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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
Liu JianJiang ( jianjiang08@163.com )
Shaoxing People's Hospital
Wu Dongping
Shaoxing People's Hospital
Shen Bin
Shaoxing People's Hospital
Chen Mengyuan
Zhejiang Cancer Hospital Department of Radiation Oncology
Zhou Xia
Zhejiang Cancer Hospital Department of Radiation Oncology
Zhang Peng
Zhejiang Cancer Hospital Department of Radiation Oncology
Qiu Guoqin
Zhejiang Cancer Hospital Department of Radiation Oncology
Ji Yongling
Zhejiang Cancer Hospital Department of Radiation Oncology
Du Xianghui
Zhejiang Cancer Hospital Department of Radiation Oncology
Yang Yang
Zhejiang Cancer Hospital Department of Radiation Oncology https://orcid.org/0000-0001-6088-5435
Research Article
Keywords: predictor, lactate dehydrogenase, limited stage,small-cell lung cancer, brain metastasis,
prophylactic cranial irradiation
Posted Date: March 1st, 2022
DOI: https://doi.org/10.21203/rs.3.rs-1384711/v1
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Abstract
Background: Small cell lung cancer (SCLC) is characterized with high risk of brain metastasis and poor
survival. This study aimed to assess the prognostic role of 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, increased LDH level was dened 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, 95 had higher pretreatment LDH levels, and serum LDH levels were
increased in 95 patients during treatment. In patients with the normal and elevated mLDH groups, the 1-,
2- and 5-year IPFS rate 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 level, patients with increased mLDH level had higher cumulative risk
of intracranial metastasis [hazard ratio (HR),3.87; 95% condence 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 of LDH level at baseline or
changes between pretreatment level and maximum level during treatment failed to predict BMs or OS
with statistical signicance.
In the multivariate analyses, both mLDH during treatment [HR,3.53; 95% CI, 1.57-7.92; P = 0.002] and
age≥60 [HR, 2.46; 95% CI,1.22-4.94; P =0.012] were independently associated with worse IPFS. Factors
signicantly 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: mLDH level during treatment, but not pretreatment level 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.
Introduction
Small cell lung cancer (SCLC) is a highly metastatic and recalcitrant carcinoma. While worldwide data for
SCLC are not available, it is estimated that SCLC accounts for ~ 15% of lung cancers and causes more
than 210,000 deaths per year [1]. The survival outcome for this malignancy is poor, with a 2-year survival
rate of ~ 20–40% and < 10% for patients with limited disease (LD) and extensive disease (ED),
respectively [2, 3]. The most important prognostic factors in SCLC are disease stage, performance status
(PS) scores, prosoma gastric secretin release peptide (Pro-GRP), neuron specic enolase (NSE) and
lactate dehydrogenase (LDH) levels [4–6].Brain metastases (BMs) are common in SCLC, with ~ 10% of
patients presenting with brain metastases at the time of diagnosis and an additional 40–50%
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subsequently developing BMs [7–8]. Prophylactic cranial irradiation (PCI) is also part of the standard
management in most patients with non-metastatic SCLC who respond to initial treatment, as it
signicantly reduces the risk of BMs and improves survival [9–10]. Though PCI can obviously reduce the
risk of brain metastases, there are still 4% patients in one year, 30% in two years, 11.2–38% in two years
and 44% in four years developing BMs after PCI in LS-SCLC patients [11–14]. Therefore, it is meaningful
to nd a prognostic factor to predict BMs in these patients.
Lactate dehydrogenase (LDH), which regulates the processing of glucose to lactic acid, were found to be
commonly increased in cancer patients and correlated with poor clinical outcome and resistance to
therapy [15]. Recent study has indicated that LDH was a powerful predictor for overall survival (OS) after
Whole Brain Radiation Therapy (WBRT) in SCLC patients with BMs [16]. Therefore, it is supposed that
there is some clinical connections between the level of serum LDH and BMs in SCLC.
The purpose of the present study was to identify LDH as a potential factor predicting BMs and overall
survival (OS) of LS-SCLC after thoracic radiotherapy (TRT) and PCI.
