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A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma

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Abstract

Single-agent sunitinib, an oral small molecule inhibitor of multiple tyrosine kinase receptors, was evaluated for treatment of patients with recurrent glioblastoma (GB) and anaplastic astrocytoma (AA). Fourteen AA and 16 GB patients, all previously treated with surgery, radiotherapy, and temozolomide, were enrolled in a prospective phase II study at either first or second relapse. Patients were treated with daily sunitinib for 4 consecutive weeks, followed by a 2-week break. For AA patients, the most common side effects were fatigue (86 %), diarrhea (43 %), hand-foot syndrome (36 %), neutropenia (36 %), thrombocytopenia (36 %), and nausea (29 %). In the GB cohort, the most common side effects were fatigue (56 %), diarrhea (44 %), neutropenia (31 %), and thrombocytopenia (25 %). Six of 14 (43 %) AA and 5 of 16 (31 %) GB patients experienced grade 3 or greater toxicities. Five patients discontinued study due to drug toxicities. There were no partial or complete responses in either cohort; 8/14 (57 %) AA and 5/16 (31 %) GB patients had stable disease at the first planned assessment. Progression-free survival at 6 months was 21.5 % (AA) and 16.7 % (GB). Median overall survival was 12.1 months (AA) and 12.6 months (GB). These results are comparable to those reported in the literature in patients treated with standard cytotoxic therapies. This is the largest reported trial of sunitinib in recurrent malignant astrocytic gliomas to date, as well as contains the largest AA cohort. Nonetheless, sunitinib did not demonstrate significant anti-glioma activity in patients with recurrent malignant astrocytic gliomas.

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References

  1. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  PubMed  CAS  Google Scholar 

  2. Wick W, Hartmann C, Engel C, Stoffels M, Felsberg J, Stockhammer F, Sabel MC, Koeppen S, Ketter R, Meyermann R, Rapp M, Meisner C, Kortmann RD, Pietsch T, Wiestler OD, Ernemann U, Bamberg M, Reifenberger G, von Deimling A, Weller M (2009) NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J Clin Oncol 27:5874–5880

    Article  PubMed  CAS  Google Scholar 

  3. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK (1999) Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 17:2572–2578

    PubMed  CAS  Google Scholar 

  4. Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF, Wen PY, Greenberg H, Abrey LE, DeAngelis LM, Hess KR, Lamborn KR, Prados MD, Yung WK (2007) A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme. J Neurooncol 81:271–277

    Article  PubMed  CAS  Google Scholar 

  5. 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 28:1168–1174

    Article  PubMed  CAS  Google Scholar 

  6. Korkolopoulou P, Patsouris E, Konstantinidou AE, Pavlopoulos PM, Kavantzas N, Boviatsis E, Thymara I, Perdiki M, Thomas-Tsagli E, Angelidakis D, Rologis D, Sakkas D (2004) Hypoxia-inducible factor 1alpha/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis. Neuropathol Appl Neurobiol 30:267–278

    Article  PubMed  CAS  Google Scholar 

  7. Lamszus K, Ulbricht U, Matschke J, Brockmann MA, Fillbrandt R, Westphal M (2003) Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A. Clin Cancer Res 9:1399–1405

    PubMed  CAS  Google Scholar 

  8. Vredenburgh JJ, Desjardins A, Herndon JE II, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS (2007) Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 13:1253–1259

    Article  PubMed  CAS  Google Scholar 

  9. Wong ET, Gautam S, Malchow C, Lun M, Pan E, Brem S (2011) Bevacizumab for recurrent glioblastoma multiforme: a meta-analysis. J Natl Compr Canc Netw 9:403–407

    PubMed  CAS  Google Scholar 

  10. Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA (2009) Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 27:740–745

    Article  PubMed  CAS  Google Scholar 

  11. Chamberlain MC, Johnston S (2009) Salvage chemotherapy with bevacizumab for recurrent alkylator-refractory anaplastic astrocytoma. J Neurooncol 91:359–367

