The vertebral 3′-deoxy-3′-18F-fluorothymidine uptake predicts the hematological toxicity after systemic chemotherapy in patients with lung cancer

  • Yukihiro UmedaEmail author
  • Tetsuya Tsujikawa
  • Masaki Anzai
  • Miwa Morikawa
  • Yuko Waseda
  • Maiko Kadowaki
  • Hiroko Shigemi
  • Shingo Ameshima
  • Tetsuya Mori
  • Yasushi Kiyono
  • Hidehiko Okazawa
  • Tamotsu Ishizuka



Although hematological toxicities (HT) are the leading adverse events of systemic chemotherapy, the estimation of severe HT is challenging. Recently, 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) accumulation with PET has been considered a biomarker of the cell proliferation. This study aims to elucidate whether the vertebral accumulation of 18F-FLT could estimate severe HT during platinum-doublet chemotherapy.


In this Institutional Review Board–approved retrospective study, 50 patients with primary lung cancer underwent 18F-FLT PET scan before platinum-doublet chemotherapy. We evaluated the standardized uptake value, total vertebral proliferation (TVP), and TVP/body surface area (TVP/BSA) of the vertebral body (Th4, Th8, Th12, and L4), and then the associations between those parameters and frequency of severe HT during platinum-doublet chemotherapy were assessed.


Severe HT (grade 3/4) was observed in 40.0% of patients during the first cycle. The ROC curve analyses revealed that the TVP/BSA of L4 was the most discriminative parameter among PET parameters for the prediction of severe HT. The multivariate logistic regression analysis revealed the TVP/BSA of L4 (odds ratio [OR], 0.94; p = 0.0036) and the frequency of the grade 3/4 hematological toxicity in previous clinical trials (OR, 1.03; p = 0.023) were independent predictors. Furthermore, the sensitivity, specificity, and accuracy of the TVP/BSA of L4 cut-off of 68.7 to predict grade 3/4 HT were 80.0%, 86.7%, and 84.0%, respectively. A low TVP/BSA of L4 (< 68.7) as a binary variable was a significant indicator of severe HT (OR, 26.0; p = 0.000026).


The low 18F-FLT uptake in the lower vertebral body is a predictor of severe HT in patients with lung cancer who receive platinum-doublet chemotherapy.

Trial registration

Trial registration: UMIN000027540

Key Points

• The vertebral 18 F-FLT uptake with PET is an independent predictor of the severe hematological toxicity during the first cycle of platinum-doublet chemotherapy.

• The 18 F-FLT uptake in L4 vertebral body estimated hematological toxicities better than that in the upper vertebra (Th4, Th8, and Th12).

• The evaluation of the amount and activity of hematopoietic cells in the bone marrow cavity using 18 F-FLT PET imaging could provide predictive data of severe hematological toxicities and help determine an appropriate drug combination or dose intensity in patients with advanced malignant diseases.


Thymidine Positron emission tomography (PET) Lung cancer Chemotherapy Lumbar vertebrae 





Area under the curve


Body mass index


Body surface area


Confidence interval


Eastern Cooperative Oncology Group


Granulocyte colony–stimulating factor


Hematological toxicity


Lumbar vertebra


Maximum intensity projection


National Cancer Institute Common Terminology Criteria for Adverse Events


Negative predictive value


Odds ratio


Positive predictive value


Proliferative vertebral volume


Performance status


Standardized uptake value


Thoracic vertebra


Total vertebral proliferation


Volume of interest


White blood cell



This work was supported by MEXT KAKENHI (Grant Number JP22790752) and a grant-in-aid from the scientific research program “Seeds of Advanced Medicine” of the University of Fukui Hospital, Japan.

Compliance with ethical standards


The scientific guarantor of this publication is Dr. Y. Umeda.

Conflict of interest

The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article.

Statistics and biometry

Three of the authors have significant statistical expertise.

Informed consent

Written informed consent was waived by the Institutional Review Board.

Ethical approval

Institutional Review Board approval was obtained.


