Abstract
Purpose
To investigate prospectively the potential of O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET in comparison to MRI for the assessment of the response of patients with recurrent high-grade glioma (rHGG) to antiangiogenic treatment.
Methods
Ten patients with rHGG were treated biweekly with bevacizumab/irinotecan (BEV/IR). MR images and dynamic 18F-FET PET scans were obtained at baseline and at follow-up after the start of treatment (median 4.9 weeks). Using MRI treatment response was evaluated according to RANO (Response Assessment in Neuro-Oncology) criteria. For 18F-FET PET evaluation, a reduction >45 % of the metabolically active tumour volume was considered as a treatment response, with the metabolically active tumour being defined as a tumour-to-brain ratio (TBR) of ≥1.6. The results of the treatment assessments were related to progression-free survival (PFS) and overall survival (OS). For further evaluation of PET data, maximum and mean TBR were calculated using region-of-interest analysis at baseline and at follow-up. Additionally, 18F-FET uptake kinetic studies were performed at baseline and at follow-up in all patients. Time–activity curves were generated and the times to peak (TTP) uptake (in minutes from the beginning of the dynamic acquisition to the maximum uptake) were calculated.
Results
At follow-up, MRI showed a complete response according to RANO criteria in one of the ten patients (10 %), a partial response in five patients (50 %), and stable disease in four patients (40 %). Thus, MRI did not detect tumour progression. In contrast, 18F-FET PET revealed six metabolic responders (60 %) and four nonresponders (40 %). In the univariate survival analyses, a response detected by 18F-FET PET predicted a significantly longer PFS (median PFS, 9 vs. 3 months; P = 0.001) and OS (median OS 23.0 months vs. 3.5 months; P = 0.001). Furthermore, in four patients (40 %), diagnosis according to RANO criteria and by 18F-FET PET was discordant. In these patients, PET was able to detect tumour progression earlier than MRI (median time benefit 10.5 weeks; range 6–12 weeks). At baseline and at follow-up, in nonresponders TTP was significantly shorter than in responders (baseline TTP 10 ± 8 min vs. 35 ± 9 min; P = 0.002; follow-up TTP 23 ± 9 min vs. 39 ± 8 min; P = 0.02). Additionally, at baseline a kinetic pattern characterized by an early peak of 18F-FET uptake followed by a constant descent was more frequently observed in the nonresponders (P = 0.018).
Conclusion
Both standard and kinetic imaging parameters derived from18F-FET PET seem to predict BEV/IR treatment failure and thus contribute important additional information for clinical management over and above the information obtained by MRI response assessment based on RANO criteria.
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References
Vredenburgh JJ, Desjardins A, Herndon 2nd JE, Marcello J, Reardon DA, Quinn JA, et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol. 2007;25:4722–9.
Macdonald DR, Cascino TL, Schold Jr SC, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8:1277–80.
Wick W, Wick A, Weiler M, Weller M. Patterns of progression in malignant glioma following anti-VEGF therapy: perceptions and evidence. Curr Neurol Neurosci Rep. 2011;11:305–12.
Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28:1963–72.
Pope WB, Young JR, Ellingson BM. Advances in MRI assessment of gliomas and response to anti-VEGF therapy. Curr Neurol Neurosci Rep. 2011;11:336–44.
Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller HW, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain. 2005;128:678–87.
Piroth MD, Pinkawa M, Holy R, Klotz J, Nussen S, Stoffels G, et al. Prognostic value of early [18F]fluoroethyltyrosine positron emission tomography after radiochemotherapy in glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2011;80:176–84.
Galldiks N, Kracht LW, Burghaus L, Thomas A, Jacobs AH, Heiss WD, et al. Use of 11C-methionine PET to monitor the effects of temozolomide chemotherapy in malignant gliomas. Eur J Nucl Med Mol Imaging. 2006;33:516–24.
Pöpperl G, Goldbrunner R, Gildehaus FJ, Kreth FW, Tanner P, Holtmannspotter M, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging. 2005;32:1018–25.
Pöpperl G, Götz C, Rachinger W, Schnell O, Gildehaus FJ, Tonn JC, et al. Serial O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma. Eur J Nucl Med Mol Imaging. 2006;33:792–800.
Galldiks N, Kracht LW, Burghaus L, Ullrich RT, Backes H, Brunn A, et al. Patient-tailored, imaging-guided, long-term temozolomide chemotherapy in patients with glioblastoma. Mol Imaging. 2010;9:40–6.
Galldiks N, Langen KJ, Holy R, Pinkawa M, Stoffels G, Nolte KW, et al. Assessment of treatment response in patients with glioblastoma using O-(2-18F-fluoroethyl)-L-tyrosine PET in comparison to MRI. J Nucl Med. 2012;53:1–10. doi:10.2967/jnumed.111.098590.
Hutterer M, Nowosielski M, Putzer D, Waitz D, Tinkhauser G, Kostron H, et al. O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma. J Nucl Med. 2011;52:856–64.
