. 2020 Mar;147(1):135-145.

doi: 10.1007/s11060-020-03407-w. Epub 2020 Jan 24.

Rate of change in maximum ¹⁸F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas

Talia C Oughourlian^{1

2

3}, Jingwen Yao^{1

4}, Jacob Schlossman^{1

2

3}, Catalina Raymond^{1

2}, Matthew Ji^{5

6}, Hiroyuki Tatekawa^{1

2}, Noriko Salamon², Whitney B Pope², Johannes Czernin⁷, Phioanh L Nghiemphu^{5

6}, Albert Lai^{5

6}, Timothy F Cloughesy^{5

6}, Benjamin M Ellingson^{8

9

10

11

12}

Affiliations

¹ UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
² Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³ Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA.
⁵ UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
⁹ Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹⁰ Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹¹ Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹² UCLA Brain Tumor Imaging Laboratory, Departments of Radiological Sciences and Psychiatry, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA. bellingson@mednet.ucla.edu.

PMID: 31981013
PMCID: PMC7080591
DOI: 10.1007/s11060-020-03407-w

Rate of change in maximum ¹⁸F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas

Talia C Oughourlian et al. J Neurooncol. 2020 Mar.

. 2020 Mar;147(1):135-145.

doi: 10.1007/s11060-020-03407-w. Epub 2020 Jan 24.

Authors

Affiliations

¹ UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
² Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
³ Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁴ Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA.
⁵ UCLA Neuro-Oncology Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁷ Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
⁸ UCLA Brain Tumor Imaging Laboratory (BTIL), Center for Computer Vision and Imaging Biomarkers, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
⁹ Department of Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹⁰ Neuroscience Interdepartmental Program, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹¹ Department of Bioengineering, Henry Samueli School of Engineering, University of California Los Angeles, Los Angeles, CA, USA. bellingson@mednet.ucla.edu.
¹² UCLA Brain Tumor Imaging Laboratory, Departments of Radiological Sciences and Psychiatry, David Geffen School of Medicine, University of California Los Angeles, 924 Westwood Blvd., Suite 615, Los Angeles, CA, 90024, USA. bellingson@mednet.ucla.edu.

PMID: 31981013
PMCID: PMC7080591
DOI: 10.1007/s11060-020-03407-w

Abstract

Purpose: To examine whether the rate of change in maximum ¹⁸F-FDOPA PET uptake and the rate of change in non-enhancing tumor volume could predict malignant transformation and residual overall survival (OS) in low grade glioma (LGG) patients who received serial ¹⁸F-FDOPA PET and MRI scans.

Methods: 27 LGG patients with ≥ 2 ¹⁸F-FDOPA PET and MRI scans between 2003 and 2016 were included. The rate of change in FLAIR volume (uL/day) and maximum normalized ¹⁸F-FDOPA specific uptake value (nSUV_max/month), were compared between histological and molecular subtypes. General linear models (GLMs) were used to integrate clinical information with MR-PET measurements to predict malignant transformation. Cox univariate and multivariable regression analyses were performed to identify imaging and clinical risk factors related to OS.

Results: A GLM using patient age, treatment, the rate of change in FLAIR and ¹⁸F-FDOPA nSUV_max could predict malignant transformation with > 67% sensitivity and specificity (AUC = 0.7556, P = 0.0248). A significant association was observed between OS and continuous rates of change in PET uptake (HR = 1.0212, P = 0.0034). Cox multivariable analysis confirmed that continuous measures of the rate of change in PET uptake was an independent predictor of OS (HR = 1.0242, P = 0.0033); however, stratification of patients based on increasing or decreasing rate of change in FLAIR (HR = 2.220, P = 0.025), PET uptake (HR = 2.148, P = 0.0311), or both FLAIR and PET (HR = 2.354, P = 0.0135) predicted OS.

Conclusions: The change in maximum normalized ¹⁸F-FDOPA PET uptake, with or without clinical information and rate of change in tumor volume, may be useful for predicting the risk of malignant transformation and estimating residual survival in patients with LGG.

Keywords: 18F-FDOPA PET; Biomarker; Low grade glioma; MRI.

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Conflict of interest statement

Conflicts of Interest:

Timothy F. Cloughesy reports advisory roles with Roche, Trizel, Medscape, Bayer, Amgen, Odonate Therapeutics, Pascal Biosciences, Bayer, Del Mar Pharmaceuticals, Tocagen, Karyopharm, GW Pharma, Kiyatec, Abbvie, Boehinger Ingelheim, VBI, Deciphera, VBL, Agios, Merck, Roche, Genocea, Celgene, Puma, Lilly, BMS, Cortice, Wellcome Trust, Novocure, Novogen, Boston Biomedical, Sunovion, Human Longevity, Insys, ProNai, Pfizer, Notable labs, Medqia. Stock options with Notable Labs. Member of the board for the 501c3 Global Coalition for Adaptive Research. U.S. Provisional Application No.: 62/819,322 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER.

Benjamin M. Ellingson reports advisory and consulting roles with MedQIA, Roche, Agios, Siemens, Medicenna, Imaging Endpoints, Novogen, Northwest Biopharmaceuticals, Image Analysis Groupm Concoceutics, BeiGene, VBL, and Tocagen. Dr. Ellingson also has research grants with Siemens, Roche, and Janssen.

All other authors declare no conflicts of interest related to the subject matter in this publication.