    Article  PubMed  CAS  Google Scholar 

  12. Norden AD, Young GS, Setayesh K, Muzikansky A, Klufas R, Ross GL, Ciampa AS, Ebbeling LG, Levy B, Drappatz J, Kesari S, Wen PY (2008) Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence. Neurology 70:779–787

    Article  PubMed  CAS  Google Scholar 

  13. Goodman VL, Rock EP, Dagher R, Ramchandani RP, Abraham S, Gobburu JV, Booth BP, Verbois SL, Morse DE, Liang CY, Chidambaram N, Jiang JX, Tang S, Mahjoob K, Justice R, Pazdur R (2007) Approval summary: sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 13:1367–1373

    Article  PubMed  CAS  Google Scholar 

  14. 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 9:412–423

    Article  PubMed  Google Scholar 

  15. Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG (1990) Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 8:1277–1280

    PubMed  CAS  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 28:1963–1972

    Article  PubMed  Google Scholar 

  17. Simon R (1989) Optimal two-stage designs for phase II clinical trials. Control Clin Trials 10:1–10

    Article  PubMed  CAS  Google Scholar 

  18. Fleming TP, Saxena A, Clark WC, Robertson JT, Oldfield EH, Aaronson SA, Ali IU (1992) Amplification and/or overexpression of platelet-derived growth factor receptors and epidermal growth factor receptor in human glial tumors. Cancer Res 52:4550–4553

    PubMed  CAS  Google Scholar 

  19. Laird AD, Christensen JG, Li G, Carver J, Smith K, Xin X, Moss KG, Louie SG, Mendel DB, Cherrington JM (2002) SU6668 inhibits Flk-1/KDR and PDGFRbeta in vivo, resulting in rapid apoptosis of tumor vasculature and tumor regression in mice. FASEB J 16:681–690

    PubMed  CAS  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 4:927–934

    Article  PubMed  CAS  Google Scholar 

  21. 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 12:822–833

    Article  PubMed  CAS  Google Scholar 

  22. 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 103:491–501

    Article  PubMed  CAS  Google Scholar 

  23. Reardon DA, Vredenburgh JJ, Coan A, Desjardins A, Peters KB, Gururangan S, Sathornsumetee S, Rich JN, Herndon JE, Friedman HS (2011) Phase I study of sunitinib and irinotecan for patients with recurrent malignant glioma. J Neurooncol 105:621–627

    Article  PubMed  CAS  Google Scholar 

  24. Koutras AK, Krikelis D, Alexandrou N, Starakis I, Kalofonos HP (2007) Brain metastasis in renal cell cancer responding to sunitinib. Anticancer Res 27:4255–4257

    PubMed  CAS  Google Scholar 

  25. Verma J, Jonasch E, Allen P, Tannir N, Mahajan A (2011) Impact of tyrosine kinase inhibitors on the incidence of brain metastasis in metastatic renal cell carcinoma. Cancer 117:4958–4965

    Article  PubMed  CAS  Google Scholar 

  26. Zhou Q, Gallo JM (2009) Differential effect of sunitinib on the distribution of temozolomide in an orthotopic glioma model. Neuro Oncol 11:301–310

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Catrina Montgomery for her work with data management and Rasa Hamilton for manuscript editing. Pfizer, Inc. provided funding for research support but did not contribute to the study design or interpretation of the study results.

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Authors and Affiliations

  1. Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL, 33612-9416, USA

    Edward Pan, Daohai Yu, Binglin Yue, Lisa Potthast & Pamela Smith

  2. Department of Neuro-Oncology, Florida Hospital Cancer Institute, Orlando, FL, USA

    Sajeel Chowdhary

  3. Department of Neurology and Neurological Surgery, Seattle Cancer Care Alliance, Seattle, WA, USA

    Marc Chamberlain

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  1. Edward Pan
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  2. Daohai Yu
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  3. Binglin Yue
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Correspondence to Edward Pan.

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Pan, E., Yu, D., Yue, B. et al. A prospective phase II single-institution trial of sunitinib for recurrent malignant glioma. J Neurooncol 110, 111–118 (2012). https://doi.org/10.1007/s11060-012-0943-z

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  • DOI: https://doi.org/10.1007/s11060-012-0943-z

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