Abstract

BACKGROUND

Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year, 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy, potential benefits and risks.

METHODS

We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer: QLQ-C30 and its complementary module BN-20 as well as the EuroQol instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion.

RESULTS

To date, 51 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 12.95) years, 34 were male, 30 were considered active cannabis users (66.6% males and 33.3% females). The mean global health score in the QLQ-C30 instrument was 68.4 (SD: 20.7) among cannabis users and 82.2 (SD: 17.5) among non-users. The mean difference in QOL scores between users and non-users was 13.8 (95%CI: 2.8, 24.8; p=0.01). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (95% CI: 0.06, 0.2; p=0.001). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p >0.001)

CONCLUSIONS

In our analysis, patients who use cannabis reported, on average, lower QOL scores. Potentially, sicker patients resort to cannabis to improve their symptoms and ultimately quality of life. The perception of patients is that cannabis usage improves overall quality of life. Findings provide support to perform prospective studies.

Abstract

BACKGROUND

Chemotherapy for high grade gliomas (HGG) is limited by the blood-brain-barrier (BBB). Convection enhanced delivery (CED) improves chemotherapy delivery by utilizing fluid convection obviating the challenges of crossing the BBB while minimizing systemic toxicity. CED of nanoliposomal-irinotecan (Onivyde) showed to be a superior delivery route for anti-tumor activity in animal models. An advance of this trial is the development and use of real time CED, which utilizes MRI to visualize the CED process with the aid of co-convected contrast agents, monitoring delivery into the brain and affording for corrective action.

METHODS

This is a 3 + 3 single dose escalation trial with 2 cohorts: 20mg/ml and 40mg/ml. Onivyde and GAD were co-infused via the same catheters in a one-time delivery. The total dose was personalized based on the patient’s tumor volume, and ranged from 20–680 mg of Onivyde, given via up to 4 catheters. Tumor diameters were allowed to be 1 – 4 cm, with injection volumes ranging from 2 – 17 mL of infusate.

RESULTS

13 patients have been treated on this protocol, all in under 5 hours. There were 9 GBs, 1 gliosarcoma, 2 AAs, and 1 oligoastrocytoma. Utilizing imaging software, we correlated pre-infusion modeling of the drug distribution with post-infusion imaging. A number of technical challenges were overcome by real time monitoring; the total volume of distribution (Vd), and the Vd to volume infused (Vi) ratio for each infusion was ~2. Of all patients, the only notable AE was encephalopathy, which was resolved.

CONCLUSIONS

Image-guided distribution allows for safe real-time placement and adjustment of CED cannula of Onivyde into patient’s brains. Such methods allow for maximum tumor coverage and warrant further studies with repeat dosing.

Abstract

BACKGROUND

Histone H3.3 or H3.1 mutant protein is commonly expressed in pediatric and adult diffuse midline gliomas, including diffuse intrinsic pontine gliomas (DIPGs), and portends a poor prognosis, regardless of histologic features. As such, “Diffuse midline glioma, H3-K27M-mutant” (DMG-H3K27M) was added to the 2016 WHO Classification as a grade IV entity. Knowledge of the clinical experience and natural history of this recently defined tumor in adults is limited.

METHODS

We retrospectively reviewed the pathology of adult (age ≥ 18) DMG-H3K27Ms diagnosed at our institution either via H3-K27M mutant-specific immunohistochemistry or via the UCSF500 targeted next-generation sequencing panel that includes the H3F3A, HIST1H3B, and HIST1H3C genes. Treatment, outcome, and imaging characteristics were reviewed.

RESULTS

We identified 26 adults with DMG-H3K27M and 2 with non-midline-H3K27M. Tumor locations included thalamus/basal ganglia (15), hypothalamus (2), pineal region (1), cerebellum (3), brainstem (2), spinal cord (2), mesial temporal (1), and non-midline sites (2). MRI imaging for 21/25 evaluable cases demonstrated enhancement. Of the 26 DMG-H3K27M cases, median age was 35 years (22–68 years). Of these, 17 patients had biopsy only. Median OS was 41 months (95%-CI 31-NA). In the 22 DMG-H3K27M patients with available clinical treatment data, 21 received radiation (19 with temozolomide) at initial diagnosis. At progression/recurrence, 11 patients received bevacizumab, 5 were re-treated with temozolomide, 8 received other chemotherapy, and 8 received > 1 course of re-irradiation.

CONCLUSION

While still poor overall, clinical outcome in adults with DMG-H3K27M is often better than that of pediatric DIPGs and other IDH-wildtype high-grade gliomas, such as glioblastoma. This may reflect a different cell of origin or other distinct biologic differences. Further investigation of both DMG-H3K27M and non-midline H3K27M mutant tumors in adults is warranted to study the genetic and epigenetic features of these rare tumors, as well as optimal treatment strategies.

