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Sunitinib administered prior to radiotherapy in patients with non-resectable glioblastoma: results of a Phase II study

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Abstract

Sunitinib is a tyrosine kinase inhibitor with direct anti-tumor and anti-angiogenesis activity targeting VEGFR 1–2, PDGFR α–β, c-kit, bFGF, (CSF-1), FLT3 and RET. The present trial examined the activity of sunitinib in 12 patients with newly diagnosed, non-resectable glioblastoma. Patients (≤75 years of age with performance status [PS] ≥2 and minimental status [MMS] ≥25) were treated post-biopsy with sunitinib 37.5 mg daily for 8 weeks pre-radiotherapy, during radiotherapy (60 Gy, 6 weeks) and post-radiotherapy until disease progression. The primary endpoints were overall response rate (ORR; RANO criteria) after 8 weeks of sunitinib and patient tolerance. Secondary endpoints were percentage of patients free of neurological deterioration pre-radiotherapy, percentage of patients completing radiotherapy, progression-free survival (PFS), overall survival (OS), and 1-year survival. A Simon 2-stage design (12 →20) based on ORR was applied to calculate the number of patients needed to detect at least 10 % response with α error of 0.05 and β error of 0.10. The trial was closed because it did not meet minimal activity criteria. ORR was 0 % with only 1/12 patients (8.3 %) achieving stable disease after sunitinib treatment. No patient showed reduction in gadolinium enhancement. The most frequent G3/4 toxicities were fatigue (24.9 %) and diarrhea (16.6 %); one patient died of a CNS hemorrhage; 10/12 patients (83.3 %) deteriorated neurologically before radiation therapy; median PFS was 7.7 weeks (95 % CI: 7.2–8.2); median OS was 12.8 weeks (95 % CI: 0.5–23.8 weeks); 1-year survival was 0 %. Sunitinib has no activity as monotherapy in glioblastoma, and further investigation of its efficacy in this setting is unwarranted.

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References

  1. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10(5):459–466

    Article  CAS  PubMed  Google Scholar 

  2. Bauchet L, Mathieu-Daude H, Fabbro-Peray P, Rigau V, Fabbro M, Chinot O, Pallusseau L, Carnin C, Laine K, Schlama A, Thiebaut A, Patru MC, Bauchet F, Lionnet M, Wager M, Faillot T, Taillandier L, Figarella-Branger D, Capelle L, Loiseau H, Frappaz D, Campello C, Kerr C, Duffau H, Reme-Saumon M, Tretarre B, Daures JP, Henin D, Labrousse F, Menei P, Honnorat J, Societe Francaise de N, Club de Neuro-Oncologie of the Societe Francaise de N, Societe Francaise de N, Association des Neuro-Oncologues d'Expression F (2010) Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004. Neuro Oncol 12(7):725–735. doi:10.1093/neuonc/noq030

    Article  PubMed Central  PubMed  Google Scholar 

  3. Balaña C, Capellades J, Teixidor P, Roussos I, Ballester R, Cuello M, Arellano A, Florensa R, Rosell R (2008) Clinical course of high-grade glioma patients with a “biopsy-only” surgical approach: a need for individualised treatment. Clin Transl Oncol 9(12):797–803. doi:10.1007/s12094-007-0142-0

    Article  Google Scholar 

  4. Chang SM, Parney IF, Huang W, Anderson FA Jr, Asher AL, Bernstein M, Lillehei KO, Brem H, Berger MS, Laws ER (2005) Patterns of care for adults with newly diagnosed malignant glioma. JAMA 293(5):557–564

    Article  CAS  PubMed  Google Scholar 

  5. Castellano A, Bello L, Michelozzi C, Gallucci M, Fava E, Iadanza A, Riva M, Casaceli G, Falini A (2012) Role of diffusion tensor magnetic resonance tractography in predicting the extent of resection in glioma surgery. Neuro Oncol 14(2):192–202

    Article  PubMed Central  PubMed  Google Scholar 

  6. Kubben PL, ter Meulen KJ, Schijns OE, ter Laak-Poort MP, van Overbeeke JJ, van Santbrink H (2011) Intraoperative MRI-guided resection of glioblastoma multiforme: a systematic review. Lancet Oncol 12(11):1062–1070

