Skip to main content

Advertisement

SpringerLink
Log in

18F-FLT PET/CT imaging in patients with advanced solid malignancies treated with axitinib on an intermittent dosing regimen

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

This study utilizes FLT PET/CT imaging to characterize changes in tumor cell proliferation and vasculature during intermittent treatment with VEGR-TKI axitinib.

Methods

Patients with metastatic solid malignancies underwent 3-week treatment cycles with axitinib (7 and 5 mg BID for safety and pharmacodynamic cohorts, respectively). Cycles consisted of 2 weeks of treatment (dosing period) followed by a 1-week treatment break (washout period). Patients in the pharmacodynamic cohort had up to six FLT PET/CT scans (three scans in each cycle 1 and cycle 3) and had plasma VEGF concentrations measured at imaging timepoints. Changes in tumor SUVs and VEGF within and across drug cycles were investigated.

Results

Eight patients enrolled in the safety cohort where it was determined 7 mg axitinib was not tolerable due to severe adverse events, including three patients who experienced significant hypertension and thrombovascular effects. Sixteen patients enrolled in the pharmacodynamic cohort demonstrated significant decreases in SUVs and increases in VEGF during dosing periods. This was followed by significant increases in SUVs and decreases in VEGF during drug washout periods. No significant differences in SUVs or VEGF were found when comparing cycle 1 with cycle 3. A mixed effects model demonstrated significant negative correlation between SUV and VEGF.

Conclusions

Response to axitinib included diminished FLT uptake during dosing periods followed by increased FLT uptake during drug washout periods. These changes were not different when comparing treatment cycle 1 versus cycle 3, suggesting that the pharmacodynamic effect of intermittent axitinib is similar across multiple drug cycles.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Folkman J (2003) Angiogenesis inhibitors: a new class of drugs. Cancer Biol Ther 2:S127–S133

    CAS  PubMed  Google Scholar 

  2. Vasudev NS, Reynolds AR (2014) Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. Angiogenesis 17:471–494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bautch V (2012) VEGF-directed blood vessel patterning: from cells to organisms. In: Klagsburn M, D'Amore P (eds) Angiogensis biology and pathology. Cold Spring Harbor, New York, pp 29–40

    Google Scholar 

  4. Sonpavde G, Hutson T, Rini B (2008) Axitinib for renal cell carcinoma. Expert Opin Investig Drugs 17(5):741–748

    Article  CAS  PubMed  Google Scholar 

  5. Rini BI, Garrett M, Poland B, Dutcher JP, Rixe O, Wilding G et al (2013) Axitinib in metastatic renal cell carcinoma: results of a pharmacokinetic and pharmacodynamic analysis. J Clin Pharamcol 53(5):491–504

    Article  CAS  Google Scholar 

  6. Hoh CK, Burris HA, Bendell JC, Tarazi J, Rosbrook B, Kim S, Infante JR, Reid TR (2014) Intermittent dosing of axitinib combined with chemotherapy is supported by 18FLT-PET in gastrointestinal tumours. Br J Cancer 110(4):875–881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Scagliotti G, Novello S, von Pawel J, Reck M, Pereira JR, Thomas M, Abrão Miziara JE, Balint B, De Marinis F, Keller A, Arén O, Csollak M, Albert I, Barrios CH, Grossi F, Krzakowski M, Cupit L, Cihon F, Dimatteo S, Hanna N (2010) Phase III study of carboplatin and paclitaxel alone or with sorafenib in advanced non-small-cell lung cancer. J Clin Oncol 28:1835–1842

    Article  CAS  PubMed  Google Scholar 

  8. Rugo H, Stopeck AT, Joy AA, Chan S, Verma S, Lluch A, Liau KF, Kim S, Bycott P, Rosbrook B, Bair AH, Soulieres D (2011) Randomized, placebo-controlled, double-blind, phase ii study of axitinib plus docetaxel versus docetaxel plus placebo in patients with metastatic breast cancer. J Clin Oncol 29(18):2459–2465

    Article  CAS  PubMed  Google Scholar 

  9. Kindler H, Ioka T, Richel DJ, Bennouna J, Létourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E (2011) Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol 12(3):256–262