Materials And Methods
Between November 2005 and October 2017, we identied 211 consecutive SCLC patients who underwent
TRT and PCI in Zhejiang Cancer Hospital. All patients had signed informed consent for TRT and PCI. We
excluded 6 patients who did not have serum LDH test before treatment or during treatment. In addition, 4
patients who had not completed PCI or TRT for various reasons and 3 patients who had underwent
surgery resection were excluded from this study. Furthermore, 1 patient who had stable disease after
chemotherapy and TRT were excluded. Therefore, a total of 197 patients were eligible for this analysis.
The characteristics of the study patients are shown in Table 1.
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Table 1
Summary of patient clinic pathological characteristics.
Clinicopathological
characteristic Maximal LDH level during
treatment < ULN (n = 102) Maximal LDH level during
treatment ≥ ULN (n = 95) P-
value*
Age (years) [median (range)] 55(27 ~ 73) 53(35–76) 0.76
< 60 72(36.5%) 65(33.0%)
≥ 60 30(15.2%) 30(15.2%)
Sex, n (%) 0.54
Male 78(39.6%) 73(37.1%)
Female 24(12.2%) 22(11.2%)
Smoking index (number/d ×
years), n (%) 0.89
< 400 44(22.3%) 40(20.3%)
≥ 400 58(29.4%) 55(27.9%)
ECOG-PS*, n (%) 0.15
0 22(11.2%) 24(12.2%)
1 72(36.5%) 69(35.0%)
2 8(4.1%) 2(1.0%)
TMN Stage at initial
diagnosis, n (%) 0.62
IA-IIB 30(15.2%) 26(13.2%)
IIIA 57(28.9%) 50(25.4%)
IIIB 15(7.6%) 19(9.6%)
Number of cycles of
chemotherapy completed, n
(%)
0.20
1 ~ 5 55(27.9%) 42(21.3%)
6 47(23.9%) 53(26.9%)
Chemotherapy regimen at
the initial treatment, n (%) 0.49
* P-value: Pearson’s χ2 test was used to calculated the p-value;*ECOG-PS = Eastern Cooperative
Oncology Group performance status, Chemo-RT = chemotherapy and radiotherapy, SCRT = sequential
chemotherapy and radiotherapy, CCRT = concurrent chemo-radiotherapy, PCI = prophylactic cranial
irradiation, SD = standard dose.
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Clinicopathological
characteristic Maximal LDH level during
treatment < ULN (n = 102) Maximal LDH level during
treatment ≥ ULN (n = 95) P-
value*
EP* 90(45.7%) 87(44.2%)
Non-EP 12(6.1%) 8(4.1%)
Combined model of Chemo-
RT *, n (%) 1.00
SCRT* 41(20.8%) 38(19.3%)
CCRT* 61(31.0%) 57(28.9%)
PCI* dose classication, n
(%) 0.46
Lower SD* (20Gy/10F or
24Gy/12F) 7(3.6%) 3(1.5%)
Medium SD(25Gy/10F or
30Gy/10-15F); 80(40.6%) 79(40.1%)
Higher SD(36Gy/18F or
40Gy/20F) 15(7.6%) 13(6.6%)
* P-value: Pearson’s χ2 test was used to calculated the p-value;*ECOG-PS = Eastern Cooperative
Oncology Group performance status, Chemo-RT = chemotherapy and radiotherapy, SCRT = sequential
chemotherapy and radiotherapy, CCRT = concurrent chemo-radiotherapy, PCI = prophylactic cranial
irradiation, SD = standard dose.
All patients had pathologically conrmed LS-SCLC without BMs, which was based on ndings from
computed tomography (CT) and/or magnetic resonance imaging (MRI). Serum LDH test data before
treatment and during treatment were available. The maximal serum LDH level (mLDH) was dened as the
maximal LDH level tested from the beginning of radiotherapy or chemotherapy to the end of PCI.IPFS
was dened as the interval from pathological diagnosis to the onset of brain metastases or death or the
last follow-up date. Diagnosis of intracranial progression mainly depends on imaging, but when the
symptoms of BMs is earlier than the imaging diagnosis, the day of symptoms of BMs is the cutoff point.
The upper limit of normal value (ULN) is 240 IU/L.