• Retrospective

• Diagnostic study or prognostic study

• Performed at one institution

Supplementary material

330_2019_6161_MOESM1_ESM.docx (52 kb)
ESM 1 (DOCX 51 kb)


  1. 1.
    Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA (2009) Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol 27:2758–2765CrossRefGoogle Scholar
  2. 2.
    Vogler JB 3rd, Murphy WA (1988) Bone marrow imaging. Radiology 168:679–693CrossRefGoogle Scholar
  3. 3.
    Chalkidou A, Landau DB, Odell EW, Cornelius VR, O’Doherty MJ, Marsden PK (2012) Correlation between Ki-67 immunohistochemistry and 18F-fluorothymidine uptake in patients with cancer: a systematic review and meta-analysis. Eur J Cancer 48:3499–3513CrossRefGoogle Scholar
  4. 4.
    Wagner M, Seitz U, Buck A et al (2003) 3′-[18F]Fluoro-3′-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-cell lymphoma model and in the human disease. Cancer Res 63:2681–2687Google Scholar
  5. 5.
    Yamamoto Y, Nishiyama Y, Ishikawa S et al (2007) Correlation of 18F-FLT and 18F-FDG uptake on PET with Ki-67 immunohistochemistry in non-small cell lung cancer. Eur J Nucl Med Mol Imaging 34:1610–1616CrossRefGoogle Scholar
  6. 6.
    Vercellino L, Ouvrier MJ, Barre E et al (2017) Assessing bone marrow activity in patients with myelofibrosis: results of a pilot study of (18)F-FLT PET. J Nucl Med 58:1603–1608CrossRefGoogle Scholar
  7. 7.
    Leimgruber A, Moller A, Everitt SJ et al (2014) Effect of platinum-based chemoradiotherapy on cellular proliferation in bone marrow and spleen, estimated by (18)F-FLT PET/CT in patients with locally advanced non-small cell lung cancer. J Nucl Med 55:1075–1080CrossRefGoogle Scholar
  8. 8.
    McGuire SM, Menda Y, Boles Ponto LL, Gross B, Buatti J, Bayouth JE (2011) 3′-Deoxy-3′-[(1)(8)F]fluorothymidine PET quantification of bone marrow response to radiation dose. Int J Radiat Oncol Biol Phys 81:888–893CrossRefGoogle Scholar
  9. 9.
    Schelhaas S, Held A, Baumer N et al (2016) Preclinical evidence that 3′-deoxy-3′-[18F]fluorothymidine PET can visualize recovery of hematopoiesis after gemcitabine chemotherapy. Cancer Res 76:7089–7095CrossRefGoogle Scholar
  10. 10.
    Lin C, Kume K, Mori T, Martinez ME, Okazawa H, Kiyono Y (2015) Predictive value of early-stage uptake of 3′-deoxy-3′-18F-fluorothymidine in cancer cells treated with charged particle irradiation. J Nucl Med 56:945–950CrossRefGoogle Scholar
  11. 11.
    Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26:3543–3551CrossRefGoogle Scholar
  12. 12.
    Barlesi F, Scherpereel A, Rittmeyer A et al (2013) Randomized phase III trial of maintenance bevacizumab with or without pemetrexed after first-line induction with bevacizumab, cisplatin, and pemetrexed in advanced nonsquamous non-small-cell lung cancer: AVAPERL (MO22089). J Clin Oncol 31:3004–3011CrossRefGoogle Scholar
  13. 13.
    Kubota K, Sakai H, Katakami N et al (2015) A randomized phase III trial of oral S-1 plus cisplatin versus docetaxel plus cisplatin in Japanese patients with advanced non-small-cell lung cancer: TCOG0701 CATS trial. Ann Oncol 26:1401–1408CrossRefGoogle Scholar
  14. 14.
    Ohe Y, Ohashi Y, Kubota K et al (2007) Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: four-arm cooperative study in Japan. Ann Oncol 18:317–323CrossRefGoogle Scholar
  15. 15.
    Lara PN Jr, Natale R, Crowley J et al (2009) Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol 27:2530–2535CrossRefGoogle Scholar
  16. 16.
    Okamoto H, Watanabe K, Kunikane H et al (2007) Randomised phase III trial of carboplatin plus etoposide vs split doses of cisplatin plus etoposide in elderly or poor-risk patients with extensive disease small-cell lung cancer: JCOG 9702. Br J Cancer 97:162–169CrossRefGoogle Scholar
  17. 17.
    Zinner RG, Obasaju CK, Spigel DR et al (2015) PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol 10:134–142CrossRefGoogle Scholar
  18. 18.
    Patel JD, Socinski MA, Garon EB et al (2013) PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. J Clin Oncol 31:4349–4357CrossRefGoogle Scholar
  19. 19.
    Okamoto I, Yoshioka H, Morita S et al (2010) Phase III trial comparing oral S-1 plus carboplatin with paclitaxel plus carboplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer: results of a west Japan oncology group study. J Clin Oncol 28:5240–5246CrossRefGoogle Scholar
