Advertisement

3′-Deoxy-3’-18F-Fluorothymidine and 18F-Fluorodeoxyglucose positron emission tomography for the early prediction of response to Regorafenib in patients with metastatic colorectal cancer refractory to all standard therapies

  • Jeong Eun Kim
  • Sun Young Chae
  • Jwa Hoon Kim
  • Hwa Jung Kim
  • Tae Won Kim
  • Kyu-pyo Kim
  • Sun Young Kim
  • Jae-Lyun Lee
  • Seung Jun Oh
  • Jae Seung Kim
  • Jin-Sook Ryu
  • Dae Hyuk Moon
  • Yong Sang HongEmail author
Original Article
  • 78 Downloads

Abstract

Purpose

The purpose of this study was to evaluate the value of 3′-deoxy-3′-18F-fluorothymidine (18F-FLT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) for early prediction of standard anatomic response and survival outcomes in patients with metastatic colorectal cancer (mCRC) receiving Regorafenib.

Methods

Sixty-eight patients with mCRC refractory to standard cytotoxic chemotherapy were enrolled and received Regorafenib (160 mg/day on days 1–21, following a 7-day break). Standard anatomical response was evaluated every 8 weeks. Both scans were performed before and on day 21 of Regorafenib.

Results

Of the 61 patients included in per-protocol analysis, complete response was not observed, but partial response was observed in 8.2% (n = 5), stable disease in 67.2% (n = 41), and progressive disease in 24.6% (n = 15). The objective response rate was 8.2% and disease control rate 75.4%. Five responders (8.2%) and 13 non-responders (21.3%) met the CT and 18F-FLT PET/CT criteria (maximum standardized uptake value decrease ≥ 10.6% for responders). Forty-three (70.5%) exhibited discordant responses on CT and 18F-FLT PET/CT (McNemar test, P < 0.001). At a median follow-up of 8.9 months, median progression-free survival (PFS) and median overall survival (OS) were 3.6 months (95% confidence interval [CI], 3.34–3.80 months) and 8.5 months (95% CI, 6.95–10.10 months), respectively. Comparison of PFS and OS according to 18F-FLT PET/CT response revealed slightly longer PFS (P = 0.015) in responders, but the correlation with OS was not significant. The PET Response Criteria in Solid Tumours (PERCIST) of 18F-FDG PET/CT revealed differences in PFS and OS between partial metabolic response (PMR) and non-PMR (P = 0.048 and P = 0.014, respectively), and between progressive metabolic disease (PMD) and non-PMD (P = 0.189 and P = 0.007, respectively).

Conclusions

Survival outcome was significantly associated with PERCIST using 18F-FDG PET/CT but the change of 18F-FLT uptake was only slightly associated with PFS. 18F-FDG PET/CT can be used as imaging biomarker to predict clinical outcomes early in patients with mCRC receiving Regorafenib.

Keywords

18F-fluorothymidine 18F-fluorodeoxyglucose Positron emission tomography Regorafenib Metastatic colorectal cancer 

Notes

Acknowledgements

This study was supported by a grant (2014-9079) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea, and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI18C2383). Regorafenib was kindly provided by Bayer.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Asan Medical Center and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material

259_2019_4330_Fig4_ESM.png (69 kb)
Online Resource 1

Kaplan-Meier curves showing the PFS and OS in patients with metastatic colorectal cancer receiving Regorafenib. (a) The median PFS was 3.6 months (95% CI, 3.34–3.80), and (b) the median OS was 8.5 months (95% CI, 6.95–10.10) (PNG 69 kb)

259_2019_4330_MOESM1_ESM.tif (743 kb)
High resolution image (TIF 742 kb)
259_2019_4330_Fig5_ESM.png (76 kb)
Online Resource 2

Kaplan-Meier curves showing the PFS and OS according to the change of 18F-FLT uptake in patients with colorectal cancer with only extrahepatic metastasis receiving Regorafenib (n = 37). (a) The median PFS was 5.9 months (95% CI, 3.30–8.57) for responders on 18F-FLT PET/CT (patients with a decrease of SUVmax ≥10.6% on day 21 of Regorafenib) and 3.4 months (95% CI, 2.94–3.94) for non-responders (P < 0.001). (b) The median OS was 14.0 months (95% CI, 6.34–21.66) for the responders on 18F-FLT PET/CT and 8.0 months (95% CI, 0.00–16.70) for the non-responders (P = 0.150) (PNG 75 kb)

259_2019_4330_MOESM2_ESM.tif (703 kb)
High resolution image (TIF 702 kb)

