Annals of Nuclear Medicine

, Volume 32, Issue 3, pp 165–174 | Cite as

Pilot study of serial FLT and FDG-PET/CT imaging to monitor response to neoadjuvant chemoradiotherapy of esophageal adenocarcinoma: correlation with histopathologic response

  • Victor H. Gerbaudo
  • Joseph H. Killoran
  • Chun K. Kim
  • Jason L. Hornick
  • Jonathan A. Nowak
  • Peter C. Enzinger
  • Harvey J. Mamon
Original Article



The aim of this prospective pilot study was to investigate the potential of serial FLT-PET/CT compared to FDG-PET/CT to provide an early indication of esophageal cancer response to concurrent neoadjuvant chemoradiation therapy.


Five patients with biopsy-proven esophageal adenocarcinomas underwent neoadjuvant chemoradiation (Tx) prior to minimally invasive esophagectomy. The presence of residual tumor was classified histologically using the Mandard et al. criteria, categorizing patients as pathologic responders and non-responders. Participants underwent PET/CT imaging 1 h after intravenous administration of FDG and of FLT on two separate days within 48 h of each other. Each patient underwent a total of 3 scan “pairs”: (1) pre-treatment, (2) during treatment, and (3) post-treatment. Image-based response to therapy was measured in terms of changes in SUVmax (ΔSUV) between pre- and post-therapeutic FLT- and FDG-PET scans. The PET imaging findings were correlated with the pathology results after surgery.


All tumors were FDG and FLT avid at baseline. Lesion FLT uptake was lower than with FDG. Neoadjuvant chemoradiation resulted in a reduction of tumor uptake of both radiotracers in pathological responders (n = 3) and non-responders (n = 2). While the difference in the reduction in mean tumor FLT uptake during Tx between responders (ΔSUV = − 55%) and non-responders (ΔSUV = − 29%) was significant (P = 0.007), for FDG it was not, [responders had a mean ΔSUV = − 39 vs. − 31% for non-responders (P = 0.74)]. The difference in the reduction in tumor FLT uptake at the end of treatment between responders (ΔSUV = − 62%) and non-responders (ΔSUV = − 57%) was not significant (P = 0.54), while for FDG there was a trend toward significance [ΔSUV of responders = − 74 vs. − 52% in non-responders (P = 0.06)].


The results of this prospective pilot study suggest that early changes in tumor FLT uptake may be better than FDG in predicting response of esophageal adenocarcinomas to neoadjuvant chemoradiation. These preliminary results support the need to corroborate the value of FLT-PET/CT in a larger cohort.


FDG FLT PET/CT Esophageal cancer Radiation therapy Response to treatment Neoadjuvant chemoradiotherapy 


Compliance with ethical standards

Conflict of interest

No potential conflicts of interest were disclosed.


