Brem, Steven

Abstract Background IDH-mutant astrocytomas are classified as WHO grade 4 in the presence of conventional high-grade histologic features and/or homozygous CDKN2A/B deletion in the 5th edition of the WHO Classification of Central Nervous System Tumour guidelines. However, work over the past decade has indicated a number of other molecular alterations that warrant consideration as potential prognostic markers. Methods We used univariate Kaplan-Meier and multivariate Cox proportional hazards regression analysis to evaluate the prognostic effects of homozygous CDKN2A/B deletion, CDK4 amplification, CCND2 amplification, PDGFRA amplification/mutation, PIK3R1 mutation, PIK3CA mutation, MYCN amplification, EGFR amplification/mutation, TERT promoter mutation, and grade 4 histologic features in two independent cohorts of WHO grade 2-4 IDH-mutant astrocytoma (n = 840 and n = 367). Results The presence of CDK4 amplification, CCND2 amplification, PDGFRA alteration, PIK3R1 mutation, MYCN amplification, and EGFR alteration were each associated with reduced overall survival compared to WHO grade 2/3 astrocytomas without these molecular features. 17.7% (148/837) of otherwise grade 2/3 astrocytomas had one or more of these molecular criteria, with resulting intermediate clinical outcome in terms of overall survival (median survival of 67.3-82.0 months) compared to grade 2/3 astrocytomas without these molecular features (median survival of 135.0-140.7 months) and grade 4 astrocytomas (median survival of 35.3-45.0 months). Conclusions The presence of CDK4, CCND2, PDGFRA, PIK3R1, MYCN, and EGFR alterations result in an intermediate patient survival in IDH-mutant astrocytoma. Adding these molecular alterations should be considered in future diagnostic classification systems to improve stratification of high-risk patients.

Abstract BACKGROUND Differentiating radiation necrosis from tumour progression after radiation therapy (RT) for brain metastases (BM) remains clinically challenging, and accurate imaging is crucial to prevent unnecessary surgery or unwarranted changes in therapy. 18F-Fluciclovine is a PET radiopharmaceutical with low background uptake in the brain and increased uptake in BM. The PURSUE study (NCT04410367) aimed to establish image interpretation criteria (IIC) for detecting suspected recurrent BM after RT using 18F-fluciclovine PET, based on several measures of lesion uptake. MATERIAL AND METHODS Across 7 US sites, 23 patients with solid tumour BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Three independent, blinded readers qualitatively rated lesion 18F-fluciclovine uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland). The primary endpoint was the diagnostic performance of different thresholds of lesion uptake on qualitative (visual) reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]), and dynamic measures. A committee, including two independent imaging physicians, reviewed all data to establish the IIC, which were subsequently used to evaluate the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions underwent histopathological analysis, with 10 (43%) being pathologically confirmed BM recurrence. The highest performing qualitative measure of 18F-fluciclovine lesion uptake was ‘marked’, rendering 92-100% and variable (40-80%) across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, the committee established IIC as: "Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely." Application of these IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% positive predictive value, and 83-85% negative predictive value across readers. CONCLUSION PURSUE is the first prospective, multicentre study to define IIC for 18F-fluciclovine PET for accurate identification of suspected recurrent BM after RT, verified by histopathology. In this initial cohort, the IIC convey excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine PET in future studies. This study was sponsored by Blue Earth Diagnostics Ltd.

Abstract BACKGROUND After radiation therapy (RT) for brain metastases (BM), differentiating radiation necrosis from tumor recurrence remains challenging. PURSUE (NCT04410367) evaluated various measures of lesion 18F-fluciclovine uptake to establish image interpretation criteria (IIC) for 18F-fluciclovine-PET to accurately diagnose recurrent BM. METHODS Patients with solid tumor BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine-PET (185 MBq) <42 days post-MRI and 1-21 days pre-craniotomy. Lesion 18F-fluciclovine uptake was qualitatively rated as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland) by three independent blinded readers. The primary endpoint was diagnostic performance of different uptake thresholds on qualitative reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]) and dynamic measures. IIC were determined by committee and subsequently used to assess the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions from 23 enrolled patients underwent histopathological analysis; 10 (43%) were pathologically-confirmed BM recurrence. The highest performing qualitative measure was ‘marked’, rendering 92-100% sensitivity and 40-80% specificity across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, IIC was established as: “Lesions with 18F-fluciclovine uptake of SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely.” Application of the IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% PPV, and 83-85% NPV across the readers. CONCLUSIONS PURSUE is the first prospective, multicenter trial to establish IIC for 18F-fluciclovine-PET for suspected recurrent BM after RT, verified by histopathology. Finalized IIC demonstrated excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine-PET in future studies.

