Abstract
BackgroundMetastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. However, a large subgroup of patients does not benefit. Tumour metabolic alterations may well be involved in the efficacy of both targeted and immunotherapy. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. The aim of this retrospective study was to provide insight into quantitative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) parameters and corresponding intra- and inter-patient heterogeneity in tumour 18F-FDG uptake among metastatic melanoma patients. Consecutive, newly diagnosed stage IV melanoma patients with a baseline 18F-FDG PET/CT scan performed between May 2014 and December 2015 and scheduled to start first-line systemic treatment were included. Volume of interests (VOIs) of all visible tumour lesions were delineated using a gradient-based contour method, and standardized uptake values (SUVs), metabolically active tumour volume (MATV) and total lesion glycolysis (TLG) were determined on a per-lesion and per-patient basis. Differences in quantitative PET parameters were explored between patient categories stratified by BRAFV600 and RAS mutational status, baseline serum lactate dehydrogenase (LDH) levels and tumour programmed death-ligand 1 (PD-L1) expression.ResultsIn 64 patients, 1143 lesions ≥ 1 ml were delineated. Median number of lesions ≥ 1 ml was 6 (range 0–168), median maximum SUVpeak 9.5 (range 0–58), median total MATV 29 ml (range 0–2212) and median total TLG 209 (range 0–16,740). Per-patient analysis revealed considerable intra- and inter-patient heterogeneity. Maximum SUVs, MATV, number of lesions and TLG per patient did not differ when stratifying between BRAFV600 or RAS mutational status or PD-L1 expression status, but were higher in the patient group with elevated LDH levels (> 250 U/l) compared to the group with normal LDH levels (P < 0.001). A subset of patients with normal LDH levels also showed above median tumour 18F-FDG uptake.ConclusionsBaseline tumour 18F-FDG uptake in stage IV melanoma is heterogeneous, independent of mutational status and cannot be fully explained by LDH levels. Further investigation of the prognostic and predictive value of quantitative 18F-FDG PET parameters is of interest.
Highlights
Metastatic melanoma patients can have durable responses to systemic therapy and even long-term survival
All patients ≥ 18 years of age with histologically proven cutaneous or mucosal metastatic melanoma (American Joint Committee on Cancer [AJCC] 7th edition stage IV melanoma [14]) without prior systemic treatment and with a baseline 18F-FDG Positron emission (PET)/Computed tomography (CT) scan performed between May 2014 and December 2015 were eligible for inclusion (n = 108)
BRAFV600 mutational status did not differ between patients with normal or elevated serum lactate dehydrogenase (LDH) (42.9% vs. 57.1%; P = 0.260)
Summary
Metastatic melanoma patients can have durable responses to systemic therapy and even long-term survival. Knowledge on in vivo tumour glucose uptake and its heterogeneity in metastatic melanoma may aid in upfront patient selection for novel (concomitant) metabolically targeted therapies. Preclinical data suggest metabolically targeted therapies can improve antitumour immune response and susceptibility to adjuvant chemo- and radiotherapy [8,9,10] In patients, such treatments can result in toxicity in highly glucose-dependent healthy tissues, such as the kidney [7, 11]. Recent in vitro studies demonstrate that not all melanomas rely on altered glucose metabolic pathways to the same extent [12, 13] This underlines the need for upfront selection of patients with highly glucose-dependent tumours in order to maximize the benefit of (concomitant) metabolic therapies and ensure a sufficiently broad therapeutic window
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