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Early imaging marker of progressing glioblastoma: a window of opportunity

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Abstract

Purpose

Therapeutic intervention at glioblastoma (GBM) progression, as defined by current assessment criteria, is arguably too late as second-line therapies fail to extend survival. Still, most GBM trials target recurrent disease. We propose integration of a novel imaging biomarker to more confidently and promptly define progression and propose a critical timepoint for earlier intervention to extend therapeutic exposure.

Methods

A retrospective review of 609 GBM patients between 2006 and 2019 yielded 135 meeting resection, clinical, and imaging inclusion criteria. We qualitatively and quantitatively analyzed 2000+ sequential brain MRIs (initial diagnosis to first progression) for development of T2 FLAIR signal intensity (SI) within the resection cavity (RC) compared to the ventricles (V) for quantitative inter-image normalization. PFS and OS were evaluated using Kaplan–Meier curves stratified by SI. Specificity and sensitivity were determined using a 2 × 2 table and pathology confirmation at progression. Multivariate analysis evaluated SI effect on the hazard rate for death after adjusting for established prognostic covariates. Recursive partitioning determined successive quantifiers and cutoffs associated with outcomes. Neurological deficits correlated with SI.

Results

Seventy-five percent of patients developed SI on average 3.4 months before RANO-assessed progression with 84% sensitivity. SI-positivity portended neurological decline and significantly poorer outcomes for PFS (median, 10 vs. 15 months) and OS (median, 20 vs. 29 months) compared to SI-negative. RC/V ratio ≥ 4 was the most significant prognostic indicator of death.

Conclusion

Implications of these data are far-reaching, potentially shifting paradigms for glioma treatment response assessment, altering timepoints for salvage therapeutic intervention, and reshaping glioma clinical trial design.

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Data availability

All data supporting the findings presented in this manuscript are available upon reasonable request directly to the corresponding author, NG. These data are not part of public domain or database as they are of the patient protected medical record and doing so would compromise the privacy of the research participants.

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Acknowledgements

We acknowledge Dr. Susan Chang, Director of the UCSF Division of Neuro-Oncology and Director of the 2019 Society for Neuro-Oncology Clinical Trials Course, Dr. Mark Gilbert, Chief of the Neuro-Oncology Branch (NOB) at the National Institutes of Health, Dr. Priya Kumthekar of Northwestern University Feinberg School of Medicine, and to Dr. Prakash Chinnaiyan, Professor, Oakland University William Beaumont School of Medicine for dedicating their time and critical review of the research. The members of the NRG Brain Tumor & Neurosurgery Committees, and the NCI Brain Malignancies Steering Committee for their involvement in critical assessment of this work. To Geisinger Research Institute leadership, Dr. David Ledbetter, and Department Chair, Dr. Neil Holland, for allowing the dedicated research time. Finally, thanks to my donors: Mr. Jeff Erdly, Mr. Jerry Sandel, The Lowe Family, and The Comp Family.

Funding

Geisinger Foundation, [01100000000000, Account #341020–752025] Philanthropic donations from Mr. Jeff Erdly, Mr. Jerry Sandel, Lowe Family, and Comp Family.

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Authors and Affiliations

  1. Neuroscience Institute, Geisinger Health, Danville, PA, 17822, USA

    Na Tosha N. Gatson, Shane P. Bross, Michel Lacroix & Andrew R. Conger

  2. Cancer Institute, Geisinger Health, Danville, PA, 17822, USA

    Na Tosha N. Gatson, Jesse J. Manikowski, Anand Mahadevan & Joseph Vadakara

  3. Geisinger Commonwealth School of Medicine, Scranton, PA, 18509, USA

    Na Tosha N. Gatson, Laura Lockard & Andrew R. Conger

  4. Department of Neuro-Oncology, Miami Cancer Institute/Baptist Health South Florida, Miami, FL, 33176, USA

    Yazmin Odia

  5. Department of Radiology, Geisinger Health, Danville, PA, 17822, USA

    Gino J. Mongelluzzo

  6. Department of Population Health Sciences, Geisinger Health, Danville, PA, 17822, USA

    Yirui Hu

  7. Department of Pathology, Geisinger Health, Danville, PA, 17822, USA

    Syed A. J. Kazmi

  8. Harvard Medical School, Center for Neuro-Oncology,, Dana-Farber Cancer Institute, Boston, MA, 02215, USA

    Lakshmi Nayak

  9. Department of Radiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    T. Linda Chi

  10. Department of Radiation Oncology, Miami Cancer Institute/Baptist Health South Florida, Miami, FL, 33176, USA

    Minesh P. Mehta

  11. Division of Neuro-Oncology, The OH State University Comprehensive Cancer Center – James and OSU Neurological Institute, Columbus, OH, 43210, USA

    Vinay K. Puduvalli

  12. Geisinger Medical Center, Neuroscience Institute MC 14-03, 100 N. Academy Ave, Danville, PA, 17822, USA

    Na Tosha N. Gatson

  13. Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Vinay K. Puduvalli

Authors
  1. Na Tosha N. Gatson
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  2. Shane P. Bross
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  3. Yazmin Odia
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Contributions

NG, VP, MM, TC—Concept development as well as the below listed contributions. SB, YO, YH—Substantial involvement in the development of the draft manuscript, contributed important intellectual content, data interpretation as well as the below listed contributions. LL, JM, GM, SK, AC, ML, AM, JV, LN—Data interpretations and development of figures, critical revisions and discussions around important intellectual content. Final approval of the planned version for publication. All authors agreed to be accountable for all aspects of the work for accuracy and are committed to the integrity of the final product.

Corresponding author

Correspondence to Na Tosha N. Gatson.

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Conflicts of interest

M. Mehta: Consulting for Karyopharm, Tocagen, Astra-Zeneca, Blue Earth Diagnostics, Celgene, Abbvie. Board of Directors: Oncoceutics. N. Gatson: Advisory Board for Novocure. Y. Odia: Advisory Board for Novocure and Abbvie and Trial Support: Novocure and BMS. All remaining authors declare that they have no conflicts of interest.

Ethics approval

As a retrospective study all treatments were part of routine care and thereby ethical approval was waived by the Geisinger Health Ethics Committee.

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Gatson, N.T.N., Bross, S.P., Odia, Y. et al. Early imaging marker of progressing glioblastoma: a window of opportunity. J Neurooncol 148, 629–640 (2020). https://doi.org/10.1007/s11060-020-03565-x

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