) curves were calculated to select the cut-off level of an increase in LDH indicating progress significance. The correlation of time of serum LDH normalization, TTP, and OS were analyzed by Pearson coefficient. Survival time from the date of initiation of chemotherapy to the date of death was calculated using the Kaplan–Meier method. All tests were two-sided with a P < 0.05 being considered statistically significant.


 > Results Top


The lactate dehydrogenase level at diagnosis

A total of 120 eligible patients were enrolled. Baseline characteristics of the subjects were listed in [Table 1]. At diagnosis, the median LDH level in SCLC patients was 232 U/L (range: 130–3149 U/L). The median LDH level in limited-stage patients amounted to 206 U/L (range: 130–537.7 U/L), the high LDH levels were found in the expensive group with a median LDH level of 268 U/L (range: 158–3149 U/L). Significant differences in LDH levels were found when the limited and expensive groups were compared [Figure 1].
Table 1: Clinical characteristic of patients

Click here to view
Figure 1: Lactate dehydrogenase levels were determined in small cell lung cancer patients before and after therapy. (a) Differences in lactate dehydrogenase levels were found between limited and extensive-stage, (P < 0.05) at the diagnosis. After two cycles of chemotherapy, lactate dehydrogenase levels were significantly decreased in extensive group (b), but not in limited group (c)

Click here to view


Predictive value of the lactate dehydrogenase level to chemotherapy response

After two cycles of therapy, 77.4% of patients achieved clinic response (72/93, CR or PR or SD). In limited group (n = 49), 27 patients (55.1%) with a decrease in LDH showed a chemotherapy response, 6 patients (12.2%) with an increase in LDH showed a chemotherapy nonresponse, 9 patients (18.4%) with an increase in LDH showed a chemotherapy response, 7 patients (14.3%) with a decrease in LDH showed a chemotherapy nonresponse which indicated that decrease or increase of LDH could not predict the chemotherapy response in this subgroup [Figure 1], P > 0.05]. However in almost all of extensive cases, the decrease (33/44) or increase (6/44) in LDH was indicative of therapy response [P < 0.05, [Table 2].
Table 2: Correlation of LDH change with chemotherapy response after two cycle

Click here to view


Lactate dehydrogenase as a prognostic follow-up parameter

Following, we compared LDH levels in the 1-month periods preceding progression with those at the time of progression. In this assessment, the progression of SCLC was detectable for 173 times. An increase in LDH with progression (140/173), no increase in LDH but progression (33/173) was observed. The data showed that LDH levels were signif icantly increased shortly upon progression [Figure 2].
Figure 2: The predictive ability of increase of lactate dehydrogenase for the progression of the disease. (a) When compared to the last 1-month periods before progression, the lactate dehydrogenase levels were significantly increased at progression, (b) the optimal “lactate dehydrogenase increase cut-off” indicating progression of the disease was found to be 51.5 U/L. This criterion for sensitivity for disease progression was found to be 75.5%, and specificity was found to be 90.2%

Click here to view


As a control, an increase in LDH but nonprogress was detectable in for 76 times. To determine the optimal cut-off level for an increase in LDH indicating progress significance, ROC curves were calculated. Variations in LDH levels were computed as a function of the difference in time between measurements, and the upper 95th percentile values of LDH differences were determined. In these calculations, the optimal prognostic “LDH increase cut-off value” predicting progression of the disease was found to be 51.5 U/L. Hence, applying the cut-off criterion the sensitivity for disease progression was found to be 75.5% and specificity was found to be 90.2% [Figure 2]. The area under the ROC curves of the “LDH increase cut-off” was 0.91.

Prolonging of lactate dehydrogenase normalization correlated to time-to-progression and overall survival

Of the 120 patients, 76 were followed up for measuring TTP (range: 0–56 m); 38 for OS (range: 1–60 m); and the time of LDH normalization (range: 0–60 m). As shown in [Figure 3], based on the Pearson correlation coefficient, the data showed that the time of LDH normalization was positively correlated with TTP (r2 = 0.8821, P < 0.05) and OS (r2 = 0.9457, P < 0.05).
Figure 3: The correlation of the time of lactate dehydrogenase normalization with time-to-progression (a) and overall survival, (b) were assessed by Pearson efficient

Click here to view


Inf luence of increasing lactate dehydrogenase on survival

Of the 120 patients, 55 had follow-ups for 36 months for observing OS. Kaplan–Meier survival curve was completed according to the level of LDH. The median survival time for patients with increased LDH >250 U/L at diagnosis amounted to 8 months, and thus was significantly shorter when compared to patients with LDH <250 U/L (15 months, at diagnosis, P < 0.05). It is suggested that an elevated LDH at diagnosis was found to be associated with a decreased probability of survival [Figure 4], P < 0.05].
Figure 4: Influence of increasing lactate dehydrogenase on survival was elevated by Kaplan–Meier survival curves. Survival was determined in patients with initial lactate dehydrogenase <250 U/L and those with >250 U/L. The differences were found to be significant during a period of 36 months (P < 0.05)

