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Serum lactate dehydrogenase predicts brain metastasis and survival in limited-stage small cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation

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Jianjiang Liu
Jianjiang Liu
Jianjiang Liu
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Dongping Wu
Dongping Wu
Dongping Wu
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Bin Shen
Bin Shen
Bin Shen
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Mengyuan Chen
Mengyuan Chen
Mengyuan Chen
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Abstract and Figures

Background Small cell lung cancer (SCLC) is characterized by a high risk of brain metastasis and poor survival. This study aims to assess the prognostic role of lactate dehydrogenase (LDH) in limited-stage small cell lung cancer (LS-SCLC) treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI). Methods This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment were checked, and an increased LDH level was defined as more than 240 IU/ml. Clinical factors were tested for associations with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan–Meier method was used to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with survival. Results Of the total patients, 28 had higher pretreatment LDH levels and mLDH levels were increased in 95 patients during treatment. In patients in the normal and elevated mLDH groups, the 1‑, 2‑, and 5‑year IPFS rates were 96.7% vs. 90.1%, 91.7% vs. 73.8%, and 87.8% vs. 61.0% (P < 0.01), respectively. Compared to those with normal LDH levels, patients with increased mLDH levels had a higher cumulative risk of intracranial metastasis (hazard ratio [HR] 3.87; 95% confidence interval [CI] 1.73–8.63; P < 0.01) and worse overall survival (HR 2.59; 95% CI 1.67–4.04; P < 0.01). The factors LDH level at baseline or changes between pretreatment level and maximum level during treatment failed to predict brain metastases or OS with statistical significance. In the multivariate analyses, both mLDH during treatment (HR 3.53; 95% CI 1.57–7.92; P = 0.002) and patient age ≥ 60 (HR 2.46; 95% CI 1.22–4.94; P = 0.012) were independently associated with worse IPFS. Factors significantly associated with worse OS included mLDH during treatment (HR 2.45; 95% CI 1.56–3.86; P < 0.001), IIIB stage (HR 1.75; 95% CI 1.06–2.88; P = 0.029), and conventional radiotherapy applied in TRT (HR 1.66; 95% CI 1.04–2.65; P = 0.034). Conclusion The mLDH level during treatment predicts brain metastasis and survival in LS-SCLC patients treated with TRT and PCI, which may provide valuable information for identifying patients with poor survival outcomes and possible candidates for treatment intensification.
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ORIGINAL ARTICLE
https://doi.org/10.1007/s00066-022-01977-4
Strahlenther Onkol (2022) 198:1094–1104
Serum lactate dehydrogenase predicts brain metastasis and survival
in limited-stage small cell lung cancer patients treated with thoracic
radiotherapy and prophylactic cranial irradiation
Jianjiang Liu1· Dongping Wu1·BinShen
1·MengyuanChen
2,3 ·XiaZhou
2,3 · Peng Zhang3·GuoqinQiu
2,3 ·
Yongling Ji2,3 · Xianghui Du2,3 · Yang Yang2,3
Received: 9 March 2022 / Accepted: 20 June 2022 / Published online: 20 July 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022
Abstract
Background Small cell lung cancer (SCLC) is characterized by a high risk of brain metastasis and poor survival. This
study aims to assess the prognostic role of lactate dehydrogenase (LDH) in limited-stage small cell lung cancer (LS-SCLC)
treated with thoracic radiotherapy (TRT) and prophylactic cranial irradiation (PCI).
Methods This study retrospectively evaluated 197 consecutive patients who underwent TRT and PCI for LS-SCLC
between November 2005 and October 2017. Both pretreatment and maximal serum LDH levels (mLDH) during treatment
were checked, and an increased LDH level was defined as more than 240IU/ml. Clinical factors were tested for associations
with intracranial progression-free survival (IPFS) and overall survival (OS) after PCI. The Kaplan–Meier method was used
to calculate survival rates, and multivariate Cox regression analyses were carried out to identify variables associated with
survival.
The authors Jianjiang Liu and Dongping Wu contributed equally
to the manuscript.
Availability of supporting data The data of this study have been
recorded in the Science and Education Department of Zhejiang
Cancer Hospital in Excel format.
