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 confirmed that serum LDH could strongly predict survival in LS-SCLC [18–23]. However, none of these studies have identified 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, significantly 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 identified five 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 benefit 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 identified 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 significant 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 confirmed 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 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 significant for predicting survival in both limited and extensive disease. Further, Suzuki R et al. [29] also identified 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.