Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging

Anne Laprie, Soléakhéna Ken, Thomas Filleron, Vincent Lubrano, Laure Vieillevigne, Fatima Tensaouti, Isabelle Catalaa, Sergio Boetto, Jonathan Khalifa, Justine Attal, Guillaume Peyraga, Carlos Gomez-Roca, Emmanuelle Uro-Coste, Georges Noel, Gilles Truc, Marie-Pierre Sunyach, Nicolas Magné, Marie Charissoux, Stéphane Supiot, Valérie Bernier, Muriel Mounier, Muriel Poublanc, Amandine Fabre, Jean-Pierre Delord, Elizabeth Cohen-Jonathan Moyal, Anne Laprie, Soléakhéna Ken, Thomas Filleron, Vincent Lubrano, Laure Vieillevigne, Fatima Tensaouti, Isabelle Catalaa, Sergio Boetto, Jonathan Khalifa, Justine Attal, Guillaume Peyraga, Carlos Gomez-Roca, Emmanuelle Uro-Coste, Georges Noel, Gilles Truc, Marie-Pierre Sunyach, Nicolas Magné, Marie Charissoux, Stéphane Supiot, Valérie Bernier, Muriel Mounier, Muriel Poublanc, Amandine Fabre, Jean-Pierre Delord, Elizabeth Cohen-Jonathan Moyal

Abstract

Background: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival.

Methods/design: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status.

Discussion: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging.

Trial registration: NCT01507506 , registration date December 20, 2011.

Keywords: Clinical trial; Dose-painting; Glioblastoma; Magnetic resonance spectroscopic imaging; Phase III,online prospective quality control; Proton spectroscopy; Radiotherapy; Spectroscopy.

Conflict of interest statement

Ethics approval and consent to participate

This trial was reviewed and approved by the French ethics committee on 28 April 2010: registration number 2009-A00594–53.

This covers all participating centers.which are:

Institut Claudius Regaud at Institut Universitaire du Cancer de Toulouse-Oncopole- Toulouse-France.

Centre Paul Strauss- Strasbourg- France.

Centre Georges-François Leclerc – Dijon- France.

Centre Léon Bérard- Lyon- France.

Institut de Cancérologie de la Loire- Saint-Priest en Jarez.

Centre Val d’aurelle – Montpellier- France.

Clinique Claude Bernard- Albi- France.

All subjects signed a written informed consent form.

Consent for publication

Consent for publication is not applicable to this article.

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Study design
Fig. 2
Fig. 2
Study workflow
Fig. 3
Fig. 3
Example of an arm B patient:3A MRSI map showing abnormalities of Cho/NAA > 2
Fig. 4
Fig. 4
a-delineated GTV1(orange), CTV1 (blue), PTV1 (pink) on T1gado MRI, 4b MRSI map, 4Bc GTV1, CTV1, PTV1 GTV2(red), CTV2(cyan), PTV2 (green) 4d resulting volumes on axial view (d), frontal view (e) sagittal view (f)
Fig. 5
Fig. 5
Corresponding dosimetry in a) axial slice, b) sagittal orientation, c) coronal orientation, GTVs, CTVs and PTVs are displayed with identical color lines as in Fig. 4. The isodoses are displayed in colorwash. In Blue 95% of 60Gy on PTV1, in orange 95% of 72Gy on PTV2