2001 Background: Differentiating radiation necrosis from tumor progression remains one of the most commonly encountered and clinically challenging scenarios after radiation therapy (RT) for brain metastases (BM). PURSUE (NCT04410367) evaluated the diagnostic performance of 18F-fluciclovine, an amino acid PET radiopharmaceutical, based on various lesion metrics, to establish image interpretation criteria (IIC) for suspected recurrent BM after RT. Methods: Patients with solid tumor BM were enrolled across 7 US sites if they had a previously irradiated ‘reference’ lesion equivocal on MRI for recurrence and were planned for craniotomy. 18F-Fluciclovine PET (185 MBq) took place <42 days post-MRI and 1-21 days pre-craniotomy. The primary endpoint was the diagnostic performance (sensitivity, specificity, positive-, and negative-predictive value [PPV/NPV]) of different thresholds of lesion 18F-fluciclovine uptake on qualitative, visual reads vs central histopathological analysis. Lesion 18F-fluciclovine uptake was assessed qualitatively by 3 independent blinded readers who visually rated the uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid), or ‘marked’ (above parotid). Secondary endpoints included the diagnostic performance based on different thresholds of quantitative (e.g., lesion SUV) and dynamic measures of uptake. A committee, including 2 expert imaging physicians independent to PURSUE, reviewed all data in round-table meetings to establish the IIC, which were subsequently used to assess diagnostic performance. Results: All 23 reference lesions in 23 subjects underwent histopathological analysis, with 10 (43%) confirmed as recurrent tumor. The highest performing qualitative measure was ‘marked’, rendering a sensitivity of 92-100%, with variable specificity of 40-80% across readers. SUVmax was a reader-independent, high-performing quantitative metric on ROC analysis (AUC 0.87, SUVmax threshold 4.8 conferring a sensitivity of 80% and specificity of 85%). Dynamic measures did not provide added diagnostic value. After analyzing these metrics, the committee established IIC as: Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely. Application of the IIC resulted in a sensitivity of 80%, specificity of 77-85%, PPV of 73-80%, and NPV of 83-85% across the readers. Conclusions: This is the first prospective multicenter trial to evaluate PET characteristics of suspected recurrent BM after RT, verified by histopathology. Qualitative and quantitative IIC show 18F-fluciclovine to be a high-performing diagnostic tool. These IIC will help evaluate the diagnostic performance of 18F-fluciclovine PET in future trials. Clinical trial information: NCT04410367 .

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of the following adult CNS cancers: glioma (WHO grade 1, WHO grade 2–3 oligodendroglioma [1p19q codeleted, IDH- mutant], WHO grade 2–4 IDH- mutant astrocytoma, WHO grade 4 glioblastoma), intracranial and spinal ependymomas, medulloblastoma, limited and extensive brain metastases, leptomeningeal metastases, non–AIDS-related primary CNS lymphomas, metastatic spine tumors, meningiomas, and primary spinal cord tumors. The information contained in the algorithms and principles of management sections in the NCCN Guidelines for CNS Cancers are designed to help clinicians navigate through the complex management of patients with CNS tumors. Several important principles guide surgical management and treatment with radiotherapy and systemic therapy for adults with brain tumors. The NCCN CNS Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding molecular profiling of gliomas.

Abstract BACKGROUND Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and METHODS Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results. RESULTS 331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p &lt; 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine. CONCLUSION Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.

The NCCN Guidelines for Central Nervous System (CNS) Cancers focus on management of adult CNS cancers ranging from noninvasive and surgically curable pilocytic astrocytomas to metastatic brain disease. The involvement of an interdisciplinary team, including neurosurgeons, radiation therapists, oncologists, neurologists, and neuroradiologists, is a key factor in the appropriate management of CNS cancers. Integrated histopathologic and molecular characterization of brain tumors such as gliomas should be standard practice. This article describes NCCN Guidelines recommendations for WHO grade I, II, III, and IV gliomas. Treatment of brain metastases, the most common intracranial tumors in adults, is also described.