Jianjiang Liu
jianjiang08@163.com
Dongping Wu
wudp6666@163.com
Bin Shen
844535823@qq.com
Mengyuan Chen
chenmy@zjcc.org.cn
Xia Zhou
zhouxia@zjcc.org.cn
Peng Zhang
zpzjcc998@126.com
Guoqin Qiu
qiugq@zjcc.org.cn
Yongling Ji
jiyl@zjcc.org.cn
Xianghui Du
duxh@zjcc.org.cn
Yang Yang
yangyang@zjcc.org.cn
1Department of Radiation Oncology, Shaoxing People’s
Hospital, 312000 Shaoxing, Zhejiang, China
2Department of Thoracic Radiotherapy, Cancer Hospital of
the University of Chinese Academy of Sciences (Zhejiang
Cancer Hospital), Hangzhou, China
3Zhejiang Key Laboratory of Radiation Oncology, Cancer
Hospital of the University of Chinese Academy of Sciences
(Zhejiang Cancer Hospital), Hangzhou, China
K
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
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... In addition, LDH-A is important for the survival and proliferation of cancer cells [21]. Liu et al. have reported that serum LDH can be used to predict BM probability in SCLC after chest radiotherapy and prophylactic cranial irradiation [22]. Moreover, LDH levels can affect the treatment outcomes of patients with lung cancer. ...
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... [23][24][25] A host of studies found that elevated LDH level was associated with poor survival in various cancers. [26][27][28][29] In this study, univariate Cox regression analysis showed that higher serum LDH was a risk factor for the OS of OC patients; however, multivariate Cox regression analysis did not uncover that LDH was associated with the prognosis of OC. Limited sample size, different treatment strategies, and clinical heterogeneity may contribute to these inconsistent findings. ...
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Prognostic Value of the Gustave Roussy Immune Score in Lung Cancer: A Meta-Analysis
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Real-world predictors of survival in patients with limited-stage small-cell lung cancer in Manitoba, Canada
Article
Full-text available
  • Dec 2023
Background Although therapy for limited-stage small-cell lung cancer (LS-SCLC) is administered with curative intent, most patients relapse and eventually die of recurrent disease. Chemotherapy (CT) with concurrent radiotherapy (RT) remains the standard of care for LS-SCLC; however, this could evolve in the near future. Therefore, understanding the current prognostic factors associated with survival is essential. Objective This real-world analysis examines factors associated with long-term survival in patients with LS-SCLC treated with CT in Manitoba, Canada. Methods A retrospective cohort study was conducted using Manitoba Cancer Registry and CancerCare Manitoba records. Eligible patients were aged >18 years and had cytologically confirmed LS-SCLC diagnosed between January 1, 2004, and December 31, 2018, for which they received CT ± RT. Baseline patient, disease, and treatment characteristics and survival duration, characterized as short (<6 months), medium (6−24 months), and long term (>24 months), were extracted. Overall survival (OS) was estimated at one, two, and five years and assessed using Kaplan-Meier methods and Cox proportional hazards models. Results Over the 15-year study period, 304 patients met the eligibility criteria. Long-term survivors comprised 39.1% of the cohort; at diagnosis, this subgroup was younger, more likely to have Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0, and have normal lactate dehydrogenase, sodium, and hemoglobin levels. OS estimates for the entire cohort at one, two, and five years were 66%, 38%, and 18%, respectively. In the ECOG PS 0 subgroup, OS estimates at one, two, and five years were 85%, 52%, and 24%, respectively; OS estimates were 60%, 35%, and 17%, respectively, for ECOG PS 1−2 and were 47%, 23%, and 10%, respectively, for ECOG PS 3−4. OS was significantly higher among patients with normal serum sodium and hemoglobin levels than those with abnormal levels. Univariable hazard regression models found that ECOG PS, age at diagnosis, receipt of prophylactic cranial irradiation (PCI), and thoracic RT were associated with survival. On multivariable hazard regression, ECOG PS and receipt of PCI were associated with survival. Conclusion Survival for greater than two years in patients with LS-SCLC treated with CT ± RT was associated with ECOG PS and receipt of PCI.
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Value of pretreatment serum lactate dehydrogenase as a prognostic and predictive factor for small‐cell lung cancer patients treated with first‐line platinum‐containing chemotherapy
Article
Full-text available
  • Nov 2021
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Targeting lactate dehydrogenase a improves radiotherapy efficacy in non-small cell lung cancer: from bedside to bench
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Full-text available
  • Apr 2021
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The usefulness of lactate dehydrogenase measurements in current oncological practice
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Full-text available
  • Dec 2020
One of the hallmarks of cancer cells is increased energy requirements associated with the higher rate of cellular proliferative activity. Metabolic changes in rapidly dividing cancer cells are closely associated with increased uptake of glucose and abnormal activity of lactate dehydrogenase (LDH), which regulates the processing of glucose to lactic acid. As serum LDH levels were found to be commonly increased in cancer patients and correlated with poor clinical outcome and resistance to therapy, the determination of LDH has become a standard supportive tool in diagnosing cancers or monitoring the effects of cancer treatment. The aim of this review is to summarize the current knowledge about methods and the practical utility for measuring both the total LDH and LDH isoenzymatic activities in the diagnosis, prognosis and prediction of cancer diseases.
