Clinical Investigation
Risk Factors for Malignant Transformation of Low-Grade Glioma

https://doi.org/10.1016/j.ijrobp.2017.12.258Get rights and content

Purpose

The incidence, risk factors, and outcomes of low-grade glioma patients who undergo malignant transformation (MT) in the era of temozolomide are not well known. This study evaluates these factors in a large group of World Health Organization grade 2 glioma patients treated at a tertiary-care institution.

Methods and Materials

Patient, tumor, and treatment factors were analyzed using an institutional review board–approved low-grade glioma database. Characteristics were compared using χ2 and Wilcoxon signed rank tests. Time to event was summarized using proportional hazards models. Univariate and multivariate survival analyses were performed.

Results

Of a total of 599 patients, 124 underwent MT; 76 (61.3%) had biopsy-proven MT. The MT incidence was 21%, and the median time to MT was 56.4 months. The 5- and 10-year progression-free survival rates were 30.6% ± 4.2% and 4.8% ± 1.9%, respectively, for MT patients and 60% ± 2.4% and 38% ± 2.7%, respectively, for non-MT patients. The 5- and 10-year overall survival rates were 75% ± 4.0% and 46% ± 5.0%, respectively, for MT patients and 87% ± 1.7% and 78% ± 2.3%, respectively, for non-MT patients. On multivariate analysis, older age (P = .001), male sex (P = .004), multiple tumor locations (P = .004), chemotherapy alone (P = .012), and extent of resection (P = .045) remained significant predictors of MT.

Conclusions

MT affects survival. Risk factors include older age, male sex, multiple tumor locations, use of chemotherapy alone, and presence of residual disease. Our finding that initial interventions could affect the rate of MT is provocative, but these data should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

Introduction

Low-grade gliomas (LGGs) consist of a heterogeneous tumor group with a wide range of survival durations (1). Initial therapy consists of maximal safe resection followed by a range of adjuvant approaches from observation (Radiation Therapy Oncology Group [RTOG] 0925–NCT01417507) (2) to chemotherapy 3, 4, radiation therapy 3, 5, 6, 7, 8, and combination chemoradiation therapy 9, 10.

Malignant transformation (MT) is progression of a low-grade tumor to a World Health Organization grade 3 or 4 tumor. The incidence of LGG MT ranges from 23% to 72% in the available literature, with the median time to MT ranging from 2.7 to 5.4 years 8, 11, 12, 13. The method of diagnosis has not been consistent across studies. In these published series, MT was determined by biopsy 8, 13, computed tomography (CT) imaging changes (12), and magnetic resonance imaging (MRI) changes (11). MT negatively affects survival, with 50% of patients dying from MT in 1 series (13) and a median time to death from MT of just 1 year (12). Prognostic factors include astrocytoma histology, less than gross total resection, and tumor size >3 cm (11).

The impact of therapy on MT is not clear. The incidence of MT was the same in 1 series whether patients received radiation therapy or not (13) or regardless of the timing of radiation therapy (8). There is mechanistic evidence that alkylating chemotherapies such as temozolomide (TMZ) can induce hypermutation, which has been observed in recurrent tumors 14, 15. In 1 report, all LGGs treated with TMZ in which hypermutation developed transformed to grade 4 tumors (15). Mutations in the RB and AKT-mTOR pathway and mismatch repair genes are demonstrated in these tumors and may be driver mutations for malignant progression (15).

The risk factors, incidence, and outcomes of LGG patients who undergo MT in the era of TMZ chemotherapy are not well known. Our study evaluates these questions using our large institutional review board–approved LGG database.

We reviewed our institutional review board–approved LGG database that includes 599 patients who received diagnoses from 1988 through 2014. The median follow-up period for these patients was 88.3 months. Data collected for this analysis included patient factors (demographic information and comorbidities); tumor factors (histology, 1p19q status, IDH status, size, and location [single tumor vs multiple discrete tumors and lobes involved]); extent of resection (determined by review of MRI and/or CT when available and medical records); initial adjuvant treatment (timing of adjuvant therapy, chemotherapy treatment, and radiation therapy treatment); MT (timing, diagnosis, and enhancement status); dates of progression; and date of death. MT was defined as pathologic confirmation of grade 3 or 4 glioma or new or increased contrast enhancement with an aggressive growth pattern as determined by a multidisciplinary central nervous system tumor board consensus.

The Pearson χ2 test and Wilcoxon signed rank test were performed for evaluation of differences between MT patients who underwent biopsy and those who did not. Overall survival (OS) and progression-free survival (PFS) were the primary endpoints for this analysis. Time-to-event data were estimated by the Kaplan-Meier method and were summarized using proportional hazards models. Univariate and multivariate analyses were performed to identify prognostic factors for MT, with P < .05 used as a cutoff for statistical significance. Age at diagnosis was used as a continuous variable. We also performed propensity score matching to estimate the effect of a treatment on an observational study. This was used to reduce the effect of selection bias between 2 treatment options. Multiple logistic regression was performed with stepwise selection to determine important predictors of treatment selection. A propensity score was calculated based on these variables; patients were then matched by the propensity score, and finally, the effect of treatment was compared. Statistical analysis was performed with the SAS software package (version 9.4; SAS Institute, Cary, NC).

Section snippets

Results

Our patients included those with the pathologic diagnoses of oligodendroglioma, astrocytoma, and mixed histologies. Of the patients, 447 (75%) had known 1p19q status: 147 (33%) had co-deleted tumors (or 1p deleted if 19q analysis had not been performed) and 300 (67%) had 1p19q non–co-deleted tumors. Patient characteristics are shown in Table 1. Gross total resection was obtained in 209 patients (35%); near total resection, in 38 (6%); and subtotal resection, in 134 (22%); biopsy was performed

Discussion

We report a crude rate of MT of 20.7% from our large LGG database, and in the majority of these patients, it was biopsy proven. This experience is noteworthy in that the chemotherapy used was primarily TMZ. This rate is similar to the experience reported in a study by Chaichana et al (11), in which 191 patients were reviewed in the MRI era with a 23% rate of MT. Of note, there did not seem to be any difference in tumor or treatment characteristics or outcomes between the patients with

Conclusions

The MT incidence is 21% in our large series, and it negatively affects survival. Risk factors for MT include older age, male sex, multiple tumor locations, use of TMZ, and less than gross total resection. Our data are hypothesis generating and should be validated using data from prospective trials. In addition to improving survival, future therapeutic efforts should focus on preventing MT.

References (26)

  • E. Shaw et al.

    Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: Initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study

    J Clin Oncol

    (2002)
  • J.C. Buckner et al.

    Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma

    N Engl J Med

    (2016)
  • K.L. Chaichana et al.

    Recurrence and malignant degeneration after resection of adult hemispheric low-grade gliomas

    J Neurosurg

    (2010)
  • Cited by (62)

    • Sex-Specific Differences in Low-Grade Glioma Presentation and Outcome

      2022, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      It is now well established that IDH mutations and 1p/19q status substantially influence patient outcomes, as well as CDKN2A/B homozygous deletion.1,5 Several studies demonstrate that along with previously defined clinical variables and molecular features, male sex has emerged as a nonmodifiable risk factor for worse survival and higher risk for malignant transformation in LGG.6-8 A similar difference in sex based outcomes in disease has been noted in several fields, including cardiology, rheumatology, neurology, and gastroenterology/hepatology.9,10

    • A Review on the Surgical Management of Insular Gliomas

      2023, Canadian Journal of Neurological Sciences
    View all citing articles on Scopus

    Conflict of interest: none.

    View full text