LDH as prognostic factor in second line treatment for advanced gastric cancer: The LINE study.
Authors: Michelotti Anna , de Scordilli Marco , Sperti Elisa , Mazzeo Roberta , Corvaja Carla , Aimar Giacomo , Gerratana Lorenzo , Guardascione Michela , Rampin Federica , Buriolla Silvia , Di Nardo Paola , Fanotto Valentina , Andreotti Victoria , Bartoletti Michele , Bertoli Elisa , Noto Claudia , Buonadonna Angela , Di Maio Massimo , Ongaro Elena , Puglisi Fabio 
Published: June 2021

e16102

Background: Lactate dehydrogenase (LDH) is recognized as indirect marker of tumor hypoxia and angiogenesis for several solid tumors. Ramucirumab is the first antiangiogenic agent approved for second-line therapy in advanced gastric cancer (GC), alone or in association with chemotherapy. To date, no reliable biomarkers can predict the potential benefit from anti-VEGFR2 treatment. This retrospective multicenter study aimed to assess the prognostic role of baseline LDH levels in patients (pts) undergoing second-line treatment for advanced GC. Methods: The study analyzed a retrospective cohort of consecutive advanced GC pts treated with second line therapy at IRCCS, CRO of Aviano and at Mauriziano Hospital of Torino, Italy, from 2010 to 2020. LDH levels prior to second-line treatment were classified as low-normal or high and standardized according to the upper limit of the reference range. To better determine the optimal LDH cut-off value, ROC analysis was performed (using PFS < 3 months as binary outcome). Normalized LDH values were subsequently sorted according to the ROC curve cut-off in order to test the association with overall survival (OS) through the Kaplan-Meier method and compared using the Log-Rank test. A multivariate Cox regression analysis assessed the prognostic impact of normalized LDH levels for OS calculated from the start of second line treatment. Results: Overall, 125 pts were enrolled. Of these, 81 pts (64.80%) received ramucirumab alone or plus paclitaxel as second line treatment, while 44 (35.20%) had taxanes or fluoropyrimidines combined with irinotecan. Median age was 68 years, 93% had an ECOG PS ≤ 1, 64.80% was first diagnosed with metastatic disease and 40.80% underwent primary tumor resection. Median second line PFS and OS were 4.2 and 7.9 months, respectively. Baseline LDH values were available for 99 pts. ROC analysis identified a normalized LDH value of 0.83 as the optimized cut-off point to define pts with poor prognosis. At univariate analyses, surgery of the primary tumor (HR 0.51, 95% CI 0.31-0.82, p = 0.005) was associated with better OS, while low-normal BMI ( < 25 kg/m2) at second line start (HR 1.99, 95% CI 1.21-3.28, p = 0.007), normalized LDH values ≥ 0.83 (HR 1.86, 95% CI 1.13-3.07, p = 0.015) and PS > 1 (HR 5.65, 95% CI 2.29-13.92, p < 0.001) were associated with poorer outcome. At multivariable model, only PS > 1 was independently associated with poor prognosis (HR 9.93, 95% CI 3.27-30.08, p < 0.001). Subgroup analyses showed no significant heterogeneity in OS outcome according to normalized LDH levels between patients treated with or without ramucirumab. Conclusions: Elevated LDH levels are indicators of worse outcome in advanced gastric cancer pts. Notably, the LDH cut-off value identified a poor prognosis subgroup among pts with normal baseline levels, suggesting that current laboratory ranges could be suboptimal for patient stratification.