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Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma

  • Clinical Study
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Abstract

Background and purpose

We evaluated whether dose-intensified chemoradiation alters patterns of failure and is associated with favorable survival in the temozolomide era.

Materials and methods

Between 2003 and 2015, 82 patients with newly diagnosed glioblastoma were treated with 66–81 Gy in 30 fractions using conventional magnetic resonance imaging. Progression-free (PFS) and overall survival (OS) were calculated using Kaplan–Meier methods. Factors associated with improved PFS, OS, and time to progression were assessed using multivariate Cox model and linear regression.

Results

Median follow-up was 23 months (95% CI 4–124 months). Sixty-one percent of patients underwent subtotal resection or biopsy, and 38% (10/26) of patients with available data had MGMT promoter methylation. Median PFS was 8.4 months (95% CI 7.3–11.0) and OS was 18.7 months (95% CI 13.1–25.3). Only 30 patients (44%) experienced central recurrence, 6 (9%) in-field, 16 (23.5%) marginal and 16 (23.5%) distant. On multivariate analysis, younger age (HR 0.95, 95% CI 0.93–0.97, p = 0.0001), higher performance status (HR 0.39, 95% CI 0.16–0.95, p = 0.04), gross total resection (GTR) versus biopsy (HR 0.37, 95% CI 0.16–0.85, p = 0.02) and MGMT methylation (HR 0.25, 95% CI 0.09–0.71, p = 0.009) were associated with improved OS. Only distant versus central recurrence (p = 0.03) and GTR (p = 0.02) were associated with longer time to progression. Late grade 3 neurologic toxicity was rare (6%) in patients experiencing long-term survival.

Conclusion

Dose-escalated chemoRT resulted in lower rates of central recurrence and prolonged time to progression compared to historical controls, although a significant number of central recurrences were still observed. Advanced imaging and correlative molecular studies may enable targeted treatment advances that reduce rates of in- and out-of-field progression.

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References

  1. Nakagawa K et al (1998) High-dose conformal radiotherapy influenced the pattern of failure but did not improve survival in glioblastoma multiforme. Int J Radiat Oncol Biol Phys 40(5):1141–1149

    Article  CAS  PubMed  Google Scholar 

  2. Fitzek MM et al (1999) Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial. J Neurosurg 91(2):251–260

    Article  CAS  PubMed  Google Scholar 

  3. Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T (2005) High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison. Lancet Oncol 6(12):953–960

    Article  PubMed  Google Scholar 

  4. Stupp R et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  CAS  Google Scholar 

  5. Tsien CI et al (2012) Concurrent temozolomide and dose-escalated intensity-modulated radiation therapy in newly diagnosed glioblastoma. Clin Cancer Res 18(1):273–279

    Article  CAS  PubMed  Google Scholar 

  6. Brandes AA et al (2009) Recurrence pattern after temozolomide concomitant with and adjuvant to radiotherapy in newly diagnosed patients with glioblastoma: correlation With MGMT promoter methylation status. J Clin Oncol 27(8):1275–1279

    Article  CAS  PubMed  Google Scholar 

  7. Gebhardt BJ et al (2014) Patterns of failure for glioblastoma multiforme following limited-margin radiation and concurrent temozolomide. Radiat Oncol 9:130

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Minniti G et al (2010) Patterns of failure and comparison of different target volume delineations in patients with glioblastoma treated with conformal radiotherapy plus concomitant and adjuvant temozolomide. Radiother Oncol 97(3):377–381

    Article  CAS  PubMed  Google Scholar 

  9. McDonald MW, Shu HK, Curran WJ Jr, Crocker IR (2011) Pattern of failure after limited margin radiotherapy and temozolomide for glioblastoma. Int J Radiat Oncol Biol Phys 79(1):130–136

    Article  CAS  PubMed  Google Scholar 

  10. Gilbert MR et al (2014) A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med 370(8):699–708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gilbert MR et al (2013) Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31(32):4085–4091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Bleehen NM, Stenning SP (1991) A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. Br J Cancer 64(4):769–774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Walker MD, Strike TA, Sheline GE (1979) An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5(10):1725–1731