Figures

**Fig. 1:**
A) Fluid attenuated inversion recover (FLAIR) MRI images, B) normalized ¹⁸F-FDOPA PET uptake, and C) MR-PET fused images in a 24-year-old female patient with a WHO II, IDH1 mutant, MGMT methylated diffuse glioma with multi-parametric MR-PET imaging showing increasing tumor extent crossing the midline and an increasing focus of ¹⁸F-FDOPA PET uptake over a period of around 1.3 years while on temozolomide. This patient expired approximately 1 year after the 2^nd PET scan. D) Fluid attenuated inversion recover (FLAIR) MRI images, E) normalized ¹⁸F-FDOPA PET uptake, and F) MR-PET fused images in a 35-year-old male patient with a WHO II, IDH1 mutant, unmethylated, 1p19q codeleted oligodendroglioma with a small tumor burden and minimal PET uptake that is relatively stable over a year of evaluation while on temozolomide. This patient expired more than 9.7 years from the time of the last PET scan.

**Fig. 2:. Comparison of Rate of Change in FLAIR Volume and Maximum Normalized ¹⁸F-FDOPA PET Uptake (nSUV_max) in Histological and Molecular Subtypes of Low-Grade Gliomas (LGGs).**
A) Correlation between rate of change in FLAIR volume and normalized maximum ¹⁸F-FDOPA PET uptake in WHO II low grade gliomas (R²*=0.1769, P=0.0289*). B) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for WHO 2007 (histological) tumor subtypes. C) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for isocitrate dehydrogenase (IDH)-1 mutant and wild type LGGs. D) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for 1p19q codeleted and non-codeleted LGGs. E) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for MGMT methylated and unmethylated LGGs. F) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for LGG patients on active treatment compared with those not on active treated during the PET and MRI examinations.

**Fig. 3:. Prediction of Malignant Transformation in LGGs Using Serial Changes in MR-PET Measurements.**
A) Rate of change in FLAIR volume and ¹⁸F-FDOPA nSUV_max for LGGs undergoing malignant transformation within 6 months of the last MR-PET scan. B) Relative risk of malignant transformation estimated using a general linear model (GLM) consisting of only the rate of change in FLAIR volume and the rate of change in maximum normalized ¹⁸F-FDOPA PET uptake. C) Relative risk of malignant transformation estimated using a GLM composed of patient age, whether they were on active treatment at the time of the MR-PET exams, the rate of change in FLAIR volume, and the rate of change in maximum normalized ¹⁸F-FDOPA PET uptake. D) Receiver-operator characteristic (ROC) curves for a) the rate of change in FLAIR volume, b) the rate of change in maximum normalized ¹⁸F-FDOPA PET uptake, c) the GLM using MRI and PET only, and d) the GLM using age, treatment, MRI, and PET. E) Comparison between area under the ROC curves (AUC) showing no significant difference between each technique (*P=0.6238*), although the GLM using both clinical and imaging characteristics demonstrated AUCs significantly higher than chance. * = *P<0.05*

**Fig. 4:**
Kaplan-Meier plots showing significant differences in residual OS from the 2^nd PET scan in patients with A) a positive or negative rate of change in FLAIR volume (*HR=2.220, P=0.025*); B) a positive or negative rate of change in PET uptake (*HR=2.148, P=0.0311*); and C) patients with a positive rate of change in both FLAIR volume and PET uptake compared to those with either a negative rate in FLAIR volume or PET uptake changes (*HR=2.354, P=0.0135*). Black = positive rate of change or high risk. Gray = negative rate of change or low risk.

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References

1. Whittle IR (2004) The dilemma of low grade glioma. J Neurol Neurosurg Psychiatry 75 Suppl 2: ii31–36 - PMC - PubMed
1. Claus EB, Walsh KM, Wiencke JK, Molinaro AM, Wiemels JL, Schildkraut JM, Bondy ML, Berger M, Jenkins R, Wrensch M (2015) Survival and low-grade glioma: the emergence of genetic information. Neurosurg Focus 38: E6 doi:10.3171/2014.10.FOCUS12367 - DOI - PMC - PubMed
1. Shaw EG, Wang M, Coons SW, Brachman DG, Buckner JC, Stelzer KJ, Barger GR, Brown PD, Gilbert MR, Mehta MP (2012) Randomized trial of radiation therapy plus procarbazine, lomustine, and vincristine chemotherapy for supratentorial adult low-grade glioma: initial results of RTOG 9802. J Clin Oncol 30: 3065–3070 doi:10.1200/JCO.2011.35.8598 - DOI - PMC - PubMed
1. Buckner JC, Chakravarti A, Curran WJ Jr. (2016) Radiation plus Chemotherapy in Low-Grade Glioma. N Engl J Med 375: 490–491 doi:10.1056/NEJMc1605897 - DOI - PubMed
1. Buckner JC, Shaw EG, Pugh SL, Chakravarti A, Gilbert MR, Barger GR, Coons S, Ricci P, Bullard D, Brown PD, Stelzer K, Brachman D, Suh JH, Schultz CJ, Bahary JP, Fisher BJ, Kim H, Murtha AD, Bell EH, Won M, Mehta MP, Curran WJ Jr. (2016) Radiation plus Procarbazine, CCNU, and Vincristine in Low-Grade Glioma. N Engl J Med 374: 1344–1355 doi:10.1056/NEJMoa1500925 - DOI - PMC - PubMed

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Rate of change in maximum ¹⁸F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas

Affiliations

Rate of change in maximum ¹⁸F-FDOPA PET uptake and non-enhancing tumor volume predict malignant transformation and overall survival in low-grade gliomas

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