The median patient age was 55 years (range: 27–73 years) for the mLDH during treatment < ULN group
(the normal group) and 53 years (range: 35–76 years) for the mLDH ≥ ULN group (the elevated group); 78
(39.6%) patients in the normal group and 73 (37.1%) in the elevated group were male, while 24 (12.2%) in
the normal group and 22 (11.2%) in the elevated group were female. At the initial TMN staging in the
normal group, 30 (15.2%), 57 (28.9%) and 15 (7.6%) patients had IA-IIB, IIIA and IIIB stage, respectively. In
the elevated group, 26 (13.2%), 50 (25.4%) and 19 (9.6%) patients had IA-IIB, IIIA and IIIB stage,
respectively.
As indicated by an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1, 94
(47.7%) patients in the normal group and 93 (47.2%) in the elevated group had good general condition,
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while 8 (4.1%) in the normal group and 2 (1.0%) in the elevated group had a poor general condition
(ECOG-PS of 2). In addition, 55 (27.9%) patients in the normal group and 42 (21.3%) in the elevated group
completed 1 ~ 5 cycles of chemotherapy, while 47 (23.9%) in the normal group and 53 (26.9%) in the
elevated group completed 6 cycles of chemotherapy. 90 (45.7%) patients in the normal group and 87
(44.2%) in the elevated group were administrated chemotherapy of etoposide and platinum (EP) regime
while 12 (6.1%) in the normal group and 8 (4.1%) in the elevated group received non-EP regime. 41
(20.8%) patients in the normal group and 38 (19.3%) in the elevated group applied combined model of
sequential chemotherapy and radiotherapy (SCRT) while 61 (31.0%) patients in the normal group and 57
(28.9%) in the elevated group applied model of concurrent chemo-radiotherapy (CCRT).
All patients were typically treated with PCI at a photon energy of 6 MV and lateral-opposed treatment
elds that encompassed the entire brain. The prescribed dose was calculated at the isocenter of the
radiation elds based on daily treatments. 7 (3.6%),80 (40.6%) and 15 (7.6%) patients in the normal group
underwent PCI with lower standard dose(SD) (20Gy/10F or 24Gy/12F), medium SD (25Gy/10F or
30Gy/10-15F) and higher SD (36Gy/18F or 40Gy/20F), respectively. 3 (1.5%),79 (40.1%) and 13 (6.6%)
patients in the elevated group underwent PCI with lower SD, medium SD and higher SD, respectively. The
median biologically effective dose (BED) was 36 (range: 24–48) Gy for both groups, when prescription
doses were corrected to the BED using the linear–quadratic model with an assumed α/β ratio of 10 Gy for
tumor tissue. In addition, 180 (91.4%) patients underwent PCI with conventional radiotherapy technique
and 17 patients applied three-dimensional conformal radiotherapy or Intensity-modulated radiotherapy
(IMRT) technique. 43 (21.8%) patients underwent TRT with conventional radiotherapy technique and 154
(78.2%) patients applied three-dimensional conformal radiotherapy or Intensity-modulated radiotherapy
(IMRT) technique. Furthermore, 180 (91.4%) patients received PCI after chemotherapy and TRT completed
and 17 patients did it before chemotherapy and TRT completed.
Statistical analysis
Data are reported as the median (range) or number (percentage). Time-to-event analyses were performed
from the start of TRT to the emergence of the event. Descriptive statistical analyses were applied to
characterize the patients in the normal and elevated groups. Chi-squared test, which was carried out with
SPSS 22.0 software (IBM Corporation, Armonk, NY, USA), was adopted for the estimation of the
differences in clinical characteristics (smoking index, ECOG-PS, TMN stage, number of cycles of
chemotherapy, chemotherapy regimen, combined model of Chemo-RT and PCI dose) and demographic
variables. The Kaplan-Meier method and the log-rank test were used to compare the curves for
intracranial progression-free survival (IPFS) and OS. Potential prognostic factors were evaluated using
the Cox proportional hazards model, and the results were reported as hazard ratios (HRs) and the
corresponding 95% condence intervals (CIs). Signicant factors that were identied in the univariate
analyses were included in the multivariate model. GraphPad prism 7 software was used to draw the
forest gure of survival analysis. The differences were considered statistically signicant at P-values of <
0.05.
