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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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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 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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Abbreviations

ATP:

Adenosine-triphosphate

BED:

Biologically effective dose

BM:

Brain metastasis

CCRT:

Concurrent chemoradiotherapy

CI:

Confidence interval

CR:

Complete response

CT:

Computed tomography

ECOG-PS:

Eastern Cooperative Oncology Group performance status

ECPFS:

Extracranial progression-free survival

ECT:

Emission computed tomography

ED:

Extensive disease

EP:

Etoposide and platinum

HR:

Hazard ratio

IMRT:

Intensity-modulated radiotherapy

IPFS:

Intracranial progression-free survival

LD:

Limited disease

LDH:

Lactate dehydrogenase

LS-SCLC:

Limited-stage small cell lung cancer

mLDH:

Maximal serum LDH levels

MRI:

Magnetic resonance imaging

NCCN:

National Comprehensive Cancer Network

NSCLC:

Non-small cell lung cancer

NSE:

Neuron-specific enolase

OS:

Overall survival

PCI:

Prophylactic cranial irradiation

PET:

Positron-emission tomography

PR:

Partial response

Pro-GRP:

Prosoma gastric secretin release peptide

PS:

Performance status

ROS:

Reactive oxygen species

SCLC:

Small cell lung cancer

SCRT:

Sequential chemotherapy and radiotherapy

SD:

Standard dose

TRT:

Thoracic radiotherapy

ULN:

Upper limit of normal value

WBRT:

Whole-brain radiation therapy

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Acknowledgements

We thank all members of the Department of Thoracic Radiation Oncology.

Funding

This work was supported by Natural Science Foundation of Zhejiang Province (no. LY20H160006).

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Authors and Affiliations

  1. Department of Radiation Oncology, Shaoxing People’s Hospital, 312000, Shaoxing, Zhejiang, China

    Jianjiang Liu, Dongping Wu & Bin Shen

  2. Department of Thoracic Radiotherapy, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China

    Mengyuan Chen, Xia Zhou, Guoqin Qiu, Yongling Ji, Xianghui Du & Yang Yang

  3. Zhejiang Key Laboratory of Radiation Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China

    Mengyuan Chen, Xia Zhou, Peng Zhang, Guoqin Qiu, Yongling Ji, Xianghui Du & Yang Yang

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  1. Jianjiang Liu
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Contributions

Jianjiang Liu and Dongping Wu are responsible for data collation and paper writing, Yang Yang is responsible for paper guidance and revision, and the remaining authors are responsible for paper revision.

Corresponding author

Correspondence to Yang Yang.

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Conflict of interest

J. Liu, D. Wu, B. Shen, M. Chen, X. Zhou, P. Zhang, G. Qiu, Y. Ji, X. Du, and Y. Yang declare that they have no competing interests.

Ethical standards

This study has been approved by the Ethics Committee of the Zhejiang Cancer Hospital. For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case. Consent for publication: All authors agree to publish.

Additional information

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.

Supplementary Information

66_2022_1977_MOESM1_ESM.tif

Supplementary figures (A, B, and C). Kaplan–Meier curves of groups of higher and normal LDH levels for extracranial progression-free survival (ECPFS). (A): Kaplan–Meier survival curve of ECPFS of higher mLDH and normal groups during treatment; (B): Kaplan–Meier survival curve of ECPFS of higher pretreatment LDH and normal groups; (C): Kaplan–Meier survival curve of ECPFS of elevated and deceased groups after comparison between pretreatment and maximum LDH level during treatment

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Liu, J., Wu, D., Shen, B. et al. Serum lactate dehydrogenase predicts brain metastasis and survival in limited-stage small cell lung cancer patients treated with thoracic radiotherapy and prophylactic cranial irradiation. Strahlenther Onkol 198, 1094–1104 (2022). https://doi.org/10.1007/s00066-022-01977-4

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  • DOI: https://doi.org/10.1007/s00066-022-01977-4

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