Assessment of the Tumor Redox Status in Head and Neck Cancer by (62)Cu-ATSM PET

PURPOSE: Tumor redox is an important factor for cancer progression, resistance to treatments, and a poor prognosis. The aim of the present study was to define tumor redox (over-reduction) using (62)Cu-diacetyl-bis(N(4)-methylthiosemicarbazone) ((62)Cu-ATSM) PET and compare its prognostic potential in head and neck cancer (HNC) with that of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG). METHODS: Thirty HNC patients (stage II–IV) underwent pretreatment (62)Cu-ATSM and (18)F-FDG PET scans. Maximum standardized uptake values (SUV(ATSM) and SUV(FDG)) and tumor-to-muscle activity concentration ratios (TMR(ATSM) and TMR(FDG)) were measured. Reductive-tumor-volume (RTV) was then determined at four thresholds (40%, 50%, 60%, and 70% SUV(ATSM)), and total-lesion-reduction (TLR) was calculated as the product of the mean SUV and RTV for (62)Cu-ATSM. In (18)F-FDG, metabolic-tumor-volume (MTV) and total-lesion-glycolysis (TLG) were obtained at a threshold of 40%. A ROC analysis was performed to determine % thresholds for RTV and TLR showing the best predictive performance, and these were then used to determine the optimal cut-off values to stratify patients for each parameter. Progression-free-survival (PFS) and cause-specific-survival (CSS) were evaluated by the Kaplan-Meier method. RESULTS: The means ± standard deviations of PFS and CSS periods were 16.4±13.4 and 19.2±12.4 months, respectively. A ROC analysis determined that the 70% SUV(ATSM) threshold for RTV and TLR was the best for predicting disease progression and cancer death. Optimal cut-offs for each index were SUV(ATSM) = 3.6, SUV(FDG) = 7.9, TMR(ATSM) = 3.2, TMR(FDG) = 5.6, RTV = 2.9, MTV = 8.1, TLR = 14.0, and TLG = 36.5. When the cut-offs for TMR(ATSM) and TLR were set as described above in (62)Cu-ATSM PET, patients with higher TMR(ATSM) (p = 0.03) and greater TLR (p = 0.02) showed significantly worse PFS, while patients with greater TLR had significantly worse CSS (p = 0.02). Only MTV in (18)F-FDG PET predicted differences in PSF and CSS (p = 0.03 and p = 0.03, respectively). CONCLUSION: Tumor redox parameters measured by (62)Cu-ATSM PET may be determinants of HNC patient outcomes and help define optimal patient-specific treatments.