Skip to main content

Advertisement

SpringerLink
Log in

Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma

  • Clinical Study
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Bevacizumab blocks the effects of VEGF and may allow for more aggressive radiotherapy schedules. We evaluated the efficacy and toxicity of hypofractionated intensity-modulated radiation therapy with concurrent and adjuvant temozolomide and bevacizumab in patients with newly diagnosed glioblastoma. Patients with newly diagnosed glioblastoma were treated with hypofractionated intensity modulated radiation therapy to the surgical cavity and residual tumor with a 1 cm margin (PTV1) to 60 Gy and to the T2 abnormality with a 1 cm margin (PTV2) to 30 Gy in 10 daily fractions over 2 weeks. Concurrent temozolomide (75 mg/m2 daily) and bevacizumab (10 mg/kg) was administered followed by adjuvant temozolomide (200 mg/m2) on a standard 5/28 day cycle and bevacizumab (10 mg/kg) every 2 weeks for 6 months. Thirty newly diagnosed patients were treated on study. Median PTV1 volume was 131.1 cm3 and the median PTV2 volume was 342.6 cm3. Six-month progression-free survival (PFS) was 90 %, with median follow-up of 15.9 months. The median PFS was 14.3 months, with a median overall survival (OS) of 16.3 months. Grade 4 hematologic toxicity included neutropenia (10 %) and thrombocytopenia (17 %). Grades 3/4 non-hematologic toxicity included fatigue (13 %), wound dehiscence (7 %) and stroke, pulmonary embolism and nausea each in 1 patient. Presumed radiation necrosis with clinical decline was seen in 50 % of patients, two with autopsy documentation. The study was closed early to accrual due to this finding. This study demonstrated 90 % 6-month PFS and OS comparable to historic data in patients receiving standard treatment. Bevacizumab did not prevent radiation necrosis associated with this hypofractionated radiation regimen and large PTV volumes may have contributed to high rates of presumed radiation necrosis.

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
Fig. 4

Similar content being viewed by others

References

  1. Stupp R, Hegi ME, Mason WP et al (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 10:459–466

    Article  CAS  PubMed  Google Scholar 

  2. Stupp R, Mason WP, van den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  3. Omuro A, DeAngelis LM (2013) Glioblastoma and other malignant gliomas: a clinical review. JAMA 310:1842–1850

    Article  CAS  PubMed  Google Scholar 

  4. Jain RK, di Tomaso E, Duda DG et al (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622

    Article  CAS  PubMed  Google Scholar 

  5. Fuks Z, Kolesnick R (2005) Engaging the vascular component of the tumor response. Cancer Cell 8:89–91

    Article  CAS  PubMed  Google Scholar 

  6. Semenza GL (2004) Intratumoral hypoxia, radiation resistance, and HIF-1. Cancer Cell 5:405–406

    Article  CAS  PubMed  Google Scholar 

  7. Wachsberger PR, Burd R, Cardi C et al (2007) VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma. Int J Radiat Oncol Biol Phys 67:1526–1537

    Article  CAS  PubMed  Google Scholar 

  8. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 2005(307):58–62

    Article  Google Scholar 

  9. Moeller BJ, Dreher MR, Rabbani ZN et al (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110

    Article  CAS  PubMed  Google Scholar 

  10. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003(3):721–732

    Article  Google Scholar 

  11. Crane CH, Eng C, Feig BW et al (2010) Phase II trial of neoadjuvant bevacizumab, capecitabine, and radiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 76:824–830

    Article  CAS  PubMed  Google Scholar 

  12. Das P, Eng C, Rodriguez-Bigas MA et al (2014) Preoperative radiation therapy with concurrent capecitabine, bevacizumab, and erlotinib for rectal cancer: a phase 1 trial. Int J Radiat Oncol Biol Phys 88:301–305

    Article  CAS  PubMed  Google Scholar 

  13. Morganti AG, Mignogna S, Caravatta L et al (2014) FOLFIRI-bevacizumab and concurrent low-dose radiotherapy in metastatic colorectal cancer: preliminary results of a phase I–II study. J Chemother 26:353–358

    Article  CAS  PubMed  Google Scholar 

  14. Schefter T, Winter K, Kwon JS et al (2014) RTOG 0417: efficacy of bevacizumab in combination with definitive radiation therapy and cisplatin chemotherapy in untreated patients with locally advanced cervical carcinoma. Int J Radiat Oncol Biol Phys 88:101–105

    Article  CAS  PubMed  Google Scholar 

  15. Reddy K, Damek D, Gaspar LE et al (2012) Phase II trial of hypofractionated IMRT with temozolomide for patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 84:655–660