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Results
Patient Characteristics and Outcomes
Of the total patients, 95 had higher pretreatment LDH level (≥ 1 ULN), and serum LDH levels were
promoted in 95 of patients during treatment. As shown in Table 1,the patient distribution between the
normal group and the elevated group was well-balanced based on the prognostic factors, including age
(p = 0.76), sex (p = 0.54), smoking index (p = 0.89), ECOG-PS (p = 0.15), TMN stage (p = 0.62), number of
chemotherapy cycles (p = 0.20), chemotherapy regimen (p = 0.49), combined model of Chemo-RT (p =
1.00)and PCI dose (p = 0.46).
Of the eligible 197 patients, 99 died during the follow-up period, and 25 were lost to follow-up within 5
years after all treatments completed. The median follow-up time was 24.2 months (range: 2.3-108.2
months). After chemotherapy and TRT, 33 (16.8%) patients developed partial response (PR) and 164
(83.2%) developed complete response (CR). 32 (16.2%) patients developed intracranial failure after PCI,
and their median intracranial failure term was 14.6 months (range: 3.9–59.1 months). 105 (53.3%)
patients developed extracranial metastasis, and their median extracranial failure term was 9.5 months
(range: 3.3–70.4 months). Figure 1 shows IPFS and OS after TRT and PCI treatment. The 1-,2-, 3- and 5-
year IPFS rates were 94.0%, 83.5%, 79.5% and 75.2%, the 1-, 2- and 5-year OS were 84.7%, 62.6% and
46.5%,respectively.
mLDH during treatment is associated with higher risk of
brain metastasis and predicts IPFS
The upper limit of the normal range was chosen as the cutoff value for LDH based on the results of the
evaluation of various cut-off values. As shown in Table2, univariate analyses revealed that longer IPFS
was associated with mLDH during treatment < ULN (P < 0.01) and age < 60 years (P < 0.01). In patients
with the normal and elevated LDH groups, the 1-, 2- and 5-year IPFS rate were 96.7% vs. 90.1%, 91.7% vs.
73.8% and 87.8% vs. 61.0% (P < 0.01), respectively (as shown in Fig.2). Compared to those patients with
normal LDH level, patients with increased mLDH level had a higher cumulative risk of intracranial
metastasis [hazard ratio (HR), 3.87; 95% condence interval (CI), 1.73–8.63; P < 0.01]. No signicant
impact on IPFS after TRT and PCI was observed for pretreatment LDH level or changes between
pretreatment LDH and maximum during treatment level (as shown in Table2).
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Table 2
Univariate analysis for intracranial progression-free survival time (IPFS) and overall survival (OS).
Clinicopathological
parameter Patients
(n = 197)
Univariate analysis
2-year
IPFS
rate
HR (95%
CI) P 2-year
OS
rate
HR (95%
CI) P
Age (years) <
0.01 0.08
< 60 137(69.5%) 87.7% 1 65.5% 1
≥ 60 60(30.5%) 72.5% 2.5(1.2-
5.0) 55.9% 1.5(0.9–
2.3)
Sex 0.21 0.84
Female 47(23.9%) 89.4% 1 64.9% 1
Male 150(76.1%) 81.5% 1.8(0.7–
4.7) 61.8% 1.0(0.6–
1.7)
ECOG-PS 0.75 0.52
0, 1 187(94.9%) 83.3% 1 63.2% 1
2 10(5.1%) 87.5% 0.7(0.1–
5.3) 50.8% 1.3(0.5–
3.3)
Smoking index 0.97 0.66
< 400 84(42.6%) 85.2% 1 63.2% 1
≥ 400 113(57.4%) 82.0% 1.0(0.5-
2.0) 62.1% 1.1(0.7–
1.7)
TMN stage at the initial
diagnosis 0.50 0.02
IA-IIIA 163(82.7%) 84.8% 1 65.9% 1
IIIB 34(17.3%) 77.1% 1.4(0.6–
3.3) 47.1% 1.8(1.1–
2.9)
Number of chemotherapy
cycles at the initial
treatment
0.50 0.79
1–5 97(49.2%) 82.9% 1 63.3% 1
6 100(50.8%) 84.4% 1.3(0.6–
2.6) 62.1% 1.1(0.7–
1.6)
* BMs = brain metastases, EP = etoposide and platinum, TRT = thoracic radiotherapy, IMRT = intensity
modulated radiotherapy, BED = biological effective dose, LDH = lactate dehydrogenase, ULN = upper
limit of normal value.