    Article  PubMed  Google Scholar 

  7. Grossman SA, Carson K, Piantadosi S, Fisher J, The NABTT CNS Consortium, Baltimore, MD (2002) Survival of adults with newly diagnosed glioblastoma multiforme (GBM) treated with experimental agents and delayed radiation therapy (RT) versus experimental agents and immediate radiation: the experience of the NABTT CNS consortium. J Clin Oncol Proc Am Soc Clin Oncol (21):Abstr 282

  8. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ, Zhu M, Ancukiewicz M, Mrugala MM, Plotkin S, Drappatz J, Louis DN, Ivy P, Scadden DT, Benner T, Loeffler JS, Wen PY, Jain RK (2007) AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11(1):83–95

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M, Wick A, Mason W, Mikkelsen T, Phuphanich S, Ashby LS, Degroot J, Gattamaneni R, Cher L, Rosenthal M, Payer F, Jurgensmeier JM, Jain RK, Sorensen AG, Xu J, Liu Q, van den Bent M (2013) Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol 31(26):3212–3218. doi:10.1200/JCO.2012.47.2464

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Chow LQ, Eckhardt SG (2007) Sunitinib: from rational design to clinical efficacy. J Clin Oncol 25(7):884–896

    Article  CAS  PubMed  Google Scholar 

  11. de Bouard S, Herlin P, Christensen JG, Lemoisson E, Gauduchon P, Raymond E, Guillamo JS (2007) Antiangiogenic and anti-invasive effects of sunitinib on experimental human glioblastoma. Neuro Oncol 9(4):412–423

    Article  PubMed Central  PubMed  Google Scholar 

  12. Giannopoulou E, Dimitropoulos K, Argyriou AA, Koutras AK, Dimitrakopoulos F, Kalofonos HP (2010) An in vitro study, evaluating the effect of sunitinib and/or lapatinib on two glioma cell lines. Invest New Drugs 28(5):554–560

    Article  CAS  PubMed  Google Scholar 

  13. Schueneman AJ, Himmelfarb E, Geng L, Tan J, Donnelly E, Mendel D, McMahon G, Hallahan DE (2003) SU11248 maintenance therapy prevents tumor regrowth after fractionated irradiation of murine tumor models. Cancer Res 63(14):4009–4016

    CAS  PubMed  Google Scholar 

  14. Zhang HP, Takayama K, Su B, Jiao XD, Li R, Wang JJ (2011) Effect of sunitinib combined with ionizing radiation on endothelial cells. J Radiat Res 52(1):1–8

    Article  PubMed  Google Scholar 

  15. Wuthrick EJ, Kamrava M, Curran WJ Jr, Werner-Wasik M, Camphausen KA, Hyslop T, Axelrod R, Andrews DW, Glass J, Machtay M, Dicker AP (2011) A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies. Cancer 117(24):5548–5559

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM (2010) Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28(11):1963–1972

    Article  PubMed  Google Scholar 

  17. Escudier B, Roigas J, Gillessen S, Harmenberg U, Srinivas S, Mulder SF, Fountzilas G, Peschel C, Flodgren P, Maneval EC, Chen I, Vogelzang NJ (2009) Phase II study of sunitinib administered in a continuous once-daily dosing regimen in patients with cytokine-refractory metastatic renal cell carcinoma. J Clin Oncol 27(25):4068–4075

    Article  CAS  PubMed  Google Scholar 

  18. George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, Deprimo SE, Harmon CS, Law CN, Morgan JA, Ray-Coquard I, Tassell V, Cohen DP, Demetri GD (2009) Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumour after imatinib failure. Eur J Cancer 45(11):1959–1968

    Article  CAS  PubMed  Google Scholar 

  19. Nobusawa S, Stawski R, Kim YH, Nakazato Y, Ohgaki H (2011) Amplification of the PDGFRA, KIT and KDR genes in glioblastoma: a population-based study. Neuropathology 31(6):583–588