    Article  CAS  PubMed  Google Scholar 

  10. Liu G, Jeraj R, Vanderhoek M, Perlman S, Kolesar J, Harrison M, Simoncic U, Eickhoff J, Carmichael L, Chao B, Marnocha R, Ivy P, Wilding G (2011) Pharmacodynamic study using FLT PET/CT in patients with renal cell cancer and other solid malignancies treated with sunitinib malate. Clin Cancer Res 17:7634–7644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bruce J, Scully PC, Carmichael LL, Eickhoff JC, Perlman SB, Kolesar JM, Heideman JL, Jeraj R, Liu G (2015) Pharmacodynamic study of axitnib in patients with advanced malignancies assessed with 18F-3′deoxy-3′fluoro-l-thymidine positron emission tomorgraphy/computed tomography. Cancer Chemother Pharmacol 76(1):187–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Shields A, Grierson J, Dohmen M, Machulla H, Stayanoff J, Lawhorn-Crews J, Obradovich J, Muzik O, Mangner T (1998) Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 4:1334–1336

    Article  CAS  PubMed  Google Scholar 

  13. Yang W, Zhang Y, Fu Z, Sun X, Mu D, Yu J (2012) Imaging proliferation of 18F-FLT PET/CT correlated with the expression of microvessel density of tumour tissue in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging 39:1289–1296

    Article  CAS  PubMed  Google Scholar 

  14. Horn K, Yap J, Agarwal N, Morton KA, Kadrmas DJ, Beardmore B, Butterfield RI, Boucher K, Hoffman JM (2015) FDG and FLT-PET for early measurment of response to 37.5 mg daily sunitinib therapy in metastatic renal cell carcinoma. Cancer Imaging 15:15

    Article  PubMed  PubMed Central  Google Scholar 

  15. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    Article  CAS  PubMed  Google Scholar 

  16. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the nurses and research specialists of the UWCCC Phase I Program for their efforts in managing this trial, the WIMR PET imaging personnel for acquiring images, and the patients for their participation in this study.

Funding

This clinical trial was funded by a Pfizer Investigator-Initiated Research Grant (PI: Liu) (WS1610530) as well as a Prostate Cancer Foundation Young Investigator Award (MSN133051). This trial was conducted within the Cancer Therapy Discovery and Development (CTD2) research program with support from the Translational Imaging Research Working Group (TIRWG) at the UW Carbone Cancer Center.

Author information

Author notes

    Authors and Affiliations

    1. Department of Medical Physics, Wisconsin Institute for Medical Research, University of Wisconsin, Room 1005, 1111 Highland Ave, Madison, WI, 53705, USA

      Matthew Scarpelli, Robert Jeraj & Glenn Liu

    2. Division of Hematology/Oncology, Department of Medicine, Wisconsin Institute for Medical Research, University of Wisconsin, Room 7105, 1111 Highland Ave, Madison, WI, 53705, USA

      Justine Yang Bruce & Glenn Liu

    3. University of Wisconsin Carbone Cancer Center, University of Wisconsin, 600 Highland Ave, Madison, WI, 53792, USA

      Justine Yang Bruce, Jens Eickhoff, Jill Kolesar, Scott Perlman, Robert Jeraj & Glenn Liu

    4. Department of Biostatistics and Medical Informatics, K6/422 Clinical Science Center, University of Wisconsin, MC 4675, 600 Highland Ave, Madison, WI, 53792, USA

      Lakeesha Carmichael & Jens Eickhoff

    5. Department of Pharmacy, K4/554 Clinical Science Center, University of Wisconsin, 600 Highland Ave, Madison, WI, 53792, USA

      Jill Kolesar

    6. Department of Radiology, Clinical Science Center, University of Wisconsin, 600 Highland Ave, Box 3252, Madison, WI, 53792, USA

      Scott Perlman

    Authors
    1. Matthew Scarpelli
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Justine Yang Bruce
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Lakeesha Carmichael
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Jens Eickhoff
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jill Kolesar
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Scott Perlman
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Robert Jeraj
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Glenn Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Justine Yang Bruce.

    Ethics declarations

    Conflict of interest

    The authors have no conflicts of interest to disclose.

    Human and animal rights

    All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional 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.

    Additional information

    Matthew Scarpelli and Justine Yang Bruce are co-first authors and have contributed equally to the research and writing of the manuscript.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Scarpelli, M., Bruce, J.Y., Carmichael, L. et al. 18F-FLT PET/CT imaging in patients with advanced solid malignancies treated with axitinib on an intermittent dosing regimen. Cancer Chemother Pharmacol 78, 1245–1252 (2016). https://doi.org/10.1007/s00280-016-3183-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00280-016-3183-7

    Keywords

    Search

    Navigation