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Clinicopathological
parameter Patients
(n = 197)
Univariate analysis
2-year
IPFS
rate
HR (95%
CI) P 2-year
OS
rate
HR (95%
CI) P
Chemotherapy regimen at
the initial treatment 0.27 0.09
EP* 177(89.8%) 81.8% 1 61.3% 1
Non-EP 20(10.1%) 95.0% 0.5(0.1–
1.9) 72.9% 0.5(0.2–
1.1)
TRT* technique 0.43 0.02
Three-dimensional
conformal radiotherapy or
IMRT*
154(78.2%) 84.8% 1 65.9% 1
Conventional radiotherapy 43(21.8%) 78.1% 1.4(0.6–
3.3) 50.8% 1.7(1.1–
2.5)
Combined model of Chemo-
RT 1 0.14
SCRT 79(40.1%) 82.9% 1 61.0% 1
CCRT 118(59.9%) 84.0% 1.0(0.5-
2.0) 64.1 0.7(0.5–
1.1)
Time of PCI 0.86 0.44
After chemotherapy and
TRT completed 180(91.4%) 84.4% 1 61.6% 1
Before chemotherapy and
TRT completed 17(8.6%) 76.9% 1.1(0.3–
3.7) 73.3% 1.3(0.7–
2.5)
PCI dose classication
(BED10*), Gy 0.40 0.55
≤ 31.25 84(42.6%) 82.0% 1 60.1% 1
> 31.25 113(57.4%) 84.5% 0.7(0.4–
1.5) 64.5% 1.1(0.7–
1.7)
Short-term ecacy 0.76 0.52
CR 164(83.2%) 83.6% 1 62.6% 1
PR 33(16.7%) 82.7% 0.8(0.3–
2.7) 57.2% 1.2(0.7–
2.2)
* BMs = brain metastases, EP = etoposide and platinum, TRT = thoracic radiotherapy, IMRT = intensity
modulated radiotherapy, BED = biological effective dose, LDH = lactate dehydrogenase, ULN = upper
limit of normal value.
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Clinicopathological
parameter Patients
(n = 197)
Univariate analysis
2-year
IPFS
rate
HR (95%
CI) P 2-year
OS
rate
HR (95%
CI) P
Maximal LDH* during
treatment <
0.01 <
0.01
< ULN* 102(51.8%) 91.7% 1 74.2% 1
≥ULN 95(48.2%) 73.8% 3.8(1.7–
8.6) 51.1% 2.6(1.7-
4.0)
LDH at baseline 0.48 0.10
< ULN 169(85.8%) 84.6% 1 65.0% 1
≥ULN 28(14.2%) 76.9% 1.4(0.6–
3.4) 50.0% 1.5(0.9–
2.6)
Changes between
pretreatment and maximum
during treatment LDH level
0.21 0.21
Decreased 40(20.3%) 87.2% 1 70.5% 1
Elevated 157(79.7%) 81.4% 1.9(0.7–
5.5) 60.8% 1.4(0.8–
2.6)
* BMs = brain metastases, EP = etoposide and platinum, TRT = thoracic radiotherapy, IMRT = intensity
modulated radiotherapy, BED = biological effective dose, LDH = lactate dehydrogenase, ULN = upper
limit of normal value.
The results of multivariate analyses are shown in Fig. 4. mLDH level during treatment ≥ ULN (P = 0.002)
and age ≥ 60 (P = 0.012) were identied as signicant independent predictors of poor IPFS.
Univariate and multivariate models for overall survival
As shown in Fig. 3, mLDH level during treatment was associated with worse survival signicantly, in
patients with the normal and elevated mLDH groups, the 1-, 2- and 5-year OS rate were 89.6% vs.