References

    1. Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era. J Neuro-Oncol. 2012;107:359–364. doi: 10.1007/s11060-011-0749-4.
    1. Ling CC, Humm J, Larson S, Amols H, Fuks Z, Leibel S, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys. 2000;47:551–560. doi: 10.1016/S0360-3016(00)00467-3.
    1. Bentzen SM, Gregoire V. Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol. 2011;21:101–110. doi: 10.1016/j.semradonc.2010.10.001.
    1. Laprie A, Catalaa I, Cassol E, McKnight TR, Berchery D, Marre D, et al. Proton magnetic resonance spectroscopic imaging in newly diagnosed glioblastoma: predictive value for the site of Postradiotherapy relapse in a prospective longitudinal study. Int J Radiat Oncol Biol Phys. 2008;70:773–781. doi: 10.1016/j.ijrobp.2007.10.039.
    1. McKnight TR, von dem Bussche MH, Vigneron DB, Lu Y, Berger MS, McDermott MW, et al. Histopathological validation of a three-dimensional magnetic resonance spectroscopy index as a predictor of tumor presence. J Neurosurg. 2002;97:794–802. doi: 10.3171/jns.2002.97.4.0794.
    1. Park I, Tamai G, Lee MC, Chuang CF, Chang SM, Berger MS, et al. Patterns of recurrence analysis in newly diagnosed glioblastoma multiforme after three-dimensional conformal radiation therapy with respect to pre-radiation therapy magnetic resonance spectroscopic findings. Int J Radiat Oncol Biol Phys. 2007;69:381–389. doi: 10.1016/j.ijrobp.2007.03.019.
    1. Pirzkall A, Li X, Oh J, Chang S, Berger MS, Larson DA, et al. 3D MRSI for resected high-grade gliomas before RT: tumor extent according to metabolic activity in relation to MRI. Int J Radiat Oncol Biol Phys. 2004;59:126–137. doi: 10.1016/j.ijrobp.2003.08.023.
    1. Crawford FW, Khayal IS, McGue C, Saraswathy S, Pirzkall A, Cha S, et al. Relationship of pre-surgery metabolic and physiological MR imaging parameters to survival for patients with untreated GBM. J Neuro-Oncol. 2009;91:337–351. doi: 10.1007/s11060-008-9719-x.
    1. Saraswathy S, Crawford FW, Lamborn KR, Pirzkall A, Chang S, Cha S, et al. Evaluation of MR markers that predict survival in patients with newly diagnosed GBM prior to adjuvant therapy. J Neuro-Oncol. 2009;91:69–81. doi: 10.1007/s11060-008-9685-3.
    1. Cho KH, Hall WA, Lo SS, Dusenbery KE. Stereotactic radiosurgery versus fractionated stereotactic radiotherapy boost for patients with glioblastoma multiforme. Technol Cancer Res Treat. 2004;3:41–49. doi: 10.1177/153303460400300105.
    1. Sultanem K, Patrocinio H, Lambert C, Corns R, Leblanc R, Parker W, et al. The use of hypofractionated intensity-modulated irradiation in the treatment of glioblastoma multiforme: preliminary results of a prospective trial. Int J Radiat Oncol Biol Phys. 2004;58:247–252. doi: 10.1016/S0360-3016(03)00819-8.
    1. Nwokedi EC, DiBiase SJ, Jabbour S, Herman J, Amin P, Chin LS. Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery. 2002;50:41–46.
    1. Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T. High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison. Lancet Oncol. 2005;6:953–960. doi: 10.1016/S1470-2045(05)70395-8.
    1. Cardinale R, Won M, Choucair A, Gillin M, Chakravarti A, Schultz C, et al. A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023. Int J Radiat Oncol Biol Phys. 2006;65:1422–1428. doi: 10.1016/j.ijrobp.2006.02.042.
    1. Laprie A, Pirzkall A, Haas-Kogan DA, Cha S, Banerjee A, Le TP, et al. Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2005;62:20–31. doi: 10.1016/j.ijrobp.2004.09.027.
    1. Ken S, Vieillevigne L, Franceries X, Simon L, Supper C, Lotterie J-A, et al. Integration method of 3D MR spectroscopy into treatment planning system for glioblastoma IMRT dose painting with integrated simultaneous boost. Radiat Oncol. 2013;8(1).