Weckesser M, Langen KJ, Rickert CH, Kloska S, Straeter R, Hamacher K, et al. O-(2-[18F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging. 2005;32:422–9. doi:10.1007/s00259-004-1705-8.
Pöpperl G, Kreth FW, Herms J, Koch W, Mehrkens JH, Gildehaus FJ, et al. Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods? J Nucl Med. 2006;47:393–403.
Pöpperl G, Kreth FW, Mehrkens JH, Herms J, Seelos K, Koch W, et al. FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging. 2007;34:1933–42. doi:10.1007/s00259-007-0534-y.
Kunz M, Thon N, Eigenbrod S, Hartmann C, Egensperger R, Herms J, et al. Hot spots in dynamic (18)FET-PET delineate malignant tumor parts within suspected WHO grade II gliomas. Neuro Oncol. 2011;13:307–16.
Calcagni ML, Galli G, Giordano A, Taralli S, Anile C, Niesen A, et al. Dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (F-18 FET) PET for glioma grading: assessment of individual probability of malignancy. Clin Nucl Med. 2011;36:841–7.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987–96.
Wolff JE, Driever PH, Erdlenbruch B, Kortmann RD, Rutkowski S, Pietsch T, et al. Intensive chemotherapy improves survival in pediatric high-grade glioma after gross total resection: results of the HIT-GBM-C protocol. Cancer. 2010;116:705–12.
Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The Polymer-brain Tumor Treatment Group. Lancet. 1995;345:1008–12.
Wick A, Pascher C, Wick W, Jauch T, Weller M, Bogdahn U, et al. Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol. 2009;256:734–41.
Wick W, Steinbach JP, Kuker WM, Dichgans J, Bamberg M, Weller M. One week on/one week off: a novel active regimen of temozolomide for recurrent glioblastoma. Neurology. 2004;62:2113–5.
Stummer W, Beck T, Beyer W, Mehrkens JH, Obermeier A, Etminan N, et al. Long-sustaining response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by interstitial photodynamic therapy using 5-ALA: case report. J Neurooncol. 2008;87:103–9.
Hamacher K, Coenen HH. Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot. 2002;57:853–6.
Vollmar S, Hampl J, Kracht L, Herholz K. Integration of functional data (PET) into brain surgery planning and neuronavigation. In: Buzug TM, Holz D, Bongartz J, Kohl-Bareis M, Hartmann U, Weber S, editors. Advances in Medical Engineering. Springer Proceedings in Physics, vol 114. Berlin: Springer; 2007. p. 98–103.
Galldiks N, Ullrich R, Schroeter M, Fink GR, Jacobs AH, Kracht LW. Volumetry of [(11)C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme. Eur J Nucl Med Mol Imaging. 2010;37:84–92. doi:10.1007/s00259-009-1219-5.
Gupta K, Radotra BD, Banerjee AK, Nijhawan R. Quantitation of angiogenesis and its correlation with vascular endothelial growth factor expression in astrocytic tumors. Anal Quant Cytol Histol. 2004;26:223–9.
Miyagawa T, Oku T, Uehara H, Desai R, Beattie B, Tjuvajev J, et al. “Facilitated” amino acid transport is upregulated in brain tumors. J Cereb Blood Flow Metab. 1998;18:500–9.
Heiss P, Mayer S, Herz M, Wester HJ, Schwaiger M, Senekowitsch-Schmidtke R. Investigation of transport mechanism and uptake kinetics of O-(2-[18F]fluoroethyl)-L-tyrosine in vitro and in vivo. J Nucl Med. 1999;40:1367–73.
Jain RK. Molecular regulation of vessel maturation. Nat Med. 2003;9:685–93.
Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.
Sorensen AG, Emblem KE, Polaskova P, Jennings D, Kim H, Ancukiewicz M, et al. Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res. 2012;72:402–7. doi:10.1158/0008-5472.CAN-11-2464.
Floeth FW, Sabel M, Ewelt C, Stummer W, Felsberg J, Reifenberger G, et al. Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas. Eur J Nucl Med Mol Imag. 2011;38:731–41.
von Baumgarten L, Brucker D, Tirniceru A, Kienast Y, Grau S, Burgold S, et al. Bevacizumab has differential and dose-dependent effects on glioma blood vessels and tumor cells. Clin Cancer Res. 2011;17:6192–205.
Huang Y, Snuderl M, Jain RK. Polarization of tumor-associated macrophages: a novel strategy for vascular normalization and antitumor immunity. Cancer Cell. 2011;19:1–2.
Acknowledgments
The authors wish to thank Suzanne Schaden, Elisabeth Theelen and Kornelia Frey for assistance in the patient studies and Dr. Johannes Ermert, Silke Grafmüller, Erika Wabbals and Sascha Rehbein for radiosynthesis of 18F-FET. The Brain Imaging Center West (BICW) supported this work.
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Galldiks, N., Rapp, M., Stoffels, G. et al. Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]Fluoroethyl-l-tyrosine PET in comparison to MRI. Eur J Nucl Med Mol Imaging 40, 22–33 (2013). https://doi.org/10.1007/s00259-012-2251-4
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DOI: https://doi.org/10.1007/s00259-012-2251-4