    Article  CAS  PubMed  Google Scholar 

  16. 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

    CAS  PubMed  Google Scholar 

  17. Roa W, Brasher PM, Bauman G et al (2004) Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol 22:1583–1588

    Article  CAS  PubMed  Google Scholar 

  18. Minniti G, De Sanctis V, Muni R et al (2009) Hypofractionated radiotherapy followed by adjuvant chemotherapy with temozolomide in elderly patients with glioblastoma. J Neurooncol 91:95–100

    Article  CAS  PubMed  Google Scholar 

  19. Floyd NS, Woo SY, Teh BS et al (2004) Hypofractionated intensity-modulated radiotherapy for primary glioblastoma multiforme. Int J Radiat Oncol Biol Phys 58:721–726

    Article  PubMed  Google Scholar 

  20. Sultanem K, Patrocinio H, Lambert C et al (2004) 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 58:247–252

    Article  PubMed  Google Scholar 

  21. Chen C, Damek D, Gaspar LE et al (2011) Phase I trial of hypofractionated intensity-modulated radiotherapy with temozolomide chemotherapy for patients with newly diagnosed glioblastoma multiforme. Int J Radiat Oncol Biol Phys 81:1066–1074

    Article  CAS  PubMed  Google Scholar 

  22. Rusthoven KE, Olsen C, Franklin W, Kleinschmidt-DeMasters BK, Kavanagh BD, Gaspar LE, Lillehei K, Waziri A, Damek DM, Chen C (2011) Favorable prognosis in patients with high-grade glioma with radiation necrosis: the University of Colorado reoperation series. Int J Radiat Oncol Biol Phys 81:211–217

    Article  PubMed  Google Scholar 

  23. Omuro A, Beal K, Gutin P, Karimi S et al (2014) Phase II study of bevacizumab, temozolomide, and hypofractionated stereotactic radiotherapy for newly diagnosed glioblastoma. Clin Cancer Res 20:5023–5031

    Article  CAS  PubMed  Google Scholar 

  24. Levin VA, Bidaut L, Hou P et al (2011) Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 79:1487–1495

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Iuchi T, Hatano K, Narita Y et al (2006) Hypofractionated high-dose irradiation for the treatment of malignant astrocytomas using simultaneous integrated boost technique by IMRT. Int J Radiat Oncol Biol Phys 64:1317–1324

    Article  PubMed  Google Scholar 

  26. Jeyaretna DS, Curry WT Jr, Batchelor TT et al (2011) Exacerbation of cerebral radiation necrosis by bevacizumab. J Clin Oncol 29:e159–e162

    Article  PubMed  Google Scholar 

  27. Chinot OL, Wick W, Mason W et al (2014) Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med 370:709–722

    Article  CAS  PubMed  Google Scholar 

  28. Gilbert MR, Dignam JJ, Armstrong TS et al (2014) Randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370:699–708

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Peca C, Pacelli R, Elefante A et al (2009) Early clinical and neuroradiological worsening after radiotherapy and concomitant temozolomide in patients with glioblastoma: tumour progression or radionecrosis? Clin Neurol Neurosurg 111:331–334

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded, in part, by Genentech. The initial results of this study were presented at the 18th Annual Scientific Meeting of the Society for Neuro-Oncology (SNO), San Francisco, CA, November 20–24, 2013.

Conflict of interest

The authors report no conflict of interest.

Author information

Author notes

  1. Allen E. Waziri

    Present address: Department of Neurosurgery, Inova Medical Group, Fairfax, VA, USA

  2. Krishna Reddy & Changhu Chen

    Present address: Department of Radiation Oncology, University of Toledo, Toledo, OH, USA

Authors and Affiliations

  1. Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA

    Douglas E. Ney, Denise M. Damek & B. K. Kleinschmidt-DeMasters

  2. Department of Neurosurgery, University of Colorado School of Medicine, Aurora, CO, USA

    Douglas E. Ney, Denise M. Damek, B. K. Kleinschmidt-DeMasters, Allen E. Waziri & Kevin O. Lillehei

  3. Department of Radiation Oncology, University of Colorado School of Medicine, Aurora, CO, USA

    Julie A. Carlson, Laurie E. Gaspar, Brian D. Kavanagh, Krishna Reddy & Changhu Chen

  4. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, USA

    B. K. Kleinschmidt-DeMasters

Authors
  1. Douglas E. Ney
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julie A. Carlson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denise M. Damek
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laurie E. Gaspar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian D. Kavanagh
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. B. K. Kleinschmidt-DeMasters
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Allen E. Waziri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kevin O. Lillehei
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Krishna Reddy
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Changhu Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Douglas E. Ney.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ney, D.E., Carlson, J.A., Damek, D.M. et al. Phase II trial of hypofractionated intensity-modulated radiation therapy combined with temozolomide and bevacizumab for patients with newly diagnosed glioblastoma. J Neurooncol 122, 135–143 (2015). https://doi.org/10.1007/s11060-014-1691-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-014-1691-z

Keywords

Search

Navigation