    Article  PubMed  Google Scholar 

  20. Puputti M, Tynninen O, Sihto H, Blom T, Maenpaa H, Isola J, Paetau A, Joensuu H, Nupponen NN (2006) Amplification of KIT, PDGFRA, VEGFR2, and EGFR in gliomas. Mol Cancer Res 4(12):927–934

    Article  CAS  PubMed  Google Scholar 

  21. Plate KH, Risau W (1995) Angiogenesis in malignant gliomas. Glia 15(3):339–347

    Article  CAS  PubMed  Google Scholar 

  22. Brada M, Ashley S, Dowe A, Gonsalves A, Huchet A, Pesce G, Reni M, Saran F, Wharram B, Wilkins M, Wilkins P (2005) Neoadjuvant phase II multicentre study of new agents in patients with malignant glioma after minimal surgery. Report of a cohort of 187 patients treated with temozolomide. Ann Oncol 16(6):942–949

    Article  CAS  PubMed  Google Scholar 

  23. Chinot OL, Barrie M, Fuentes S, Eudes N, Lancelot S, Metellus P, Muracciole X, Braguer D, Ouafik L, Martin PM, Dufour H, Figarella-Branger D (2007) Correlation between O 6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide. J Clin Oncol 25(12):1470–1475

    Article  CAS  PubMed  Google Scholar 

  24. Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, Brada M, Spence A, Hohl RJ, Shapiro W, Glantz M, Greenberg H, Selker RG, Vick NA, Rampling R, Friedman H, Phillips P, Bruner J, Yue N, Osoba D, Zaknoen S, Levin VA (2000) A phase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 83(5):588–593

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Chahal M, Xu Y, Lesniak D, Graham K, Famulski K, Christensen JG, Aghi M, Jacques A, Murray D, Sabri S, Abdulkarim B (2010) MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib. Neuro Oncol 12(8):822–833

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Ananthnarayan S, Bahng J, Roring J, Nghiemphu P, Lai A, Cloughesy T, Pope WB (2008) Time course of imaging changes of GBM during extended bevacizumab treatment. J Neurooncol 88(3):339–347

    Article  PubMed  Google Scholar 

  27. Neyns B, Sadones J, Chaskis C, Dujardin M, Everaert H, Lv S, Duerinck J, Tynninen O, Nupponen N, Michotte A, De Greve J (2011) Phase II study of sunitinib malate in patients with recurrent high-grade glioma. J Neurooncol 103(3):491–501

    Google Scholar 

  28. Kreisl TN, Smith P, Sul J, Salgado C, Iwamoto FM, Shih JH, Fine HA (2013) Continuous daily sunitinib for recurrent glioblastoma. J Neurooncol 111(1):41–48. doi:10.1007/s11060-012-0988-z

    Article  CAS  PubMed  Google Scholar 

  29. Fetell MR, Grossman SA, Fisher JD, Erlanger B, Rowinsky E, Stockel J, Piantadosi S (1997) Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium. J Clin Oncol 15(9):3121–3128

    CAS  PubMed  Google Scholar 

  30. Hochberg F, Grossman SA, Mikkelsen T, Glantz M, Fisher JD, Piantadosi S (2000) Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium. Neuro Oncol 2(1):29–33

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Wick W, Platten M, Meisner C, Felsberg J, Tabatabai G, Simon M, Nikkhah G, Papsdorf K, Steinbach JP, Sabel M, Combs SE, Vesper J, Braun C, Meixensberger J, Ketter R, Mayer-Steinacker R, Reifenberger G, Weller M (2012) Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol 13(7):707–715. doi:10.1016/S1470-2045(12)70164-X

    Article  CAS  PubMed  Google Scholar 

  32. Malmstrom A, Gronberg BH, Marosi C, Stupp R, Frappaz D, Schultz H, Abacioglu U, Tavelin B, Lhermitte B, Hegi ME, Rosell J, Henriksson R (2012) Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol 13(9):916–926. doi:10.1016/S1470-2045(12)70265-6