  20. 20.
    Socinski MA, Bondarenko I, Karaseva NA et al (2012) Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol 30:2055–2062CrossRefGoogle Scholar
  21. 21.
    National Comprehensive Cancer Network (2017) Non-small cell lung cancer, Version 8.2017. National Comprehensive Cancer Network, Inc., Pennsylvania. Available via Accessed 1 Dec 2017
  22. 22.
    National Comprehensive Cancer Network (2017) Small cell lung cancer, Version 2.2017. National Comprehensive Cancer Network, Inc., Pennsylvania. Available via Accessed 8 Apr 2018
  23. 23.
    The Japan Lung Cancer Society (2017) Guidelines for diagnosis and treatment of the lung cancer 2017. The Japan Lung Cancer Society, Tokyo. Available via Accessed 9 Apr 2018
  24. 24.
    Menda Y, Ponto LL, Dornfeld KJ et al (2010) Investigation of the pharmacokinetics of 3′-deoxy-3′-[18F]fluorothymidine uptake in the bone marrow before and early after initiation of chemoradiation therapy in head and neck cancer. Nucl Med Biol 37:433–438CrossRefGoogle Scholar
  25. 25.
    Kricun ME (1985) Red-yellow marrow conversion: its effect on the location of some solitary bone lesions. Skeletal Radiol 14:10–19CrossRefGoogle Scholar
  26. 26.
    National Comprehensive Cancer Network (2017) Myeloid growth factors, Version1.2017. National Comprehensive Cancer Network, Inc., Pennsylvania. Available via Accessed 8 Aug 2017
  27. 27.
    National Comprehensive Cancer Network (2017) Older adult oncology. Version 2.2017. National Comprehensive Cancer Network, Inc., Pennsylvania. Available via Accessed 8 Aug 2017
  28. 28.
    Extermann M, Chen H, Cantor AB et al (2002) Predictors of tolerance to chemotherapy in older cancer patients: a prospective pilot study. Eur J Cancer 38:1466–1473CrossRefGoogle Scholar
  29. 29.
    Extermann M, Boler I, Reich RR et al (2012) Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score. Cancer 118:3377–3386CrossRefGoogle Scholar
  30. 30.
    Hurria A, Togawa K, Mohile SG et al (2011) Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol 29:3457–3465CrossRefGoogle Scholar
  31. 31.
    Razzaghdoust A, Mofid B, Moghadam M (2018) Development of a simplified multivariable model to predict neutropenic complications in cancer patients undergoing chemotherapy. Support Care Cancer.
  32. 32.
    Mishra S, Radhakrishnan V, Ganesan P et al (2017) Predictors of chemotherapy related toxicities in elderly lymphoma patients: experience from a tertiary cancer centre. Indian J Hematol Blood Transfus 33:470–476CrossRefGoogle Scholar
  33. 33.
    Moreau M, Klastersky J, Schwarzbold A et al (2009) A general chemotherapy myelotoxicity score to predict febrile neutropenia in hematological malignancies. Ann Oncol 20:513–519CrossRefGoogle Scholar
  34. 34.
    Lopez-Pousa A, Rifa J, Casas de Tejerina A et al (2010) Risk assessment model for first-cycle chemotherapy-induced neutropenia in patients with solid tumours. Eur J Cancer Care (Engl) 19:648–655CrossRefGoogle Scholar
  35. 35.
    Pfeil AM, Vulsteke C, Paridaens R et al (2014) Multivariable regression analysis of febrile neutropenia occurrence in early breast cancer patients receiving chemotherapy assessing patient-related, chemotherapy-related and genetic risk factors. BMC Cancer 14:201CrossRefGoogle Scholar
  36. 36.
    Pettengell R, Bosly A, Szucs TD et al (2009) Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study. Br J Haematol 144:677–685CrossRefGoogle Scholar

Copyright information

© European Society of Radiology 2019

Authors and Affiliations

  • Yukihiro Umeda
    • 1
    Email author
  • Tetsuya Tsujikawa
    • 2
  • Masaki Anzai
    • 1
  • Miwa Morikawa
    • 1
  • Yuko Waseda
    • 1
  • Maiko Kadowaki
    • 1
  • Hiroko Shigemi
    • 1
  • Shingo Ameshima
    • 1
    • 3
  • Tetsuya Mori
    • 2
  • Yasushi Kiyono
    • 2
  • Hidehiko Okazawa
    • 2
  • Tamotsu Ishizuka
    • 1
  1. 1.Third Department of Internal Medicine, Faculty of Medical SciencesUniversity of FukuiFukuiJapan
  2. 2.Biomedical Imaging Research CenterUniversity of FukuiFukuiJapan
  3. 3.Department of Internal MedicineSakai Municipal Mikuni HospitalSakaiJapan

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