Click here to view



 > Discussion Top


Cancer cells rely on anaerobic respiration for the conversion of glucose to lactate even under oxygen-sufficient conditions. This mechanism allows tumor cells to convert the majority of their glucose stores into lactate regardless of oxygen availability, shifting use of glucose metabolites from simple energy production to the promotion of accelerated cell growth and replication.[4],[5] For this reason, LDH may be used as a tumor biomarker, measuring LDH levels can be helpful in monitoring treatment for cancer.[6],[7],[8] At present, there is much evidence suggesting that the serum LDH levels reflect the extent of various neoplasms and serve as a nonspecific indicator of cellular death in many diseases.[9],[10],[11],[12],[13] Several studies have revealed that the serum LDH levels could individually predict the survival outcomes in various types of cancers including lung cancer.[14],[15],[16] However at the same time, it is not useful in identifying a specific kind of cancer.

In the present study, we determined serum levels of LDH were a potentially useful prognostic factor for SCLC patients. At first, differences in LDH levels were found between limited and extensive stage. In a limited group, chemotherapy did not significantly decreased LDH levels, partly because it was mostly close to normal levels for LDH. In contrast, in a subgroup of extensive patients, the decrease or increase in LDH was accompanied by signs of the clinic response or progression after two cycles of chemotherapy. Then, we expanded the data to the application of levels of LDH in predicting disease progression. Obviously, patients with disease progression were found to develop shortly higher LDH levels during their follow-up compared to stable stage. An increase in LDH by 51.5 U/L has an acceptable sensitivity and high specificity for a significantly higher probability of disease progression, when chest and extra-pulmonary scan was employed to confirm the prediction. During the whole observation period, normalization of serum LDH titer was consistently accurate in predicting treatment success in SCLC patients, and the time of LDH normalization was positively correlated with OS and TTP. In support, a significantly reduced probability of survival in patients with increasing LDH in the follow-up was seen.

It is known that other disorders can raise LDH levels such as heart failure, hypothyroidism, anemia, and infectious disease.[17],[18] In this study, complications of SCLC included respiratory failure and infection. Although noncancerous conditions could also raise LDH levels in this study, it is believed that the complication was signs of progression of the disease, in turn produced influence on survival.

Recently, LDH has been identified as a promising target in cancer treatments. Koukourakis et al. reported some benefit of vatalanib (vascular endothelial growth factor tyrosine kinase receptor inhibitor) in colorectal cancer patients presenting high serum LDH levels.[19] Yang et al. also examined the effects of oxamate, one classic inhibitor of LDH-A, in NSCLC cells.[20] The results provided useful clues for targeting LDH-A in NSCLC treatment and promising insights into the combined autophagy inhibition. Here, our data suggested that LDH is a potentially useful follow-up parameter in SCLC, which might assist in recognition of disease progression and thus help in risk stratif ication and early intervention.

Financial support and sponsorship

This work was supported by Project of Department of Health of Jiangsu Province (H201208) and Natural Science Foundation of Jiangsu Province University (13KJB320021) and Jiangsu Provincial Special Program of Medical Science (BL2012023)

Conflicts of interest

There are no conflicts of interest.

 
 > References Top

1.
Jackman DM, Johnson BE. Small-cell lung cancer. Lancet 2005;366:1385-96.  Back to cited text no. 1
[PUBMED]    
2.
Rodriguez E, Lilenbaum RC. Small cell lung cancer: past, present, and future. Curr Oncol Rep 2010;12:327-34.  Back to cited text no. 2
[PUBMED]    
3.
Molina R, Auge JM, Escudero JM, Marrades R, Viñolas N, Carcereny E, et al. Mucins CA 125, CA 19.9, CA 15.3 and TAG-72.3 as tumor markers in patients with lung cancer: comparison with CYFRA 21-1, CEA, SCC and NSE. Tumour Biol 2008;29:371-80.  Back to cited text no. 3
    