    Article  CAS  PubMed  Google Scholar 

  14. Souhami L et al (2004) 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 60(3):853–860

    Article  PubMed  Google Scholar 

  15. Selker RG et al (2002) The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery 51(2):343–355 (discussion 355-347)

    Article  PubMed  Google Scholar 

  16. Massaccesi M et al (2013) Accelerated intensity-modulated radiotherapy plus temozolomide in patients with glioblastoma: a phase I dose-escalation study (ISIDE-BT-1). Int J Clin Oncol 18(5):784–791

    Article  CAS  PubMed  Google Scholar 

  17. Reddy K 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(3):655–660

    Article  CAS  PubMed  Google Scholar 

  18. Iuchi T et al (2014) Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. Int J Radiat Oncol Biol Phys 88(4):793–800

    Article  CAS  PubMed  Google Scholar 

  19. Bedard PL, Hansen AR, Ratain MJ, Siu LL (2013) Tumour heterogeneity in the clinic. Nature 501(7467):355–364

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Verhaak RG et al (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17(1):98–110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Brennan CW et al (2013) The somatic genomic landscape of glioblastoma. Cell 155(2):462–477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Patel AP et al (2014) Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science 344(6190):1396–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nobusawa S et al (2010) Intratumoral patterns of genomic imbalance in glioblastomas. Brain Pathol 20(5):936–944

    CAS  PubMed  Google Scholar 

  24. Sottoriva A et al (2013) Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamics. Proc Natl Acad Sci USA 110(10):4009–4014

    Article  PubMed  Google Scholar 

  25. Kim J et al (2015) Spatiotemporal evolution of the primary glioblastoma genome. Cancer Cell 28(3):318–328

    Article  CAS  PubMed  Google Scholar 

  26. Lee JK et al (2017) Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet 49(4):594–599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Asselin MC, O’Connor JP, Boellaard R, Thacker NA, Jackson A (2012) Quantifying heterogeneity in human tumours using MRI and PET. Eur J Cancer 48(4):447–455

    Article  PubMed  Google Scholar 

  28. Diehn M et al (2008) Identification of noninvasive imaging surrogates for brain tumor gene-expression modules. Proc Natl Acad Sci USA 105(13):5213–5218

    Article  PubMed  Google Scholar 

  29. Itakura H et al (2015) Magnetic resonance image features identify glioblastoma phenotypic subtypes with distinct molecular pathway activities. Sci Transl Med 7(303):303ra138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Jamshidi N, Diehn M, Bredel M, Kuo MD (2014) Illuminating radiogenomic characteristics of glioblastoma multiforme through integration of MR imaging, messenger RNA expression, and DNA copy number variation. Radiology 270(1):1–2

    Article  PubMed  Google Scholar 

  31. Bell EH et al (2017) Molecular-based recursive partitioning analysis model for glioblastoma in the temozolomide era: a correlative analysis based on NRG oncology RTOG 0525. JAMA Oncol 3:784

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

There was no specific funding for this research.

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Authors and Affiliations

  1. Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA

    Michelle M. Kim, Corey Speers, Pin Li, Matthew Schipper, Daniel E. Spratt, Daniel R. Wahl, Yue Cao & Theodore S. Lawrence

  2. Department of Neurology, University of Michigan, Ann Arbor, MI, USA

    Larry Junck, Denise Leung & Yoshie Umemura

  3. Department of Neurosurgery, University of Michigan, Ann Arbor, MI, USA

    Daniel Orringer & Jason Heth

  4. Department of Radiation Oncology, Washington University in St. Louis, St. Louis, MO, USA

    Christina I. Tsien

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  1. Michelle M. Kim
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  2. Corey Speers
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Correspondence to Michelle M. Kim.

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Kim, M.M., Speers, C., Li, P. et al. Dose-intensified chemoradiation is associated with altered patterns of failure and favorable survival in patients with newly diagnosed glioblastoma. J Neurooncol 143, 313–319 (2019). https://doi.org/10.1007/s11060-019-03166-3

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  • DOI: https://doi.org/10.1007/s11060-019-03166-3

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