Martin C Tom1, Deborah Y J Park2, Kailin Yang3, C Marc Leyrer4, Wei Wei5, Xuefei Jia6, Vamsi Varra7, Jennifer S Yu8, Samuel T Chao8, Ehsan H Balagamwala3, John H Suh8, Michael A Vogelbaum9, Gene H Barnett10, Richard A Prayson11, Glen H J Stevens12, David M Peereboom13, Manmeet S Ahluwalia13, Erin S Murphy8. 1. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: MURPHYE3@ccf.org. 2. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio. 3. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. 4. Wake Forest Baptist Health, Winston Salem, North Carolina. 5. Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. 6. Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, Ohio. 7. Case Western Reserve University School of Medicine, Cleveland, Ohio. 8. Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio. 9. Department of Neuro-Oncology, Moffitt Cancer Center, Tampa, Florida. 10. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. 11. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio. 12. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; Department of Neurology, Neurological Institute, Cleveland Clinic, Cleveland, Ohio. 13. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio; Department of Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
Abstract
PURPOSE: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG. METHODS AND MATERIALS: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus. RESULTS: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008). CONCLUSIONS: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.
PURPOSE: Malignant transformation (MT) of adult grade 2 glioma (low-grade glioma [LGG]) is associated with adverse survival. We sought to describe the incidence, outcomes, and risk factors for MT of molecularly classified LGG. METHODS AND MATERIALS: We reviewed a single-institutional database of adults who received a diagnosis of LGG with data allowing for molecular classification from 1980 to 2018 to evaluate time to MT and its associated risk factors. MT was defined as pathologic confirmation of grade 3-4 glioma and/or imaging characteristics consistent with MT by multidisciplinary consensus. RESULTS: Among the included 486 adults with molecularly classified LGG, median age was 39 years (range, 18-78), median tumor size was 3.9 cm (range, 0.3-13.0), and 262 (54%) were male. Molecular classification was IDHmut1p/19qcodel in 169 (35%), IDHmut1p/19qintact in 125 (26%), and IDHwt in 192 (40%) patients. Adjuvant management was observation in 246 (51%) patients, temozolomide alone in 82 (16%), radiation therapy alone in 63 (13%), and radiation therapy concurrent with temozolomide in 81 (17%). Temozolomide monotherapy was more likely to be given to IDHmut1p/19qcodel patients (P < .001). Median follow-up was 5.3 years. MT occurred in 84 (17%) patients, with a 5-year freedom from MT of 86% (95% confidence interval [CI], 82%-90%). Median overall survival after MT was 2.4 years (95% CI, 1.5-3.3) and was associated with molecular classification (P = .03) and grade at MT (P < .001). Factors associated with MT were male sex (hazard ratio [HR], 2.1; 95% CI, 1.2-3.6; P = .009), tumor size ≥5 cm (HR, 3.5; 95% CI, 2.0-6.2; P < .001), IDHmut1p/19qintact (HR, 2.7; 95% CI, 1.3-5.6; P = .009) or IDHwt classification (HR, 5.5; 95% CI, 2.5-11.8; P < .001), and adjuvant temozolomide monotherapy (HR, 3.8; 95% CI, 1.4-10.3; P = .008). CONCLUSIONS: MT of LGG has a poor prognosis associated with unfavorable molecular groups. Analysis of our large cohort identified adjuvant temozolomide monotherapy as the only modifiable risk factor for MT and provides the first clinical evidence of temozolomide-associated MT among molecularly classified adult LGG. This novel finding supplements our understanding of temozolomide-induced hypermutation and informs precision management of LGG.
Authors: Yao Yu; Javier Villanueva-Meyer; Matthew R Grimmer; Stephanie Hilz; David A Solomon; Serah Choi; Michael Wahl; Tali Mazor; Chibo Hong; Anny Shai; Joanna J Phillips; Bruce H Wainer; Michael McDermott; Daphne Haas-Kogan; Jennie W Taylor; Nicholas Butowski; Jennifer L Clarke; Mitchel S Berger; Annette M Molinaro; Susan M Chang; Joseph F Costello; Nancy Ann Oberheim Bush Journal: Neuro Oncol Date: 2021-11-02 Impact factor: 13.029
Authors: Margot A Lazow; Lindsey Hoffman; Austin Schafer; Diana S Osorio; Daniel R Boué; Sarah Rush; Erin Wright; Adam Lane; Mariko D DeWire-Schottmiller; Teresa Smolarek; Jared Sipple; Heather Taggert; Jaime Reuss; Ralph Salloum; Trent R Hummel; Peter de Blank; Natasha Pillay-Smiley; Mary E Sutton; Anthony Asher; Charles B Stevenson; Rachid Drissi; Jonathan L Finlay; Maryam Fouladi; Christine Fuller Journal: Acta Neuropathol Commun Date: 2020-11-05 Impact factor: 7.801