79.8%,74.2% vs. 51.1% and 58.2% vs. 29.4% (P < 0.01), respectively. However, no signicant impact on OS
after TRT and PCI was observed for pretreatment LDH levels or changes between pretreatment LDH and
maximum during treatment levels (Table 2). Compared to patients with normal LDH level, patients with
increased mLDH level had higher cumulative risk of worse overall survival [HR, 2.59; 95% CI, 1.67–4.04; P
< 0.01]. Factors associated with improved OS were: mLDH during treatment < ULN (P < 0.01), IA-IIIA stage
at the initial diagnosis (P = 0.02) and three dimensional conformal or IMRT applied in TRT (P = 0.02).
Other factors, such as age and chemotherapy regimens, were suspected predictors, although the p value
was slightly greater than 0.05 (Table 2).
Figure 4 was the OS results of multivariate analysis, in addition to the statistically signicant indicators in
the univariate analysis, other factors that might affect the results, such as age, sex, chemotherapy
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regimen and pre-treatment LDH, were also included in this analysis. As shown in Fig. 4, mLDH level
during treatment ≥ ULN (P = 0.002), conventional technique applied in TRT (P = 0.034) and IIIB stage at
the initial diagnosis after treatment (P = 0.029) were identied as signicant independent predictors of
poor OS.
Discussion
As a key enzyme in glycolysis, LDH has been reported to be enhanced in transformed cells and play a
vital role in tumor initiation, proliferation, invasion and metastasis [17]. Serum LDH has been proved to be
a powerful predictor in various cancers. Some studies also conrmed that serum LDH could strongly
predict survival in LS-SCLC [18–23]. However, none of these studies have identied LDH as a prognostic
indicator to predict brain metastasis and survival in LS-SCLC after PCI,or explored the relationship
between LDH and brain metastasis.
Elevated LDH level represents a high activity of glycolysis, which might promote cancer invasion and
metastasis. Some studies have indicated that energy metabolism plays an important role in cerebral
metastasis [24, 25]. Glycolysis inhibition might be a useful strategy to reduce the risk of cerebral
metastasis in the LS-SCLC. Our previous study [26] has revealed that oxamate, an inhibitor of LDH-A,
signicantly suppressed the proliferation of NSCLC cells, while it exerted a much lower toxicity in normal
cells. LDH-A inhibition resulted in ATP reduction and ROS (reactive oxygen species) burst in cancer cells,
which lead to apoptosis and G2/M arrest and increase radiosensitivity in NSCLC cells [27].
Up to now, we still have no idea whether some early stage (e.g. stage IA-IIB) SCLC patients with good
prognosis could avoid PCI. Our previous mate-analysis identied ve retrospective studies and included a
total of 1691 patients, 315 of them received PCI. For all the resected patients, PCI was associated with
improved overall survival (HR: 0.52, 95% CI: 0.33–0.82), and reduced brain metastasis risk (RR: 0.50,
95%CI: 0.32–0.78). However, with regard to p-stage I patients, no survival benet was brought by PCI (HR:
0.87, 95% CI: 0.34–2.24) [28]. Due to this study, NCCN guidelines 2019 version 1 did not recommend PCI
for p-stage I (T1-2N0M0) patients who had underwent radical surgery (category IIA). Our present study
showed that elevated LDH during treatment might indicated disease recurrence and brain metastasis. For
those patients, MRI is necessary. Recently, Anami S et al. evaluated 48 consecutive patients who
underwent WBRT for BMs from SCLC, and the results revealed the presence of symptoms due to BMs and
LDH values independently predicted prognosis [16]. Suzuki R et al. also identied high pretreatment
platelet counts (1.649, 95%CI 1.130–2.408, P = 0.010) and pretreatment LDH > 543U/L (HR 1.870, 95% CI
1.290–2.710, P = 0.001) were associated with increased rates of brain metastasis in patients with SCLC
with no evidence of brain disease at diagnosis [29]. These studies suggest that there are some clinical
links between BMs and elevated LDH. In the present study, elevated mLDH during treatment represent
signicant independent prognostic indicators for IPFS in LS-SCLC after TRT and PCI (HR for IPFS, 3.53;
95% CI, 1.57–7.92; P = 0.002). This further conrmed the connections between BMs and elevated LDH.
