Journal of Neuro-Oncology

, Volume 137, Issue 2, pp 313–319 | Cite as

Normalization of ADC does not improve correlation with overall survival in patients with high-grade glioma (HGG)

  • Lei Qin
  • Angie Li
  • Jinrong Qu
  • Katherine Reinshagen
  • Xiang Li
  • Su-Chun Cheng
  • Annie Bryant
  • Geoffrey S. Young
Clinical Study


Mixed reports leave uncertainty about whether normalization of apparent diffusion coefficient (ADC) to a within-subject white matter reference is necessary for assessment of tumor cellularity. We tested whether normalization improves the previously reported correlation of resection margin ADC with 15-month overall survival (OS) in HGG patients. Spin-echo echo-planar DWI was retrieved from 3 T MRI acquired between maximal resection and radiation in 37 adults with new-onset HGG (25 glioblastoma; 12 anaplastic astrocytoma). ADC maps were produced with the FSL DTIFIT tool (Oxford Centre for Functional MRI). 3 neuroradiologists manually selected regions of interest (ROI) in normal appearing white matter (NAWM) and in non-enhancing tumor (NT) < 2 cm from the margin of residual enhancing tumor or resection cavity. Normalized ADC (nADC) was computed as the ratio of absolute NT ADC to NAWM ADC. Reproducibility of nADC and absolute ADC among the readers’ ROI was assessed using intra-class correlation coefficient (ICC) and within-subject coefficient of variation (wCV). Correlations of ADC and nADC with OS were compared using receiver operating characteristics (ROC) analysis. A p value 0.05 was considered statistically significant. Both mean ADC and nADC differed significantly between patients subgrouped by 15-month OS (p = 0.0014 and 0.0073 respectively). wCV and ICC among the readers were similar for absolute and normalized ADC. In ROC analysis of correlation with OS, nADC did not perform significantly better than absolute ADC. Normalization does not significantly improve the correlation of absolute ADC with OS in HGG, suggesting that normalization is not necessary for clinical or research ADC analysis in HGG patients.


Diffusion weighted imaging (DWI) Apparent diffusion coefficient (ADC) ADC normalization High-grade glioma (HGG) 


Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this retrospective study consent is not required.