    Article  PubMed  Google Scholar 

  33. Taal W, Brandsma D, de Bruin HG, Bromberg JE, Swaak-Kragten AT, Smitt PA, van Es CA, van den Bent MJ (2008) Incidence of early pseudo-progression in a cohort of malignant glioma patients treated with chemoirradiation with temozolomide. Cancer 113(2):405–410

    Article  CAS  PubMed  Google Scholar 

  34. van den Bent MJ, Brandes AA, Rampling R, Kouwenhoven MC, Kros JM, Carpentier AF, Clement PM, Frenay M, Campone M, Baurain JF, Armand JP, Taphoorn MJ, Tosoni A, Kletzl H, Klughammer B, Lacombe D, Gorlia T (2009) Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 27(8):1268–1274

    Article  PubMed Central  PubMed  Google Scholar 

  35. Dresemann G, Weller M, Rosenthal MA, Wedding U, Wagner W, Engel E, Heinrich B, Mayer-Steinacker R, Karup-Hansen A, Fluge O, Nowak A, Mehdorn M, Schleyer E, Krex D, Olver IN, Steinbach JP, Hosius C, Sieder C, Sorenson G, Parker R, Nikolova Z (2010) Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol 96(3):393–402

    Article  CAS  PubMed  Google Scholar 

  36. Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF, Cher LM, Mason W, Weller M, Hong S, Musib L, Liepa AM, Thornton DE, Fine HA (2010) Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J Clin Oncol 28(7):1168–1174

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgements

The study was made possible by a grant from Pfizer who provided the drug sunitinib and logistical support for adequate monitoring of the trial. We thank Anna del Prado from MFAR (Marketing Farmacéutico & Investigación Clínica, S.L.) for her expert technical assistance. Statistical analyses were performed by Juan José de la Cruz Troca of the Department of Preventive Medicine and Public Health, Faculty of Medicine, Autonomous University of Madrid.

Conflict of interest

C.B. declares no conflict of interest. M.J. declares no conflict of interest. P.P. declares no conflict of interest. G.R. declares no conflict of interest. O.G. declares no conflict of interest. T.R. declares no conflict of interest. She received a grant from GEINO supported by Pfizer for her work on centralized review of pathological samples. J.C. declares no conflict of interest. He received a Grant from GEINO supported by Pfizer for his work on centralized review of images. S.G. declares no conflict of interest. E.V. declares no conflict of interest.

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Authors and Affiliations

  1. Medical Oncology Service, Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Carretera Canyet sn, 08916, Badalona, Spain

    Carmen Balaña

  2. Medical Oncology Service, Catalan Institute of Oncology (ICO), IDIBELL Hospital Duran I Reynalds, Gran Via s/n Km 2.7, 08907, L’Hospitalet, Barcelona, Spain

    Miguel J. Gil

  3. Medical Oncology Service, Hospital Clinico San Carlos, Calle Profesor Martin Lagos, s/n, 28040, Madrid, Spain

    Pedro Perez

  4. Medical Oncology Service, Hospital La Fe, Bulevar del Sur, 46026, Valencia, Spain

    Gaspar Reynes

  5. Medical Oncology Service, Hospital de la Santa Creu i de Pau, Calle Sant Antoni M. Claret 167, 08025, Barcelona, Spain

    Oscar Gallego

  6. Department of Pathology, Hospital Clinic Provincial, Calle Villarroel 170, 08036, Barcelona, Spain

    Teresa Ribalta

  7. Radiology Service, Parc de Salut Mar., Hospital del Mar., Passeig Marítim 25-29, 08003, Barcelona, Spain

    Jaume Capellades & Sofia Gonzalez

  8. Radiotherapy Service, Hospital Clinic Provincial, Calle Villarroel 170, 08036, Barcelona, Spain

    Eugenia Verger

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  1. Carmen Balaña
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Correspondence to Carmen Balaña.

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Balaña, C., Gil, M.J., Perez, P. et al. Sunitinib administered prior to radiotherapy in patients with non-resectable glioblastoma: results of a Phase II study. Targ Oncol 9, 321–329 (2014). https://doi.org/10.1007/s11523-014-0305-1

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