4.
Kim HS, Lee HE, Yang HK, Kim WH. High lactate dehydrogenase 5 expression correlates with high tumoral and stromal vascular endothelial growth factor expression in gastric cancer. Pathobiology 2014;81:78-85.  Back to cited text no. 4
[PUBMED]    
5.
Simaga S, Osmak M, Babic D, Sprem M, Vukelic B, Abramic M. Quantitative biochemical analysis of lactate dehydrogenase in human ovarian tissues: correlation with tumor grade. Int J Gynecol Cancer 2005;15:438-44.  Back to cited text no. 5
[PUBMED]    
6.
Xu HN, Kadlececk S, Profka H, Glickson JD, Rizi R, Li LZ. Is higher lactate an indicator of tumor metastatic risk? A pilot MRS study using hyperpolarized (13) C-pyruvate. Acad Radiol 2014;21:223-31.  Back to cited text no. 6
[PUBMED]    
7.
Koukourakis MI, Giatromanolaki A, Winter S, Leek R, Sivridis E, Harris AL. Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology 2009;77:285-92.  Back to cited text no. 7
[PUBMED]    
8.
Kolev Y, Uetake H, Takagi Y, Sugihara K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol 2008;15:2336-44.  Back to cited text no. 8
[PUBMED]    
9.
Tas F, Aydiner A, Demir C, Topuz E. Serum lactate dehydrogenase levels at presentation predict outcome of patients with limited-stage small-cell lung cancer. Am J Clin Oncol 2001;24:376-8.  Back to cited text no. 9
[PUBMED]    
10.
Koukourakis MI, Giatromanolaki A, Sivridis E, Bougioukas G, Didilis V, Gatter KC, et al. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 2003;89:877-85.  Back to cited text no. 10
[PUBMED]    
11.
Koukourakis MI, Giatromanolaki A, Sivridis E; Tumour and Angiogenesis Research Group. Lactate dehydrogenase isoenzymes 1 and 5: differential expression by neoplastic and stromal cells in non-small cell lung cancer and other epithelial malignant tumors. Tumour Biol 2003;24:199-202.  Back to cited text no. 11
[PUBMED]    
12.
Scartozzi M, Giampieri R, Maccaroni E, Del Prete M, Faloppi L, Bianconi M, et al. Pre-treatment lactate dehydrogenase levels as predictor of efficacy of first-line bevacizumab-based therapy in metastatic colorectal cancer patients. Br J Cancer 2012;106:799-804.  Back to cited text no. 12
[PUBMED]    
13.
Faloppi L, Scartozzi M, Bianconi M, Svegliati Baroni G, Toniutto P, Giampieri R, et al. The role of LDH serum levels in predicting global outcome in HCC patients treated with sorafenib: implications for clinical management. BMC Cancer 2014;14:110.  Back to cited text no. 13
[PUBMED]    
14.
Jeremic B, Milicic B, Dagovic A, Aleksandrovic J, Nikolic N. Pretreatment clinical prognostic factors in patients with stage IV non-small cell lung cancer (NSCLC) treated with chemotherapy. J Cancer Res Clin Oncol 2003;129:114-22.  Back to cited text no. 14
[PUBMED]    
15.
Cerny T, Blair V, Anderson H, Bramwell V, Thatcher N. Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients. Int J Cancer 1987;39:146-9.  Back to cited text no. 15
[PUBMED]    
16.
Byhardt RW, Hartz A, Libnoch JA, Hansen R, Cox JD. Prognostic influence of TNM staging and LDH levels in small cell carcinoma of the lung (SCCL). Int J Radiat Oncol Biol Phys 1986;12:771-7.  Back to cited text no. 16
[PUBMED]    
17.
Jovanovic S, Du Q, Sukhodub A, Jovanovic A. M-LDH physically associated with sarcolemmal K ATP channels mediates cytoprotection in heart embryonic H9C2 cells. Int J Biochem Cell Biol 2009;41:2295-301.  Back to cited text no. 17
    
18.
Uchide N, Ohyama K, Bessho T, Toyoda H. Lactate dehydrogenase leakage as a marker for apoptotic cell degradation induced by influenza virus infection in human fetal membrane cells. Intervirology 2009;52:164-73.  Back to cited text no. 18
[PUBMED]    
19.
Koukourakis MI, Giatromanolaki A, Sivridis E, Gatter KC, Trarbach T, Folprecht G, et al. Prognostic and predictive role of lactate dehydrogenase 5 expression in colorectal cancer patients treated with PTK787/ZK 222584 (vatalanib) antiangiogenic therapy. Clin Cancer Res 2011;17:4892-900.  Back to cited text no. 19
[PUBMED]    
20.
Yang Y, Su D, Zhao L, Zhang D, Xu J, Wan J, et al. Different effects of LDH-A inhibition by oxamate in non-small cell lung cancer cells. Oncotarget 2014;5:11886-96.  Back to cited text no. 20
[PUBMED]    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  >Abstract>Introduction>Patients and Methods>Results>Discussion>Article Figures>Article Tables
  In this article
>References

 Article Access Statistics
    Viewed1557    
    Printed11    
    Emailed0    
    PDF Downloaded60    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]