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Rates of Overall Survival and Intracranial Control in the Magnetic Resonance Imaging Era for Patients With Limited-Stage Small Cell Lung Cancer With and Without Prophylactic Cranial Irradiation
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Full-text available
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  • Jan 2020
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Full-text available
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on population‐based cancer occurrence. Incidence data (through 2016) were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data (through 2017) were collected by the National Center for Health Statistics. In 2020, 1,806,590 new cancer cases and 606,520 cancer deaths are projected to occur in the United States. The cancer death rate rose until 1991, then fell continuously through 2017, resulting in an overall decline of 29% that translates into an estimated 2.9 million fewer cancer deaths than would have occurred if peak rates had persisted. This progress is driven by long‐term declines in death rates for the 4 leading cancers (lung, colorectal, breast, prostate); however, over the past decade (2008‐2017), reductions slowed for female breast and colorectal cancers, and halted for prostate cancer. In contrast, declines accelerated for lung cancer, from 3% annually during 2008 through 2013 to 5% during 2013 through 2017 in men and from 2% to almost 4% in women, spurring the largest ever single‐year drop in overall cancer mortality of 2.2% from 2016 to 2017. Yet lung cancer still caused more deaths in 2017 than breast, prostate, colorectal, and brain cancers combined. Recent mortality declines were also dramatic for melanoma of the skin in the wake of US Food and Drug Administration approval of new therapies for metastatic disease, escalating to 7% annually during 2013 through 2017 from 1% during 2006 through 2010 in men and women aged 50 to 64 years and from 2% to 3% in those aged 20 to 49 years; annual declines of 5% to 6% in individuals aged 65 years and older are particularly striking because rates in this age group were increasing prior to 2013. It is also notable that long‐term rapid increases in liver cancer mortality have attenuated in women and stabilized in men. In summary, slowing momentum for some cancers amenable to early detection is juxtaposed with notable gains for other common cancers.
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Outcomes of prophylactic cranial irradiation in patients with small cell lung cancer in the modern era of baseline magnetic resonance imaging of the brain
Article
  • Sep 2021
Background For decades many patients with small cell lung cancer (SCLC) have been offered prophylactic cranial irradiation (PCI) to prevent brain metastases (BM). However, the role of PCI is debated in the modern era of increased brain magnetic resonance imaging (MRI) availability. BM in SCLC patients may respond to chemotherapy, and if a negative MRI is used in the decision to use of PCI in the treatment strategy, the timing of brain MRI may be crucial when evaluating the effect of PCI. This retrospective study investigates the impact of PCI outcomes in patients with SCLC staged with brain MRI prior to chemotherapy. Materials and methods This study included 245 patients diagnosed SCLC/mixed NSCLC-SCLC treated between 2012 and 2019. The population was analyzed separately for limited disease (LS-SCLC) and extensive disease (ES-SCLC). Patients were divided into groups based on baseline brain MRI prior to chemotherapy and PCI. The primary endpoint was time to symptomatic BM. Secondary endpoints were overall survival (OS), and progression-free survival (PFS). Results In patients with LS-SCLC staged with brain MRI the probability of developing symptomatic BM at one year was 4% vs. 22% (p < 0.05), median OS was 55 vs. 24 months (p < 0.05), and median PFS was 30 vs. 10 months (p < 0.05) with and without PCI, respectively. No differences in probability of symptomatic BM and survival outcomes were observed in ES-SCLC. In a multivariate regression analysis, no variables were statistically significant associated with the risk of developing symptomatic BM in patients with LS-SCLC and ES-SCLC. For patients with ES-SCLC staged with brain MRI, PS (HR = 3.33, CI; 1.41–7.89, p < 0.05) was associated with poor survival. Conclusion This study found that PCI in LS-SCLC patients staged with brain MRI had lower incidence of symptomatic BM and improved survival outcomes suggesting PCI as standard of care. Similar benefit of PCI in patients with ES-SCLC was not found.