  1. 1.
    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(11):1963–1972. CrossRefPubMedGoogle Scholar
  2. 2.
    Padhani AR, Liu G, Mu-Koh D, Chenevert TL, Thoeny HC, Takahara T, Dzik-Jurasz A, Ross BD, Van Cauteren M, Collins D, Hammoud DA, Rustin GJS, Taouli B, Choyke PL (2009) Diffusion-weighted magnetic resonance imaging as a cancer biomarker: consensus and recommendations. Neoplasia 11(2):102–125CrossRefGoogle Scholar
  3. 3.
    Schaefer PW, Grant PE, Gonzalez RG (2000) Diffusion-weighted MR imaging of the brain. Radiology 217(2):331–345. CrossRefPubMedGoogle Scholar
  4. 4.
    Murakami R, Sugahara T, Nakamura H, Hirai T, Kitajima M, Hayashida Y, Baba Y, Oya N, Kuratsu J, Yamashita Y (2007) Malignant supratentorial astrocytoma treated with postoperative radiation therapy: prognostic value of pretreatment quantitative diffusion-weighted MR imaging. Radiology 243(2):493–499. CrossRefPubMedGoogle Scholar
  5. 5.
    Yamasaki F, Sugiyama K, Ohtaki M, Takeshima Y, Abe N, Akiyama Y, Takaba J, Amatya VJ, Saito T, Kajiwara Y, Hanaya R, Kurisu K (2010) Glioblastoma treated with postoperative radio-chemotherapy: prognostic value of apparent diffusion coefficient at MR imaging. Eur J Radiol 73(3):532–537. CrossRefPubMedGoogle Scholar
  6. 6.
    Nakamura H, Murakami R, Hirai T, Kitajima M, Yamashita Y (2013) Can MRI-derived factors predict the survival in glioblastoma patients treated with postoperative chemoradiation therapy? Acta Radiol 54(2):214–220. CrossRefPubMedGoogle Scholar
  7. 7.
    Saksena S, Jain R, Narang J, Scarpace L, Schultz LR, Lehman NL, Hearshen D, Patel SC, Mikkelsen T (2010) Predicting survival in glioblastomas using diffusion tensor imaging metrics. J Magn Reson Imaging 32(4):788–795. CrossRefPubMedGoogle Scholar
  8. 8.
    Qu J, Qin L, Cheng S, Leung K, Li X, Li H, Dai J, Jiang T, Akgoz A, Seethamraju R, Wang Q, Rahman R, Li S, Ai L, Jiang T, Young GS (2016) Residual low ADC and high FA at the resection margin correlate with poor chemoradiation response and overall survival in high-grade glioma patients. Eur J Radiol 85(3):657–664. CrossRefPubMedGoogle Scholar
  9. 9.
    Hein PA, Eskey CJ, Dunn JF, Hug EB (2004) Diffusion-weighted imaging in the follow-up of treated high-grade gliomas: tumor recurrence versus radiation Injury. Am J Neuroradiol 25(2):201–209PubMedGoogle Scholar
  10. 10.
    Guo AC, Cummings TJ, Dash RC, Provenzale JM (2002) Lymphomas and high-grade astrocytomas: comparison of water diffusibility and histologic characteristics. Radiology 224(1):177–183. CrossRefPubMedGoogle Scholar
  11. 11.
    Oh J, Henry RG, Pirzkall A, Lu Y, Li X, Catalaa I, Chang S, Dillon WP, Nelson SJ (2004) Survival analysis in patients with glioblastoma multiforme: predictive value of choline-to-n-acetylaspartate index, apparent diffusion coefficient, and relative cerebral blood volume. J Magn Reson Imaging 19(5):546–554. CrossRefPubMedGoogle Scholar
  12. 12.
    Saraswathy S, Crawford FW, Lamborn KR, Pirzkal A, Chang S, Cha S, Nelson SJ (2009) Evaluation of MR markers that predict survival in patients with newly diagnosed GBM prior to adjuvant therapy. J Neuro-Oncol 91(1):69–81. CrossRefGoogle Scholar
  13. 13.
    Elson A, Bovi J, Siker M, Schultz C, Paulson E (2015) Evaluation of absolute and normalized apparent diffusion coefficient (ADC) values within the post-operative T2/FLAIR volume as adverse prognostic indicators in glioblastoma. J Neuro-Oncol 122(3):549–558. CrossRefGoogle Scholar
  14. 14.
    Rodriguez Gutierrez D, Manita M, Jaspan T, Dineen RA, Grundy RG, Auer DP (2013) Serial MR diffusion to predict treatment response in high-grade pediatric brain tumors: a comparison of regional and voxel-based diffusion change metrics. Neuro-Oncology 15(8):981–989. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shankar JJ, Bata A, Ritchie K, Hebb A, Walling S (2016) Normalized apparent diffusion coefficient in the prognostication of patients with glioblastoma multiforme. Canadian J Neurol Sci Le journal canadien des sciences neurologiques 43(1):127–133. CrossRefGoogle Scholar
  16. 16.
    Sasaki M, Yamada K, Watanabe Y, Matsui M, Ida M, Fujiwara S, Shibata E (2008) Variability in absolute apparent diffusion coefficient values across different platforms may be substantial: a multivendor, multi-institutional comparison study. Radiology 249(2):624–630. CrossRefGoogle Scholar
  17. 17.
    Grech-Sollars M, Hales PW, Miyazaki K, Raschke F, Rodriguez D, Wilson M, Gill SK, Banks T, Saunders DE, Clayden JD, Gwilliam MN, Barrick TR, Morgan PS, Davies NP, Rossiter J, Auer DP, Grundy R, Leach MO, Howe FA, Peet AC, Clark CA (2015) Multi-centre reproducibility of diffusion MRI parameters for clinical sequences in the brain. NMR Biomed 28(4):468–485. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Barnhart HX, Barboriak DP (2009) Applications of the repeatability of quantitative imaging biomarkers: a review of statistical analysis of repeat data sets. Transl Oncol 2(4):231–235CrossRefGoogle Scholar
  19. 19.
    Barnhart HX, Haber MJ, Lin LI (2007) An overview on assessing agreement with continuous measurements. J Biopharm Stat 17(4):529–569. CrossRefPubMedGoogle Scholar
  20. 20.
    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, European Organisation for R, Treatment of Cancer Brain T, Radiotherapy G, National Cancer Institute of Canada Clinical Trials G (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. New Engl J Med 352(10):987–996. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lei Qin
    • 1
    • 2
  • Angie Li
    • 3
    • 4
  • Jinrong Qu
    • 3
    • 5
  • Katherine Reinshagen
    • 2
    • 3
    • 6
  • Xiang Li
    • 3
    • 5
  • Su-Chun Cheng
    • 7
  • Annie Bryant
    • 1
    • 8
  • Geoffrey S. Young
    • 1
    • 2
    • 3
  1. 1.Department of ImagingDana-Farber Cancer InstituteBostonUSA
  2. 2.Department of RadiologyHarvard Medical SchoolBostonUSA
  3. 3.Department of RadiologyBrigham and Women’s HospitalBostonUSA
  4. 4.The Robert Larner, M.D. College of MedicineUniversity of VermontBurlingtonUSA
  5. 5.Department of RadiologyAffiliated Cancer Hospital of Zhengzhou UniversityZhengzhouChina
  6. 6.Department of RadiologyMassachusetts Eye and Ear InfirmaryBostonUSA
  7. 7.Department of Biostatistics and Computational BiologyDana-Farber Cancer InstituteBostonUSA
  8. 8.Department of Behavioral NeuroscienceNortheastern UniversityBostonUSA

Personalised recommendations