Thus, for the patients with elevated LDH during treatment, more positive treatments should be taken so
as to reduce the risk of BMs. At least, PCI, which has been proved strongly to improve IPFS, should been
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applied urgently. Others, such as drugs of LDH inhibitors or glycolysis inhibitors, can be used for BMs
prevention. At present, these drugs were lack, and randomized trials on the use of relevant drugs for BMs
prevention can be conducted.
In this study, pretreatment LDH level or changes between pretreatment and maximum during treatment
LDH level failed to independently predict IPFS and OS in our study. This is not consistent with the results
reported by Sagman U et al. and He M et al [21, 22]. In Sagman U’s study, patients with LS-SCLC and
elevated levels of pretreatment LDH manifested a higher relative death rate (1.63:1) when compared with
patients with LS-SCLC and LDH in the normal range (P = 0.0083), but the survival of patients with
extensive stage did not differ between those with normal and elevated levels of LDH (P = 0.273). In He M’s
study, the multivariate analysis revealed that pretreatment LDH ≥ 215.70 U/L was an independent
prognostic factor for poor survival (HR: 1.468, 95% CI: 1.069–2.017, P = 0.018); In the subgroup analysis,
pretreatment LDH level was signicant for predicting survival in both limited and extensive disease.
Further, Suzuki R et al. [29] also identied pretreatment LDH as a powerful prognostic factor for BMs in
patients with SCLC with no evidence of brain disease at diagnosis. Our results are different from others
reported in above studies, probably because in those studies, the sample of patients with SCLC included
all TMN stage or limited stage without PCI, and diverse samples may make difference in performance of
predicting BMs and survival. Others such as small patient sample and inconsistency of
clinicopathological parameters in various studies may also contribute to the different results.
In addition, the 1-,2-, 3- and 5-year IPFS rates were 94.0%, 83.5%, 79.5% and 75.2%, the 1-, 2- and 5-year OS
were 84.7%, 62.6% and 46.5%,respectively. The 2-year OS rate of our study was relatively high, which was
much better than the report of Kamran SC et al [30] (62.6% vs. 47%). Some possible reasons might be
explained as follows: Firstly,40% patient in their study have not underwent PCI while all of the patients in
our study completed PCI, and as we know PCI can improve 5.4% OS of LS-SCLC [31]; Secondly,18%
patients in their study have ECOG-PS of 2–3 while only 5.1% patients in our study have ECOG-PS of 2,and
ECOG-PS is also a potential prognosis. Thirdly, the proportion of stage IA-IIIA patients in our study is
much higher than it in their study (40% vs. 17.3%), and TMN stage is a very powerful predictor in many
studies as well as our study.
In conclusion, mLDH levels during treatment predicts brain metastasis and survival in LS-SCLC patients
treated with TRT and PCI, which may provide valuable information for identifying patients underwent PCI
for LS-SCLC who could have with poor survival outcomes. Future studies should develop a
comprehensive scoring tool to better help clinicians make decision whether to administrate PCI in LS-
SCLC patients.
Declarations
Acknowledgments
Page 14/20
This work was supported by the fund of Zhejiang Province National Natural Science Foundation (No.
LY20H160006).
Conict of interest statement
The authors declare no conicts of interest.
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Figures
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Figure 1
Intracranial progression-free survival and overall survival of 197 patients after PCI.
Page 18/20
Figure 2
Kaplan-Meier survival and cumulative risk curves between groups of higher and normal LDH groups for
IPFS.
(C): K-M survival curve of IPFS between higher mLDH and normal groups during treatment;
(D): Cumulative risk of IPFS between higher mLDH and normal groups during treatment;
(E): K-M survival curve of IPFS between higher pretreatment LDH and normal groups;
(F): K-M survival curve of IPFS between elevated group and decrease group after comparison between
pretreatment and maximum during treatment LDH level;
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Figure 3
Kaplan-Meier survival and cumulative risk curves between groups of higher and normal LDH groups for
OS.
(G): K-M survival curve of OS between higher mLDH and normal groups during treatment;
(H): Cumulative risk of OS between higher mLDH and normal groups during treatment;
(I): K-M survival curve of OS between higher pretreatment LDH and normal groups;
(J): K-M survival curve of OS between elevated group and decrease group after comparison between
pretreatment and maximum during treatment LDH level;
Page 20/20
Figure 4
Multivariate analysis for IPFS and OS.