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Estimation of MU for Glucose in Human Serum Using Bottom-up Approach
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  • Dec 2020
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Background: Glucose is an important material in human metabolism. The establishment of glucose reference measurement procedures and to study the uncertainties of measurement is of great significance. Linear fitting and dilution of reference material were used in the measurement of glucose concentration and they are common operations in daily work. Investigation of the measurement uncertainty of these operations will be of important significance to clinical laboratory medicine. However, in the field of laboratory medicine, related research was rarely reported. Methods: The spectrometric quantification of glucose is an application of the enzymatic reference method with hexokinase. The sources of uncertainty in the measurement process were analyzed. The measurement uncertainties in the study were evaluated according to GUF method and the method introduced by Quantifying Uncertainty in Analytical Measurement (QUAM) was also applied in the evaluation of the measurement of linear fitting. Results: The standard curve was built successfully according to the measurement procedure recommended by the CDC and the linear equation was y = 0.000807x + 0.001213 (R2 = 0.999179). The measurement uncertainty of glucose in the sample was 0.450,408 mmol/L. Conclusions: The method for the determination of serum glucose concentration by hexokinase in our laboratory has been successfully established. The measurement uncertainty was consistent with the GUF method and the method introduced by Quantifying Uncertainty in Analytical Measurement (QUAM) in the process of linear fitting when the glucose concentration was measured by the reference method (hexokinase method).
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Prognostic Significance of Combined Biomarkers in Small Cell Lung Cancer
Article
  • Sep 2020
  • CLIN LAB
Background: Small cell lung cancer is an aggressive form of lung cancer with poor prognosis. Combined serum biomarkers may give us more information and predictive value. Methods: We retrospectively analyzed data and samples collected from 120 small cell lung cancer patients who had undergone surgery in Tianjin Medical University Cancer Institute and Hospital between June 2014 and November 2016. Correlations between serum biomarker levels and survival parameters were analyzed and prognostic factors were identified. Results: By univariate analysis, limited disease (p < 0.001), more than 4 cycles of first line chemotherapy (p = 0.002), thoracic irradiation (p < 0.001), PCI (p = 0.013)), higher SCCA level (p = 0.058), and normal LDH level (p = 0.027) were significantly correlated with a good PFS. By multivariate analysis, clinical stage, number of chemotherapy cycles, thoracic irradiation, PCI, and SCCA level were independent prognostic factors for PFS. Higher ProGRP or NSE level with higher LDH, higher NSE with higher D-dimer had poor prognostic index. Conclusions: We observed that NSE, CEA, and CYFRA 21-1 were closely associated with tumor burden. The combination of NSE and ProGRP with LDH and D-dimer worked as prognostic factors for tumor progression in SCLC patients.
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Selective application of neuroendocrine markers in the diagnosis and treatment of small cell lung cancer
Article
  • Jun 2020
  • CLIN CHIM ACTA
Aims Here, we explored the potential application and selection of neuroendocrine biomarkers in the diagnosis and treatment of small cell lung cancer. Methods We retrospectively analyzed 118 patients with small cell lung cancer (SCLC), 166 patients with non-small cell lung cancer (NSCLC), 33 patients with benign lung disease (BLD), and 200 healthy individuals admitted to Zhejiang Provincial People’s Hospital between January 1, 2015 and May 31, 2019. All the patients were newly diagnosed with either SCLC, NSCLC, or BLD and previously untreated. Peripheral blood levels of ProGRP, NSE, CEA, and CYFRA21-1 were analyzed during the follow-up treatment, and 2-fold reference intervals were defined as effective elevation. We used paired results to analyze the diagnostic efficiency of proGRP and NSE on SCLC. Results In the 118 SCLC patients, proGRP levels were significantly higher compared with NSE levels. The diagnostic efficiencies of NSE and ProGRP for SCLC were 0.8554 and 0.9053, respectively. The combined diagnostic efficiency (0.9426) was higher relative to NSE, but there was no significant difference compared with proGRP. The effective elevation rate of proGRP was 45.3% higher than that of NSE in the limited stage of SCLC. In the extensive disease of SCLC patients, 70.7 % cases had more than 10-fold increase in proGRP value, whereas 56.9 % cases had less than 5-fold increase in NSE value. Compared with pre-treatment, the median concentrations of proGRP increased by 204.0% higher than that of NSE (71.3%) in the progressive group. Besides, the dynamic change in imaging characteristics and tumor size had a strong correlation with the levels of proGRP. Significance ProGRP is a reliable neuroendocrine biomarker in SCLC. The effective elevation of proGRP has a potential diagnostic and efficacy value in the evaluation of SCLC. However, the combined detection of proGRP and NSE does not significantly improve the diagnosis of lung cancer.
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