Advertisement

Strahlentherapie und Onkologie

, Volume 186, Issue 10, pp 558–564 | Cite as

Single-Arm Phase II Study of Conformal Radiation Therapy and Temozolomide plus Fractionated Stereotactic Conformal Boost in High-Grade Gliomas

Final Report
  • Mario Balducci
  • Giuseppina Apicella
  • Stefania Manfrida
  • Annunziato Mangiola
  • Alba Fiorentino
  • Luigi Azario
  • Giuseppe Roberto D’Agostino
  • Vincenzo Frascino
  • Nicola Dinapoli
  • Giovanna Mantini
  • Alessio Albanese
  • Pasquale de Bonis
  • Silvia Chiesa
  • Vincenzo Valentini
  • Carmelo Anile
  • Numa Cellini
Original Article

Abstract

Purpose:

To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs).

Patients and Methods:

Patients affected by HGG, with a CTV1(clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV1diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m2) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150–200 mg/m2) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion–powered analysis.

Results:

41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1–2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6–56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months.

Conclusion:

FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG.

Key Words

Malignant glioma Stereotactic radiotherapy Temozolomide Boost 

Einarmige Phase-II-Studie zur konformalen Strahlentherapie mit Temozolomid plus fraktionierter stereotaktischer konformaler Boostbestrahlung bei höhergradigen Gliomen. Abschlussbericht

Zusammenfassung

Ziel:

Untersuchung von Uberleben, lokaler Tumorkontrolle und Toxizitat einer fraktionierten stereotaktischen konformalen Strahlentherapie (FSCRT) mit Boostbestrahlung in Kombination mit Temozolomid bei hochmalignen Gliomen (HMG).

Patienten und Methodik:

Patienten mit HMG und einem CTV1(klinisches Zielvolumen, d. h. Tumorbett ± Resttumor + einem Sicherheitsabstand von 5 mm) ≤ 8 cm wurden in diese Phase-II-Studie eingeschlossen. Die Strahlentherapie (Gesamtdosis 6 940 cGy) wurde als Kombination aus zwei unterschiedlichen Techniken appliziert: dreidimensionale konformale Strahlentherapie (3D-CRT, um eine Strahlendosis von 5 040 oder 5 940 cGy zu erreichen) und lokale Dosisaufsattigung mit FSCRT-Boost (19 oder 10 Gy), die auf den CTV1-Durchmesser (≤ 6 cm bzw. > 6 cm) zugeschnitten war. Temozolomid (75 mg/m2) wurde wahrend der ersten 2 oder 4 Wochen der Strahlentherapie verabreicht. Nach dem Ende der Strahlentherapie erhielten die Patienten Temozolomid (150–200 mg/m2) fur wenigstens sechs Zyklen. Die Fallzahl wurde mit Hilfe eines einfach-proportionalen Testverfahrens („single proportion-powered analysis“) bei 41 Patienten bestimmt.

Ergebnisse:

41 Patienten (36 mit Glioblastoma multiforme [GBM] und funf mit anaplastischem Astrozytom [AA]) wurden behandelt; Neurotoxizitat gemas RTOG-Skala G1–2 bzw. G3 wurde in 12% bzw. 3% der Patienten beobachtet. Zwei Falle von Radionekrose traten auf. Bei einer mittleren Beobachtungszeit von 44 Monaten (Range 6–56 Monate) lagen die mittlere Gesamt- und die GBM-spezifische Uberlebenszeit (OS) bei 30 und 28 Monaten. Die 2-Jahres-Uberlebensrate war signifikant besser im Vergleich zur Standardbehandlung (63% vs. 26,5%; p < 0.00001). Die mittlere progressionsfreie Uberlebenszeit (PFS) betrug 11 Monate, bei GBM-Patienten 10 Monate.

Schlussfolgerung:

FSCRT-Boostbestrahlung plus Temozolomid wird gut toleriert und scheint im Vergleich zur Standardbehandlung die Uberlebenszeit von Patienten mit HMG zu verbessern.