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics 2017. CA: A Cancer J Clin. 2017;67:7–30.Google Scholar
  2. 2.
    Blot WJ, Devesa SS, Kneller RW, Fraumeni JF Jr. Rising incidence of adenocarcinoma of the esophagus and gastric cardia. JAMA. 1991;265:1287–9.CrossRefPubMedGoogle Scholar
  3. 3.
    Sjoquist KM, Burmeister BH, Smithers BM, Zalcberg JR, Simes RJ, Barbour A, Gebski V. Australasian Gastro-Intestinal Trials Group. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis. Lancet Oncol. 2011;12:681–92.CrossRefPubMedGoogle Scholar
  4. 4.
    Ronellenfitsch U, Schwarzbach M, Hofheinz R, Kienle P, Kieser M, Slanger TE, et al. Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data. Eur J Cancer. 2013;49:3149 – 3148.CrossRefPubMedGoogle Scholar
  5. 5.
    Oppedijk V, van der Gaast A, van Lanschot JJ, van Hagen P, van Os R, van Rij CM, et al. Patterns of recurrence after surgery alone versus preoperative chemoradiotherapy and surgery in the CROSS trials. J Clin Oncol. 2014;32:385–91.CrossRefPubMedGoogle Scholar
  6. 6.
    Davies AR, Gossage JA, Zylstra J, Mattsson F, Lagergren J, Maisey N, et al. Tumor stage after neoadjuvant chemotherapy determines survival after surgery for adenocarcinoma of the esophagus and esophagogastric junction. J Clin Oncol. 2014;32:2983–90.CrossRefPubMedGoogle Scholar
  7. 7.
    Schmidt T, Sicic L, Blank S, Becker K, Weichert W, Bruckner T, et al. Prognostic value of histopathological regression in 850 neoadjuvantly treated oesophagogastric adenocarcinomas. Br J Cancer. 2014;110:1712–20.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Ancona E, Ruol A, Santi S, Merigliano S, Sileni VC, Koussis H, Zaninotto G, et al. Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma: final report of a randomized, controlled trial of preoperative chemotherapy versus surgery alone. Cancer. 2001;91:2165–74.CrossRefPubMedGoogle Scholar
  9. 9.
    Le Prise E, Etienne PL, Meunier B, Maddern G, Ben Hassel M, Gedouin D, et al. A randomized study of chemotherapy, radiation therapy, and surgery versus surgery for localized squamous cell carcinoma of the esophagus. Cancer. 1994;73:1779–84.CrossRefPubMedGoogle Scholar
  10. 10.
    Walsh TN, Noonan N, Hollywood D, Kelly A, Keeling N, Hennessy TP. A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med. 1996;335:462–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Urba SG, Orringer MB, Turrisi A, Iannettoni M, Forastiere A, Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol. 2001;19:305–13.CrossRefPubMedGoogle Scholar
  12. 12.
    Goodman KA, Niedzwiecki D, Hall N, et al. Initial results of CALGB 80803 (Alliance): a randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer. Presented at: 2017 Gastrointestinal Cancers Symposium. January 19–21, 2017; San Francisco, California; Abstract 1.Google Scholar
  13. 13.
    Zuccaro G Jr, Rice TW, Goldblum J, Medendorp SV, Becker M, Pimentel R, et al. Endoscopic ultrasound cannot determine suitability for esophagectomy after aggressive chemoradiotherapy for esophageal cancer. Am J Gastroenterol. 1999;94:906–12.CrossRefPubMedGoogle Scholar
  14. 14.
    Jones DR, Parker LA Jr, Detterbeck FC, Egan TM. Inadequacy of computed tomography in assessing patients with esophageal carcinoma after induction chemoradiotherapy. Cancer. 1999;85:1026–32.CrossRefPubMedGoogle Scholar
  15. 15.
    Swisher SG, Erasmus J, Maish M, Correa AM, Macapinlac H, Ajani JA, et al. 2-Fluoro-2-deoxy-D-glucose positron emission tomography imaging is predictive of pathologic response and survival after preoperative chemoradiation in patients with esophageal carcinoma. Cancer. 2004;101:1776–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Flamen P, Van Cutsem E, Lerut A, Cambier JP, Haustermans K, Bormans G, et al. Positron emission tomography for assessment of the response to induction radiochemotherapy in locally advanced oesophageal cancer. Ann Oncol. 2002;13:361–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Wieder HA, Brücher BL, Zimmermann F, Becker K, Lordick F, Beer A, et al. Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment. J Clin Oncol. 2004;22:900–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Brücher BL, Weber W, Bauer M, Fink U, Avril N, Stein HJ, et al. Neoadjuvant therapy of esophageal squamous cell carcinoma: response evaluation by positron emission tomography. Ann Surg. 2001;233:300–9.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mamede M, Abreu-E-Lima P, Oliva MR, Nosé V, Mamon H, Gerbaudo VH. FDG-PET/CT tumor segmentation-derived indices of metabolic activity to assess response to neoadjuvant therapy and progression-free survival in esophageal cancer: correlation with histopathology results. Am J Clin Oncol. 2007;30:377–88.CrossRefPubMedGoogle Scholar
