|Year : 2018 | Volume
| Issue : 9 | Page : 336-340
Clinical evaluation of potential usefulness of serum lactate dehydrogenase level in follow-up of small cell lung cancer
Cheng Chen, Ye-Han Zhu, Jian-An Huang
Department of Respiratory, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
|Date of Web Publication||29-Jun-2018|
Department of Respiratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou 215006
Source of Support: None, Conflict of Interest: None
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 18];14:336-40. Available from: http://www.cancerjournal.net/text.asp?2018/14/9/336/235351
| > Introduction|| |
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., 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). 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|| |
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 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|| |
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].
|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)|
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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|
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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%|
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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|
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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)|
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| > Discussion|| |
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., For this reason, LDH may be used as a tumor biomarker, measuring LDH levels can be helpful in monitoring treatment for cancer.,, 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.,,,, Several studies have revealed that the serum LDH levels could individually predict the survival outcomes in various types of cancers including lung cancer.,, 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., 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. Yang et al. also examined the effects of oxamate, one classic inhibitor of LDH-A, in NSCLC cells. 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.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]