Schlüsselwörter

Maligne Gliome Stereotaktische Radiotherapie Temozolomid Boost 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Aydın H, Sillenberg I, von Lieven H, et al. Patterns of failure following CT-based 3-D irradiation for malignant glioma. Strahlenther Onkol 2001;177:424–31CrossRefPubMedGoogle Scholar
  2. 2.
    Balducci M, D’Agostino GR, Manfrida S, et al. Radiotherapy and concomitant temozolomide during the first and last weeks in high grade gliomas: long-term analysis of a phase II study. J Neurooncol 2010;97:95–100CrossRefPubMedGoogle Scholar
  3. 3.
    Baumert BG, Lutterbach J, Bernays R, et al. Fractionated stereotactic radiotherapy boost after post-operative radiotherapy in patients with high-grade gliomas. Radiother Oncol 2003;67:183–90CrossRefPubMedGoogle Scholar
  4. 4.
    Cardinale R, Won M, Choucair A, 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;65:1422–8CrossRefPubMedGoogle Scholar
  5. 5.
    Chan JL, Lee SW, Fraass BA, et al. Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. J Clin Oncol 2002;20:1635–42CrossRefPubMedGoogle Scholar
  6. 6.
    Cho KH, Hall WA, Lo SS, et al. Stereotactic radiosurgery versus fractionated stereotactic radiotherapy boost for patients with glioblastoma multiforme. Technol Cancer Res Treat 2004;3:41–9PubMedGoogle Scholar
  7. 7.
    Cox DR. Regression models and life tables. J R Stat Soc 1972;34:187–229Google Scholar
  8. 8.
    Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys 1995;31:1341–6CrossRefPubMedGoogle Scholar
  9. 9.
    Curran WJ Jr, Scott CB, Horton J, et al. Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704–10CrossRefPubMedGoogle Scholar
  10. 10.
    Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic radiation. Int J Radiat Oncol Biol Phys 1991;21:109–22PubMedGoogle Scholar
  11. 11.
    Erlich SS, Davis RL. Spinal subarachnoid metastasis from primary intracranial glioblastoma multiforme. Cancer 1978;42:2854–64CrossRefPubMedGoogle Scholar
  12. 12.
    Fokas E, Wacker U, Gross MW, et al. Hypofractionated stereotactic reirradiation of recurrent glioblastomas. A beneficial treatment option after high-dose radiotherapy? Strahlenther Onkol 2009;185:235–40CrossRefPubMedGoogle Scholar
  13. 13.
    Glas M, Happold C, Rieger W, et al. Long-term survival of patients with glioblastoma treated with radiotherapy and lomustine plus temozolomide. J Clin Oncol 2009;27:1257–61CrossRefPubMedGoogle Scholar
  14. 14.
    Henke G, Paulsen F, Steinbach JP, et al. Hypofractionated reirradiation for recurrent malignant glioma. Strahlenther Onkol 2009;185:113–9CrossRefPubMedGoogle Scholar
  15. 15.
    Iliades G, Selviaridis P, Kalogera-Fountzila A, et al. The importance of tumor volume in the prognosis of patients with glioblastoma. Comparison of computerized volumetry and geometric models. Strahlenther Onkol 2009;185:743–50CrossRefGoogle Scholar
  16. 16.
    Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457CrossRefGoogle Scholar
  17. 17.
    Lai A, Filka E, McGibbon B, et al. Phase II pilot study of bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: interim analysis of safety and tolerability. Int J Radiat Oncol Biol Phys 2008;71:1372–80CrossRefPubMedGoogle Scholar
  18. 18.
    Lamborn KR, Chang SM, Prados MD. Prognostic factors for survival of patients with glioblastoma: recursive partitioning analysis. Neuro Oncol 2004;6:227–35CrossRefPubMedGoogle Scholar
  19. 19.
    Lee SW, Fraass BA, Marsh LH, et al. Patterns of failure following high-dose 3-D conformal radiotherapy for high-grade astrocytomas: a quantitative dosimetric study. Int J Radiat Oncol Biol Phys 1999;43:79–88CrossRefPubMedGoogle Scholar
  20. 20.
    Macdonald DR, Cascino TL, Schold SC, et al. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277–80PubMedGoogle Scholar
  21. 21.
    Mangiola A, de Bonis P, Maira G, et al. Invasive tumor cells and prognosis in a selected population of patients with glioblastoma multiforme. Cancer 2008;113:841–6CrossRefPubMedGoogle Scholar
  22. 22.
    Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 1966;5:163–70Google Scholar
  23. 23.
    Marks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: incidence and risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol Phys 1981;7:243–52CrossRefPubMedGoogle Scholar
  24. 24.
    Mirinamoff RO, Gorlia T, Mason W, et al. Radiotherapy and temozomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol 2006;24:2563–9CrossRefGoogle Scholar
  25. 25.
    Nakagawa K, Aoki Y, Fujimaki T, et al. High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 1998;40:1141–9CrossRefPubMedGoogle Scholar
  26. 26.
    Narayana A, Golfinos JG, Fischer I, et al. Feasibility of using bevacizumab with radiation therapy and temozolomide in newly diagnosed high-grade glioma. Int J Radiat Oncol Biol Phys 2008;72:383–9CrossRefPubMedGoogle Scholar
  27. 27.
    Nieder C, Andratschke N, Wiedenmann N, et al. Radiotherapy for high-grade gliomas. Does altered fractionation improve the outcome? Strahlenther Onkol 2004;180:401–7CrossRefPubMedGoogle Scholar
  28. 28.
    Nwokedi EC, DiBiase SJ, Jabbour S, et al. Gamma knife stereotactic radiosurgery for patients with glioblastoma multiforme. Neurosurgery 2002;50:41–6CrossRefPubMedGoogle Scholar
  29. 29.
    Park I, Tamai G, Lee MC, 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;69:381–9CrossRefPubMedGoogle Scholar
  30. 30.
    Regine WF, Patchell RA, Strottmann JM, et al. Preliminary report of a phase I study of combined fractionated stereotactic radiosurgery and conventional external beam radiation therapy for unfavourable gliomas. Int J Radiat Oncol Biol Phys 2000;48:421–6CrossRefPubMedGoogle Scholar
  31. 31.
    Rickhey M, Koelbl O, Eilles C, Bogner L. A biologically adapted dose-escalation approach, demonstrated for 18F-FET-PET in brain tumors. Strahlenther Onkol 2008;184:536–42CrossRefPubMedGoogle Scholar
  32. 32.
    Sarkaria JN, Mehta MP, Loeffler JS, et al. Radiosurgery in the initial management of malignant gliomas: survival comparison with the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys 1995;32:931–41CrossRefPubMedGoogle Scholar
  33. 33.
    Shepherd SF, Laing RW, Cosgrove VP, et al. Hypofractionated stereotactic radiotherapy in the management of recurrent glioma. Int J Radiat Oncol Biol Phys 1997;37:393–8CrossRefPubMedGoogle Scholar
  34. 34.
    Souhami L, Seiferheld W, Brachman D, et al. Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol. Int J Radiat Oncol Biol Phys 2004;60:853–60CrossRefPubMedGoogle Scholar
  35. 35.
    Stupp R, Hegi ME, Gilbert MR, Chakravarti A. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol 2007; 25:4127–36CrossRefPubMedGoogle Scholar
  36. 36.
    Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987–96CrossRefPubMedGoogle Scholar
  37. 37.
    Walker MD, Strike T, Sheline GE. An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 1979;5:1725–31PubMedGoogle Scholar

