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PURPOSE. Tumor-Treating Fields (TTFields) is an FDA-approved treatment approach for patients with both newly-diagnosed and recurrent glioblastoma. The main purpose of the present study was to explore if amino acid positron emission tomography (PET) is able to detect an early, objective metabolic tumor response during the first months of TTFields therapy. METHODS. Patients with MRI signs of recurrent glioblastoma eligible for TTFields along with maintenance temozolomide were recruited for PET scanning with alpha[C-11]-methyl-L-tryptophan (AMT) at baseline (before start of TTFields application) and up to 3 months later. Serial MRIs were also performed in 1-2 months intervals. AMT accumulation in the MRI-detected tumor mass was measured by standardized uptake values (SUVs), and PET-based tumor volumes were also calculated. Interval changes of these PET variables were compared to changes in areas of MRI enhancement. RESULTS. Out of 7 recruited patients, 5 showed appropriate compliance (>75%) with the device and underwent follow-up PET. Four of the 5 patients showed a clear metabolic response during TTF treatment on PET imaging. Two patients, who received TTFields treatment only (in addition to maintenance temozolomide), showed 25% and 100% decrease of PET-based tumor volumes, respectively. MRI was stable (patient #1) or showed increasing contrast enhancement (#2) during the same period. In this latter patient, TTFields was continued with bevacizumab treatment, leading to decreased contrast enhancement and further decrease of AMT uptake on a second follow-up PET. In two other patients (#3 and #4), TTFields were combined with bevacizumab rescue treatment. Patient #3 showed a markedly decreased tumoral AMT uptake and metabolic volume along with stable MRI enhancement. Patient #4 showed interval decrease of tryptophan PET uptake 2 months after initiation of TTFields therapy. Finally, patient #5 showed an interval expansion of the PET-based tumor volume along with MRI progression during a 2-month follow-up despite TTFields combined with bevacizumab and carboplatin. CONCLUSIONS. This is the first study to demonstrate an objective metabolic response of recurrent glioblastoma within 1.5-3 months after initiation of TTFields. The data suggest that amino acid PET can identify early responders to TTFields therapy. Citation Format: Sandeep Mittal, Geoffrey R. Barger, Edit Bosnyak, Varun B. Shah, Csaba Juhasz. Early metabolic response to tumor-treating fields in patients with recurrent glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3730. doi:10.1158/1538-7445.AM2017-3730