Brown, Paul D.

Abstract Background Pilocytic astrocytoma is a rare tumor in adults. This report is of a prospective clinical trial with long-term follow-up. Methods Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. Results At the time of analysis (median follow-up, 20.8 years), 2 patients (10%) have died and 18 patients (90%) are alive. Neurologic and cognitive function were stable or improved over time for the majority of patients. No toxic effects of treatment or malignant transformations have been recorded at last follow-up. For the entire cohort the 20-year time to progression and overall survival rates are 95% and 90% respectively. The cause of death (2.2 and 16.1 years after enrollment) in both patients was unrelated to tumor although both were biopsy-only patients. One subtotally resected tumor progressed 1 month after enrollment requiring P32 injection into an enlarging cyst. Because of further progression this patient required RT 18 months later. This patient is alive without evidence of progression 18 years after RT. Conclusion The long-term follow-up results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. Close observation is recommended for adults with pilocytic astrocytomas, reserving RT for salvage, as the majority remain stable after gross or subtotal resection and no adjuvant therapy.

Abstract Introduction Recent advances in stereotactic radiosurgery (SRS) have improved clinical outcomes in patients with limited intracranial metastases. As a result of this high-dose radiation delivery to a focal area within the brain, tissue structural and functional changes within the treatment field are often difficult to distinguish from local tumor recurrence based on conventional imaging techniques. Here, we demonstrate that elevation of circulating cells of myeloid origin, the key regulators of inflammation and immune responses, can serve as a potential surrogate marker to differentiate radiation-induced tissues changes from local tumor recurrence. Materials and Methods We retrospectively identified 96 patients who were initially treated with Gamma-knife radiosurgery at MD Anderson Cancer Center from 2009-2013 for brain metastases, and subsequently underwent surgical resection of previous irradiated lesions after presenting with clinical symptoms and radiographic findings suggestive of tumor progression. All surgical specimens were centrally reviewed by neuropathology. Pre-operative circulating blood cell profiles were analyzed for monocytic, granulocytic and lymphocytic sub-populations. Results A total of 11 and 85 patients who underwent surgical resection after prior SRS for brain metastasis were pathologically confirmed to have radiation-induced changes or tumor recurrence, respectively. Among patients with confirmed recurrence vs. those with radiation-induced changes, the number of circulating immature granulocytes (mean = 0.093 × 103ul−1 vs 0.032 × 103ul−1, p = 0.075) and monocytes (mean = 0.632 × 103ul−1 vs 0.401 × 103ul−1, p = 0.007) were elevated when compared to patients with radiation-induced changes (combined: mean = 0.71 × 103ul−1 vs 0.43 × 103ul−1, p = 0.002). No statistically significant differences were observed among mature granulocytic or lymphocytic populations between the two groups. Receiver operating characteristic analysis showed significant discriminative utility of pre-operative myeloid cell count when compared to reference line of no discrimination (AUC = 0.774, p = 0.003). The cut-point for myeloid cell population was found be > = 0.5 × 103ul−1, which corresponds to a detection sensitivity of 73.3% and specificity of 72.7% for tumor recurrence. Conclusion Bone marrow cells of myeloid origin play important roles in mediate acute inflammatory reactions and in regulating adaptive immunity. We showed here that certain primitive cells of myeloid lineage may potentially be used to aid the differentiation of tumor recurrence from radiation-induced changes in patients who had SRS for brain metastasis. The identification of potential circulating biomarkers that can complement traditional imaging to distinguish the two distinct pathological entities has significant implications in the management of these patients. Note: This abstract was not presented at the meeting. Citation Format: Wen Jiang, Yvo Rodriguez, Nicolas S. Boehling, Sujit S. Prabhu, Betty Y.S. Kim, Patrick Hwu, Erik P. Sulman, Paul D. Brown, Jing Li. Circulating myeloid precursor profile as potential marker to differentiate radiation changes from tumor recurrence after brain stereotactic radiosurgery. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 532. doi:10.1158/1538-7445.AM2015-532

Abstract Background: Glioblastomas (GBMs) are aggressive primary brain tumors with high levels of genomic heterogeneity impacting prognosis and treatment response. A recurrent in-frame deletion within the extracellular domain of the epidermal growth factor receptor (EGFR variant III, or vIII) is found in a substantial fraction of GBMs. Methods: The Radiation Therapy Oncology Group (RTOG) 0525 trial of temozolomide dosing in newly-diagnosed GBM enrolled 1174 patients. Of these, 494 eligible GBMs were analyzed for EGFRvIII expression by RT-PCR. The Kaplan-Meier method was used to compare the progression free survival (PFS) and overall survival (OS) of GBMs expressing EGFRvIII with those not expressing EGFRvIII. Results: 142 of 494 tested GBMs (29%) had expressed EGFRvIII. There were no significant differences in PFS or OS between patients whose tumors did (494) or did not (631) undergo EGFRvIII expression analysis. EGFRvIII expression was significantly associated with age (p=0.005), Karnofsky performance status (p=0.02), and RTOG recursive partitioning analysis (RPA) class (p=0.005). EGFRvIII expression analyzed in the entire study population did not reveal an association with PFS or OS. In a univariate subgroup analysis of patients treated on the standard-of-care arm of RTOG-0525, EGFRvIII expression was was significantly associated with worse PFS (HR=1.43, 95% CI: [1.05, 1.96], p=0.025), and worse OS (HR 1.45, 95% CI:[1.03, 2.05], p=0.032). However, in multivariate models, when adjusted for RPA class and MGMT methylation status, EGFRvIII was not an independent predictor of either PFS or OS. Conclusion: For GBMs treated with standard-of-care therapy in RTOG-0525, EGFRvIII expression was associated with worse PFS and OS. However, well-established stratification metrics such as age, KPS, and RPA override this prognostic association, suggesting that trials of therapeutic modalities directed against EGFRvIII should utilize these standard prognostic variables when survival is being analyzed or compared. Project Support: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough Corporation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A110. Citation Format: Daniel P. Cahill, Asha George, Mark R. Gilbert, Arnab Chakravarti, Roger Stupp, Monika Hegi, Paul Brown, Kurt A. Jaeckle, Benjamin Corn, Erik P. Sulman, Luis Souhami, Maria Werner-Wasik, Bethany M. Anderson, Minesh Mehta, Kenneth D. Aldape. EGFRvIII expression is associated with shorter progression-free and overall survival in glioblastoma patients treated with standard-of-care temozolomide and radiation: A report from the RTOG-0525 trial. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A110.