References

  1. 1.
    Bennouna J, Sastre J, Arnold D, Osterlund P, Greil R, Van Cutsem E, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol. 2013;14:29–37.CrossRefGoogle Scholar
  2. 2.
    Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.CrossRefGoogle Scholar
  3. 3.
    Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008;26:2013–9.CrossRefGoogle Scholar
  4. 4.
    Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.CrossRefGoogle Scholar
  5. 5.
    Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.CrossRefGoogle Scholar
  6. 6.
    Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, et al. Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28:4697–705.CrossRefGoogle Scholar
  7. 7.
    Peeters M, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, et al. Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. 2010;28:4706–13.CrossRefGoogle Scholar
  8. 8.
    Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–12.CrossRefGoogle Scholar
  9. 9.
    Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski P, Gelderblom H, et al. Efficacy and safety of Regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:295–302.CrossRefGoogle Scholar
  10. 10.
    Li J, Qin S, Xu R, Yau TC, Ma B, Pan GH, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619–29.CrossRefGoogle Scholar
  11. 11.
    Cousin S, Taieb S, Penel N. A paradigm shift in tumour response evaluation of targeted therapy: the assessment of novel drugs in exploratory clinical trials. Curr Opin Oncol. 2012;24:338–44.CrossRefGoogle Scholar
  12. 12.
    Milano A, Perri F, Ciarmiello A, Caponigro F. Targeted-therapy and imaging response: a new paradigm for clinical evaluation? Rev Recent Clin Trials. 2011;6:259–65.CrossRefGoogle Scholar
  13. 13.
    Desar IM, van Herpen CM, van Laarhoven HW, Barentsz JO, Oyen WJ, van der Graaf WT. Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy. Cancer Treat Rev. 2009;35:309–21.CrossRefGoogle Scholar
  14. 14.
    Boellaard R, O'Doherty MJ, Weber WA, Mottaghy FM, Lonsdale MN, Stroobants SG, et al. FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0. Eur J Nucl Med Mol Imaging. 2010;37:181–200.CrossRefGoogle Scholar
  15. 15.
    Pauwels EK, Ribeiro MJ, Stoot JH, McCready VR, Bourguignon M, Maziere B. FDG accumulation and tumor biology. Nucl Med Biol. 1998;25:317–22.CrossRefGoogle Scholar
  16. 16.
    Bollineni VR, Kramer GM, Jansma EP, Liu Y, Oyen WJ. A systematic review on [(18)F]FLT-PET uptake as a measure of treatment response in cancer patients. Eur J Cancer. 2016;55:81–97.CrossRefGoogle Scholar
  17. 17.
    Chen W, Delaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007;25:4714–21.CrossRefGoogle Scholar
  18. 18.
    Herrmann K, Wieder HA, Buck AK, Schoffel 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.CrossRefGoogle Scholar
  19. 19.
    Kahraman D, Scheffler M, Zander T, Nogova L, Lammertsma AA, Boellaard R, et al. Quantitative analysis of response to treatment with erlotinib in advanced non-small cell lung cancer using 18F-FDG and 3′-deoxy-3'-18F-fluorothymidine PET. J Nucl Med. 2011;52:1871–7.CrossRefGoogle Scholar
  20. 20.
    Kim SJ, Lee JS, Im KC, Kim SY, Park SA, Lee SJ, et al. Kinetic modeling of 3′-deoxy-3'-18F-fluorothymidine for quantitative cell proliferation imaging in subcutaneous tumor models in mice. J Nucl Med. 2008;49:2057–66.CrossRefGoogle Scholar
  21. 21.
    McKinley ET, Smith RA, Zhao P, Fu A, Saleh SA, Uddin MI, et al. 3′-Deoxy-3'-18F-fluorothymidine PET predicts response to (V600E)BRAF-targeted therapy in preclinical models of colorectal cancer. J Nucl Med. 2013;54:424–30.CrossRefGoogle Scholar
  22. 22.
    Nakajo M, Nakajo M, Kajiya Y, Jinguji M, Nishimata N, Shimaoka S, et al. Diagnostic performance of (1)(8)F-fluorothymidine PET/CT for primary colorectal cancer and its lymph node metastasis: comparison with (1)(8)F-fluorodeoxyglucose PET/CT. Eur J Nucl Med Mol Imaging. 2013;40:1223–32.CrossRefGoogle Scholar
  23. 23.
    Sohn HJ, Yang YJ, Ryu JS, Oh SJ, Im KC, Moon DH, et al. [18F]Fluorothymidine positron emission tomography before and 7 days after gefitinib treatment predicts response in patients with advanced adenocarcinoma of the lung. Clin Cancer Res. 2008;14:7423–9.CrossRefGoogle Scholar