  20. 20.
    Lordick F, Ott K, Krause BJ, Weber WA, Becker K, Stein HJ, et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial. Lancet Oncol. 2007;8:797–805.CrossRefPubMedGoogle Scholar
  21. 21.
    Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y. Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol. 2002;29:281–7.CrossRefPubMedGoogle Scholar
  22. 22.
    Dittmann H, Dohmen BM, Kehlbach R, Bartusek G, Pritzkow M, Sarbia M, et al. Early changes in [18F]FLT uptake after chemotherapy: an experimental study. Eur J Nucl Med Mol Imaging. 2002;29:1462–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Perumal M, Pillai RG, Barthel H, Leyton J, Latigo JR, Forster M, et al. Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. Cancer Res. 2006;66:8558–64.CrossRefPubMedGoogle Scholar
  24. 24.
    Apisarnthanarax S, Alauddin MM, Mourtada F, Ariga H, Raju U, Mawlawi O, et al. Early detection of chemoradioresponse in esophageal carcinoma by 3′-deoxy-3′-3H-fluorothymidine using preclinical tumor models. Clin Cancer Res. 2006;12:4590–7.CrossRefPubMedGoogle Scholar
  25. 25.
    Pio BS, Park CK, Pietras R, Hsueh WA, Satyamurthy N, Pegram MD, et al. Usefulness of 3′-[F-18]fluoro-3′-deoxythymidine with positron emission tomography in predicting breast cancer response to therapy. Mol Imaging Biol. 2006;8:36–42.CrossRefPubMedGoogle Scholar
  26. 26.
    Herrmann K, Wieder HA, Buck AK, Schöffel M, Krause BJ, Fend F, et al. Early response assessment using 3′-deoxy-3′[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin’s lymphoma. Clin Cancer Res. 2007;13:3552–8.CrossRefPubMedGoogle Scholar
  27. 27.
    Yue J, Chen L, Cabrera AR, Sun X, Zhao S, Zheng F, et al. Measuring tumor cell proliferation with 18F-FLT PET during radiotherapy of esophageal squamous cell carcinoma: a pilot clinical study. J Nucl Med. 2010;51:528–34.CrossRefPubMedGoogle Scholar
  28. 28.
    Park SH, Ryu JS, Oh SJ, Park SI, Kim YH, Jung HY, et al. The feasibility of (18)F-Fluorothymidine PET for prediction of tumor response after induction chemotherapy followed by chemoradiotherapy with S-1/oxaliplatin in patients with resectable esophageal cancer. Nucl Med Mol Imaging. 2012;46:57–64.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Edge SB, Byrd DR, Compton CC et al, editors Esophagus and esophagogastric junction. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010: pp. 103–15.Google Scholar
  30. 30.
    Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction. Br J Surg. 1998;85:1457–9.CrossRefPubMedGoogle Scholar
  31. 31.
    Mamede M, El Fakhri G, Abreu-e-Lima P, Gandler W, Nosé V, Gerbaudo VH. Pre-operative estimation of esophageal tumor metabolic length in FDG-PET images with surgical pathology confirmation. Ann Nucl Med. 2007;21:553–62.CrossRefPubMedGoogle Scholar
  32. 32.
    Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer. 1994;73:2680–6.CrossRefPubMedGoogle Scholar
  33. 33.
    Brown RS, Leung JY, Kison PV, Zasadny KR, Flint A, Wahl RL. Glucose transporters and FDG uptake in untreated primary human non-small cell lung cancer. J Nucl Med. 1999;40:556–65.PubMedGoogle Scholar
  34. 34.
    Chen H, Li Y, Wu H, Sun L, Lin Q, Zhao L. 3′-deoxy-3′-[18F]-fluorothymidine PET/CT in early determination of prognosis in patients with esophageal squamous cell cancer: comparison with [18F]-FDG PET/CT. Strahlenther Onkol. 2015;191:141–52.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Nuclear Medicine 2018

Authors and Affiliations

  • Victor H. Gerbaudo
    • 1
  • Joseph H. Killoran
    • 2
  • Chun K. Kim
    • 1
  • Jason L. Hornick
    • 3
  • Jonathan A. Nowak
    • 3
  • Peter C. Enzinger
    • 4
  • Harvey J. Mamon
    • 2
    • 4
  1. 1.Division of Nuclear Medicine and Molecular Imaging, Department of RadiologyBrigham and Women’s Hospital, Harvard Medical SchoolBoston, MassachusettsUSA
  2. 2.Department of Radiation OncologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of PathologyBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  4. 4.Center for Esophageal and Gastric CancerDana Farber Cancer Institute, Harvard Medical SchoolBostonUSA

Personalised recommendations