Clinical Outcomes in High Risk WHO Grade II Glioma Patients Treated with Upfront TMZ-Based Chemoradiotherapy

Abstract

<h3>Purpose/Objective(s)</h3> The RTOG 9802 study demonstrated improved survival with use of chemoradiotherapy (CRT) over radiotherapy (RT) alone for WHO Grade II gliomas (LGG). PCV chemotherapy, utilized in that trial, is less commonly used in the U.S. and is associated with significant toxicity. We analyze our retrospective dataset of predominantly temozolomide (TMZ)-based CRT in LGG patients who would have been eligible for RTOG 9802. <h3>Materials/Methods</h3> Retrospective review of LGG patients (2000–2017) in a single institution pathology database was performed. Patients with histologies that included oligodendroglioma (OD), astrocytoma (AC) or astrocytoma (OA) who received upfront RT +/- chemotherapy were included in the analysis. We identified 67 eligible patients during this interval. Characteristics including age>40, RTOG high-risk features (age≥40 at time of diagnosis OR lack of a gross total resection (GTR)), tumor size>6 cm, tumor crossing midline, pathology (n= 37 AC, 20 OD, or 9 OA), presence of neurologic deficit at diagnosis, and utilization of RT and chemotherapy were determined. The CRT cohort (n=40) consisted primarily of TMZ (n=36) administered concurrently with RT. 27 patients received RT alone. RT for both cohorts consisted of a median dose of 54 Gy (range 50.4 - 54 Gy). 65/67 patients had "high risk" LGG as defined by RTOG 9802 criteria. Kaplan Meier analysis was used to assess overall survival (OS) and progression free survival (PFS). <h3>Results</h3> 5-year PFS for patients receiving CRT was 64% vs. 44% in those receiving RT alone (log rank p=0.009). This PFS curve shows increased separation of curves after 2 years similar to what was seen in RTOG 9802. Difference in PFS due to chemotherapy was driven by AC histology (57% vs. 21% PFS at 5 years, log rank p=0.002) while OD/OA PFS was not statistically altered with the addition of chemotherapy (79% vs. 72% PFS at 5 years, p=0.21). 5-year OS for patients receiving CRT was 76% vs. 69% in those receiving RT alone (p=0.11), with the CRT arm not yet reaching median survival<b>.</b> Cox Proportional Hazards analysis revealed that patients with astrocytoma (HR=6.14, p=0.0034), neurological deficit at presentation (HR=2.37, p=0.023) and tumor>6 cm (HR=-2.69, p=0.03) had an increased risk of death. Cox Proportional Hazards analysis showed that use of upfront CRT (HR=0.4, p=0.009) was the only factor that decreased the risk of earlier progression. Patients with AC (HR=3.21, p-0.018) or neurological deficit at presentation (HR=2.49, p=0.01) had increased risk of progression. <h3>Conclusion</h3> Use of upfront predominantly TMZ-based CRT has a PFS benefit over RT alone in a population of WHO grade II gliomas. This benefit of upfront TMZ-based CRT, a regimen generally significantly less toxic than PCV and better tolerated, appears to extend beyond the "very high risk" cohort from RTOG 0424 to include the "high risk" group from RTOG 9802, indicating a potential role for TMZ in a larger subset of LGG patients than previously-thought. This benefit appears to be driven by AC histology.