  24. 24.
    Hong YS, Kim HO, Kim KP, Lee JL, Kim HJ, Lee SJ, et al. 3′-Deoxy-3'-18F-fluorothymidine PET for the early prediction of response to leucovorin, 5-fluorouracil, and oxaliplatin therapy in patients with metastatic colorectal cancer. J Nucl Med. 2013;54:1209–16.CrossRefGoogle Scholar
  25. 25.
    Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.CrossRefGoogle Scholar
  26. 26.
    Lee SJ, Oh SJ, Chi DY, Lee BS, Ryu JS, Moon DH. Comparison of synthesis yields of 3′-deoxy-3′-[18F] fluorothymidine by nucleophilic fluorination in various alcohol solvents. J Labelled Compd. 2008;51:80–2.CrossRefGoogle Scholar
  27. 27.
    Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122s–50s.CrossRefGoogle Scholar
  28. 28.
    JH O, Lodge MA, Wahl RL. Practical PERCIST: a simplified guide to PET response criteria in solid tumors 1.0. Radiology. 2016;280:576–84.CrossRefGoogle Scholar
  29. 29.
    Benner A. Sample size tables for clinical studies. In: Machin D, Campbell MJ, Fayers PM, APY P, editors. Stat Med. 2nd ed. Oxford: Blackwell Science Ltd; 1999. p. 494–5.Google Scholar
  30. 30.
    Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18] FLT and positron emission tomography. Nat Med. 1998;4:1334–6.CrossRefGoogle Scholar
  31. 31.
    Contractor K, Challapalli A, Tomasi G, Rosso L, Wasan H, Stebbing J, et al. Imaging of cellular proliferation in liver metastasis by [18F] fluorothymidine positron emission tomography: effect of therapy. Phys Med Biol. 2012;57:3419–33.CrossRefGoogle Scholar
  32. 32.
    Desar IM, Gilles R, van Herpen CM, Timmer-Bonte AJ, Cantarini MV, van der Graaf WT, et al. (18)F-FLT-PET for response evaluation of MEK inhibitor Selumetinib (AZD6244, ARRY-142886) in patients with solid tumors. World J Nucl Med. 2012;11:65–9.CrossRefGoogle Scholar
  33. 33.
    Mogensen MB, Loft A, Aznar M, Axelsen T, Vainer B, Osterlind K, et al. FLT-PET for early response evaluation of colorectal cancer patients with liver metastases: a prospective study. EJNMMI Res. 2017;7:56.CrossRefGoogle Scholar
  34. 34.
    de Geus-Oei LF, van Laarhoven HW, Visser EP, Hermsen R, van Hoorn BA, Kamm YJ, et al. Chemotherapy response evaluation with FDG-PET in patients with colorectal cancer. Ann Oncol. 2008;19:348–52.CrossRefGoogle Scholar
  35. 35.
    Juweid ME, Cheson BD. Positron-emission tomography and assessment of cancer therapy. N Engl J Med. 2006;354:496–507.CrossRefGoogle Scholar
  36. 36.
    Poliakova M, Aebersold DM, Zimmer Y, Medova M. The relevance of tyrosine kinase inhibitors for global metabolic pathways in cancer. Mol Cancer. 2018;17:27.CrossRefGoogle Scholar
  37. 37.
    Lastoria S, Piccirillo MC, Caraco C, Nasti G, Aloj L, Arrichiello C, et al. Early PET/CT scan is more effective than RECIST in predicting outcome of patients with liver metastases from colorectal cancer treated with preoperative chemotherapy plus bevacizumab. J Nucl Med. 2013;54:2062–9.CrossRefGoogle Scholar
  38. 38.
    Lim Y, Bang JI, Han SW, Paeng JC, Lee KH, Kim JH, et al. Total lesion glycolysis (TLG) as an imaging biomarker in metastatic colorectal cancer patients treated with Regorafenib. Eur J Nucl Med Mol Imaging. 2017;44:757–64.CrossRefGoogle Scholar
  39. 39.
    Eckel F, Herrmann K, Schmidt S, Hillerer C, Wieder HA, Krause BJ, et al. Imaging of proliferation in hepatocellular carcinoma with the in vivo marker 18F-fluorothymidine. J Nucl Med. 2009;50:1441–7.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jeong Eun Kim
    • 1
  • Sun Young Chae
    • 2
  • Jwa Hoon Kim
    • 1
  • Hwa Jung Kim
    • 3
  • Tae Won Kim
    • 1
  • Kyu-pyo Kim
    • 1
  • Sun Young Kim
    • 1
  • Jae-Lyun Lee
    • 1
  • Seung Jun Oh
    • 2
  • Jae Seung Kim
    • 2
  • Jin-Sook Ryu
    • 2
  • Dae Hyuk Moon
    • 2
  • Yong Sang Hong
    • 1
    Email author
  1. 1.Department of Oncology, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  2. 2.Department of Nuclear Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea
  3. 3.Department of Preventive Medicine, Asan Medical CenterUniversity of Ulsan College of MedicineSeoulRepublic of Korea

Personalised recommendations