Copyright information

© Urban &amp; Vogel, Muenchen 2010

Authors and Affiliations

  • Mario Balducci
    • 1
  • Giuseppina Apicella
    • 1
    • 2
    • 5
  • Stefania Manfrida
    • 1
  • Annunziato Mangiola
    • 3
  • Alba Fiorentino
    • 1
  • Luigi Azario
    • 4
  • Giuseppe Roberto D’Agostino
    • 1
  • Vincenzo Frascino
    • 1
  • Nicola Dinapoli
    • 1
  • Giovanna Mantini
    • 1
  • Alessio Albanese
    • 3
  • Pasquale de Bonis
    • 3
  • Silvia Chiesa
    • 1
  • Vincenzo Valentini
    • 1
  • Carmelo Anile
    • 3
  • Numa Cellini
    • 1
  1. 1.Department of RadiotherapyCatholic University of the Sacred HeartRomeItaly
  2. 2.Department of RadiotherapyUniversity Hospital Maggiore della CaritáNovaraItaly
  3. 3.Department of NeurosurgeryCatholic University of the Sacred HeartRomeItaly
  4. 4.Department of PhysicsCatholic University of the Sacred HeartRomeItaly
  5. 5.Department of RadiotherapyUniversity Hospital Maggiore della CaritàNovaraItaly

Personalised recommendations