    1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJB, et al. Radiotherapy plus concomitant and adjuvant Temozolomide for glioblastoma. N Engl J Med. 2005;352:987–996. doi: 10.1056/NEJMoa043330.
    1. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9:453–461. doi: 10.1016/S1470-2045(08)70125-6.
    1. Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, et al. Response assessment in neuro-oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncology. 2016;18:1199–1208. doi: 10.1093/neuonc/now058.
    1. Lips IM, van der Heide UA, Haustermans K, van Lin EN, Pos F, Franken SP, et al. Single blind randomized phase III trial to investigate the benefit of a focal lesion ablative microboost in prostate cancer (FLAME-trial): study protocol for a randomized controlled trial. Trials. 2011;12:255. doi: 10.1186/1745-6215-12-255.
    1. Oehlke O, Mix M, Graf E, Schimek-Jasch T, Nestle U, Götz I, et al. Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1) BMC Cancer. 2016;16:769. doi: 10.1186/s12885-016-2806-z.
    1. Fleckenstein J, Hellwig D, Kremp S, Grgic A, Gröschel A, Kirsch C-M, et al. F-18-FDG-PET confined radiotherapy of locally advanced NSCLC with concomitant chemotherapy: results of the PET-PLAN pilot trial. Int J Radiat Oncol. 2011;81:e283–e289. doi: 10.1016/j.ijrobp.2011.01.020.
    1. Welz S, Mönnich D, Pfannenberg C, Nikolaou K, Reimold M, La Fougère C, et al. Prognostic value of dynamic hypoxia PET in head and neck cancer: results from a planned interim analysis of a randomized phase II hypoxia-image guided dose escalation trial. Radiother Oncol. 2017.
    1. Even AJG, Reymen B, La Fontaine MD, Das M, Jochems A, Mottaghy FM, et al. Predicting tumor hypoxia in non-small cell lung cancer by combining CT, FDG PET and dynamic contrast-enhanced CT. Acta Oncol (Madr) 2017;56:1591–1596. doi: 10.1080/0284186X.2017.1349332.
    1. Carrie C, Grill J, Figarella-Branger D, Bernier V, Padovani L, Habrand JL, et al. Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. J Clin Oncol. 2009;27:1879–1883. doi: 10.1200/JCO.2008.18.6437.
    1. Peters LJ, O’Sullivan B, Giralt J, Fitzgerald TJ, Trotti A, Bernier J, et al. Critical impact of radiotherapy protocol compliance and quality in the treatment of advanced head and neck Cancer: results from TROG 02.02. J Clin Oncol. 2010;28:2996–3001. doi: 10.1200/JCO.2009.27.4498.
    1. Ohri N, Shen X, Dicker AP, Doyle LA, Harrison AS, Showalter TN. Radiotherapy protocol deviations and clinical outcomes: a meta-analysis of cooperative group clinical trials. JNCI J Natl Cancer Inst. 2013;105:387–393. doi: 10.1093/jnci/djt001.
    1. Weber DC, Tomsej M, Melidis C, Hurkmans CW. QA makes a clinical trial stronger: evidence-based medicine in radiation therapy. Radiother Oncol. 2012;105:4–8. doi: 10.1016/j.radonc.2012.08.008.
    1. Khalifa J, Tensaouti F, Chaltiel L, Lotterie J-A, Catalaa I, Sunyach MP, et al. Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation. Eur Radiol. 2016;26:4194–4203. doi: 10.1007/s00330-016-4234-5.
    1. Khalifa J, Tensaouti F, Lotterie J-A, Catalaa I, Chaltiel L, Benouaich-Amiel A, et al. Do perfusion and diffusion MRI predict glioblastoma relapse sites following chemoradiation? J Neuro-Oncol. 2016;130.
    1. Deviers A, Ken S, Filleron T, Rowland B, Laruelo A, Catalaa I, et al. Evaluation of the lactate-to-N-acetyl-aspartate ratio defined with magnetic resonance spectroscopic imaging before radiation therapy as a new predictive marker of the site of relapse in patients with glioblastoma multiforme. Int J Radiat Oncol Biol Phys. 2014;90:385–393. doi: 10.1016/j.ijrobp.2014.06.009.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit