Efficacy of 4′-[methyl-11C] thiothymidine PET/CT before and after neoadjuvant therapy for predicting therapeutic responses in patients with esophageal cancer: a pilot study

Hotta et al. EJNMMI Research (2019) 9:10 https://doi.org/10.1186/s13550-019-0478-9 ORIGINAL RESEARCH Open Access Efficacy of 4′-[methyl-11C] thiothymidine PET/CT before and after neoadjuvant therapy for predicting therapeutic responses in patients with esophageal cancer: a pilot study Masatoshi Hotta1,4* , Ryogo Minamimoto1, Kazuhiko Yamada2, Kyoko Nohara2, Daisuke Soma2, Kazuhiko Nakajima1, Jun Toyohara3 and Kei Takase4 Abstract Background: 4′-[Methyl-11C] thiothymidine (4DST) has been introduced as a new cell proliferation imaging PET tracer that incorporates into DNA directly. The aim of this prospective study was to evaluate the efficacy of 4DST PET/CT for predicting responses to neoadjuvant therapy in patients with esophageal cancer comparing with FDG PET/CT. Methods: Twenty-six patients who had pre- and post-therapeutic 4DST and FDG PET/CT and underwent esophagectomy following neoadjuvant therapy were used for the analysis. Based on pathological findings, patients were divided into two groups: non-responders and responders. The maximum standardized uptake value (SUVmax), metabolic tumor volume, total lesion glycolysis, and total lesion proliferation of the primary lesion were measured for FDG and 4DST PET. Results: The pathological diagnosis revealed 16 responders and 10 non-responders. Non-responders showed significantly higher 4DST post-therapeutic SUVmax (postSUVmax) than responders, whereas FDG postSUVmax showed no statistically significant difference (non-responders vs. responders: 4DST, 6.7 vs. 3.3, p = 0.001; FDG, 6.1 vs. 4.5, p = 0.11). Responders showed a greater reduction in percentage changes of 4DST and FDG SUVmax (ΔSUVmax) from baseline to post-therapeutic PET (non-responders vs. responders: 4DST, − 2.9% vs. − 56.7%, p < 0.001; FDG, − 36.3% vs. − 72.6%, p < 0.001). In ROC analysis, ΔSUVmax and postSUVmax with 4DST provided great diagnostic performance for predicting responses (area under the curve: 4DST ΔSUVmax = 0.92, 4DST postSUVmax = 0.88). Conclusions: 4DST PET/CT has a great potential for predicting pathologic response to neoadjuvant therapy in patients with esophageal cancer; it may be slightly superior to that with FDG PET/CT. Keywords: 4DST, Esophageal cancer, PET/CT, FDG, Therapeutic response * Correspondence: 1 Division of Nuclear Medicine, Department of Radiology, National Center for Global Health and Medicine, 1-21-1, Toyama, Shinjuku-ku, Tokyo 162-8655, Japan 4 Department of Diagnostic Radiology, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8574, Japan Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. Hotta et al. EJNMMI Research (2019) 9:10 Background The prognosis of patients with advanced esophageal cancer continues to be poor, despite advances in management. Neoadjuvant chemotherapy or chemoradiation therapy before esophagectomy is a standard-of-care and commonly applied in clinical practice for locally advanced and operable esophageal cancer [1–3]. Once neoadjuvant therapy is completed, assessment of response is necessary [3]. When a persistent local lesion is indicated, esophagectomy is strongly recommended because the presence of residual tumor after neoadjuvant therapy in the resected specimen leads to shorter overall survival [3–5]. On the contrary, if there is no evidence of residual viable lesion, surveillance can be a possible option [3]. Generally, FDG PET/CT and/or contrastenhanced chest CT is used for the evaluation of treatment response of neoadjuvant therapy in esophageal cancer [3]. It is sometimes difficult to distinguish a viable residual tumor form reactive changes with a chest CT. In contrast, FDG PET/CT provides a more accurate diagnosis compared to that with chest CT due to its evaluation of metabolic activity. However, the value of FDG-PET/CT for evaluating response to neoadjuvant therapy in esophageal cancer is still controversial [6–8], so it is basically not recommended for the selection of patients for esophagectomy following neoadjuvant therapy [3]. Recently, Toyohara et al. developed 4′-[methyl-11C] thiothymidine (4DST) as a new DNA synthesis imaging agent [9, 10]. Although 3′-fluoro-3′-deoxythymidine Fig. 1 Flow diagram of patient selection Page 2 of 9 (FLT) has been established as a cell proliferation PET tracer, 4DST has advantages for proliferation measurement [11]. 4DST incorporates into DNA directly, whereas FLT does not incorporate into DNA and reflects salvage pathway of DNA synthesis [12]. We have previously reported on the great potential of 4DST PET/CT for proliferation imaging in malignancies such as lung cancer and renal cell carcinoma [13–15]. In addition, Hoshikawa et al. have reported that 4DST PET shows a higher prognostic value in patients with head and neck carcinoma compared to FDG PET [16]. These results suggest that 4DST PET can potentially predict a response to neoadjuvant therapy in esophageal cancer. The aim of this study was to evaluate the diagnostic value of 4DST for predicting response to neoadjuvant therapy in patients with esophageal cancer as compared to that with FDG. Methods Patients This prospective study was approved by the institutional review board of our hospital, and written informed consent was obtained from all patients. We enrolled patients with biopsy-proven esophageal cancer. A total of 49 consecutive treatment-naïve patients underwent baseline 4DST and FDG PET/CT from August 2015 to September 2018 and were assessed for eligibility for this prospective study (Fig. 1). Among them, 11 patients were treated with definitive chemoradiation therapy (8 patients declined to undertake esophagectomy, and 3 Hotta et al. EJNMMI Research (2019) 9:10 Page 3 of 9 patients were regarded as inoperable due to newly diagnosed lung and/or bone metastasis), 5 patients were treated with esophagectomy without neoadjuvant therapy, and 5 patients did not have 4DST and/or FDG PET/ CT after neoadjuvant therapy. In addition, 2 patients with adenocarcinoma were excluded because of the different biological entity between adenocarcinoma and squamous cell carcinoma. Therefore, we analyzed 26 patients with esophageal squamous cell carcinoma (23 men and 3 women, mean ± SD age 66.4 ± 9.7 years). They all underwent esophagectomy following neoadjuvant therapy. Exclusion criteria for these 26 patients were (1) uncontrolled diabetes or (2) non-avid tumors on FDG or 4DST PET/CT, but no patients met these exclusion criteria. Patients’ demographics including tumor markers are shown in Table 1. Regarding the regimen (...truncated)