The Value Of Lactate Dehydrogenase In Metastatic Nasopharyngeal Carcinoma

Background:Nasopharyngeal carcinoma（NPC）is a distinct entity of head and neck cancer that is invariably associated with Epstein-Barr virus（EBV）infection in the endemic parts of the world.While it is exquisitely sensitive to platinum-based chemotherapy（CT）and radiotherapy（RT）,NPC still has a propensity for distant metastatic relapses,which occur in approximately 20%of patients treated with intensity-modulated RT（IMRT）.Nowadays,the metastasis has become the main pattern of treatment failure in NPC.Conventionally,patients on treatment are monitored every two to three cycles with interval imaging.Response to treatment is evaluated using RECIST（Response Evaluation Criteria in Solid Tumours）,and depending on the radiological/clinical response,patients are either continued on the existing therapy or switched to second-line regimes.Nonetheless,gross responses on imaging and clinical examination are often not an accurate indication of the tumour clonal sensitivity to the treatment and progressive disease predicting.Thus,there is a clinical need for more sensitive biomarkers to detect early responses to CT,which would in turn offer the opportunity for the treating physician to adapt treatment intensity,accordingly.Lactate dehydrogenase（LDH）has been established as a prognostic biomarker for the endemic variant of NPC.It has long been demonstrated as a significantly parameter associated with tumour burden and prognosis.Moreover,patients with low LDH levels at the end of therapy showing better potential on prognostic risk predicting.In this regard,we hypothesize if LDH could remedy the limitation of radiological imaging,furthermore,if the dynamic variation of LDH could assess the prognostic risk better.Purpose:Here,1)we investigate if serial changes in LDH level between CT cycles are associated with tumour response and determined if early trends of this marker predict subsequent progressive disease.2)to assess the prognostic value of LDH kinetics in the treatment of metastatic NPC（mNPC）.Methods:Medical records of 670 mNPC patients diagnosed between June2009 and December 2016 were screened from an NPC-specific database at the Guangxi Medical University Cancer Hospital,including recurrent or treatment-na（?）ve mNPC.All patients had received at least two cycles of platinum-based doublet or triplet CT as first-line treatment regimen.1)For patients with serial assessment of LDH prior to every cycle of chemotherapy（CT1-6）.response was assessed after every two cycles of CT by RECIST.Tests of association were performed between baseline and longitudinal LDH levels with tumour response.2)For patients with LDH assessment prior to every two cycles of CT,the association between dynamic change of LDH and prognosis were evaluated.Results:1)A total of 158 patients were permitted,including 77 recurrent and81 treatment-na（?）ve mNPC.High baseline LDH was associated with tumour burden and an inferior overall survival（Hazard Ratio[HR]1.93 for≥240 IU/L vs<240 IU/L,95%Confidence Interval[CI][1.34-2.77],P<0.001）and progression-free survival（HR 2.07,95%CI[1.47-2.92],P<0.001）,which is consistent with published literature.Next,we observed that LDH levels fluctuated between CT1-6;this was most pronounced between baseline and CT1.Using a LDH ratio(LDH_CTn+1:LDH_CTn),we found that both absolute LDH levels and LDH ratios were associated with tumour response（Partial response vs Progression disease（PD）:[Ratio]0.738-0.988 vs 1.039-1.406）,albeit LDH ratio had a tighter variance between patients.Finally,we showed that the LDH ratio cut-off of 1.0 at CT1,CT3 and CT5 was predictive of PD at CT2,CT4,CT6（AUC 0.73[0.65-0.80]）,and yields a sensitivity of 0.79 and specificity of 0.62.2)A total of 92 patients were eligible,we found elevated LDH levels at diagnosis was associated with poor PFS（HR 1.81,95%CI[1.12-2.93],P<0.01）and OS（HR 1.72,95%CI[1.04-2.84],P<0.05）,which is consistent with the results above and published literature.In addition,different tumour burden and treatment intensity were also related to the survival（P<0.05）.Moreover,we observed that elevated LDH levels at the mid and at the end of chemotherapy were both linked to the adverse prognosis（P<0.05）.Of note,for patients with low LDH levels during the whole treatment could receive the optimum survival,and the next was the one who received low LDH levels at the end of therapy,unsurprisingly,the patients with high LDH levels all the time suffered from the worst prognosis.Multivariate showed the LDH levels at the mid of treatment and number of metastatic sites were the independent prognostic parameters of PFS,while the LDH levels at the end of chemotherapy was the independent factor of PFS and OS,which further indicating the significance of LDH kinetics during treatment.Conclusions:1)Herein,we characterized the longitudinal variation of LDH in response to CT in NPC.We demonstrate the potential of interval LDH_CTn+1:LDH_CTnto predict subsequent tumour response to CT,and may be useful for early treatment adaptation.2)we showed that serum LDH levels at different time point of treatment is a feasible indicator of prognosis,and the LDH levels post treatment could predict prognostic risk better.Take together,our results suggest LDH kinetics is a favorable indicator of prognosis,and has the potential to predict PD early which would assist in risk stratification and early customization of treatment.