Abstract Anaplastic oligodendrogliomas are a type of high grade glioma defined molecularly by the 1p19q co-deletion. Currently, there is no curative therapy, and some studies have estimated median survival is estimated to be approximately 5 years. Current standard of care includes surgical resection followed by radiation and chemotherapy. However, the benefit of up-front radiation with chemotherapy compared to chemotherapy alone following surgical resection has not been shown in a randomized control trial. Given the long-term cognitive consequences of radiation therapy and the high percentage of patients who lives beyond 15 years with AO, there is an effort to balance longevity with radiation toxicity. As such we performed a retrospective single institution analysis of survival of patients with anaplastic oligodendroglioma over 20 years. 159 patients were identified as diagnosed with an anaplastic oligodendroglioma between 1996–2016. Of those, 57 patients were found to have anaplastic olidodendroglioma at original diagnosis and had long term follow-up. Sixty-six percent of patients were between the ages of 30–50 and mean KPS was 87.3. At the time of analysis, 33% of patients had died. In this cohort, 60% of patients were initially treated with radiation and chemotherapy (either temozolomide or CCNU) at diagnosis and 40% were treated with chemotherapy alone. Median overall survival for the entire cohort was 142 months. The related risk of progression in the upfront chemotherapy only group is approximately 5.87 times higher than the patients who received radiation and chemotherapy (Hazard ratio=5.87, 1.92–17.90, p=0.002). However, there was no significant difference in overall survival in patients treated with upfront chemotherapy compared to patients treated upfront with chemotherapy and radiation (p=0.14). On univariate analysis, there was no association between age, KPS, EOR, or upfront vs. delayed radiation and survival. As such initial treatment with chemotherapy alone may be an option for some patients with anaplastic oligodendroglioma.

Abstract Functional activation of the PI3K/AKT/mTOR pathway is seen in ~50% of low-grade gliomas and correlates with worse survival. Everolimus is a selective inhibitor of mTOR that targets mTOR-raptor signaling, halting proliferation and indirectly inhibiting angiogenesis. This phase 2 study evaluated the efficacy of everolimus in untreated grade II diffuse glioma. Patients were stratified by 1p19q status and PI3K pathway activation (via phosphorylation of PRAS-40) into three arms: 1) 1p19q intact, PRAS-40 phosphorylated received everolimus monotherapy; 2) 1p19q intact, PRAS-40 not phosphorylated received everolimus with temozolomide; and 3) 1p19q co-deleted received everolimus monotherapy. Primary outcome was landmark PFS-33 months for Arms 1 and 2; and PFS-38 months for Arm 3 (null hypothesis 50% for all arms individually). Key eligibility criteria included central pathology confirmation, no prior treatment, and initiation of everolimus within 120 days of most recent tissue sampling. From 05/2014 to 07/2018, 27 patients were enrolled – 16 into Arm 1; 2 into Arm 2; and 9 into Arm 3. Median age at enrollment was 38 years (range 21 – 65); median KPS 90 (range 70 – 100) and a majority were male (74%). Although follow-up is not complete, as of 05/2019 11 of 16 patients had progressed prior to 33 months in Arm 1, and 5 of 9 patients had progressed prior to 38 months in Arm 3. Toxicity was as expected with frequent grade 1/2 AEs of diarrhea, rash, and mucositis. Headache was the most common grade 3 AE and was seen in three cases. The study was closed prematurely secondary to slow accrual and loss of drug support. Updated survival data as well as results of secondary and exploratory analyses will be reported. In summary, everolimus was well tolerated in previously untreated low-grade gliomas. However, it failed to meet primary outcome of extending PFS in this population.

Abstract

OBJECTIVE

To assess feasibility and effect on cognitive function and Health-Related Quality of Life (HRQoL) of an iPad-based intervention in grade 2 and 3 glioma patients stable off treatment. Patients with lower grade glioma suffer significant cognitive dysfunctions that impact their HRQoL. Formal cognitive rehabilitation is a limited resource that may be more available if deployed with a mobile device such as an iPad.

METHODS

Stable, grade 2 and 3 glioma patients with subjective cognitive complaints, complete a baseline computerized battery of standardized cognitive tests using the NIH Toolbox and HRQOL assessment with the FACT-BR. Patients then completed a novel, evidence-based, iPad based, brain tumor specific, cognitive rehabilitation program called ReMind over the next 3 months (~3 hours per week). NIH Toolbox and HRQOL assessments were repeated after completion of the rehabilitation, and again 9 months after baseline. Primary endpoint was feasibility with secondary endpoints of changes in cognitive scores and HRQOL assessments.

RESULTS

To date, 10 patients have enrolled and completed baseline testing, of whom 5 have completed ReMind rehabilitation. Median age is 56 years. Median disease duration is 7.6 years. 5 patients have Oligodendrogliomas (IDH mutated and 1p19q deleted), 3 patients have Astrocytomas, IDH mutated, and 2 patients have Astrocytomas NOS. 5 are grade II and 5 are grade III. 5 had left hemisphere tumors, 4 had right hemisphere tumors, and 1 was bilateral. 10 had prior chemotherapy and 8 prior radiation. We anticipate enrolling another 5 – 10 patients and will present the updated feasibility data as well as changes in cognitive and HRQOL scores.

CONCLUSION

As patients with lower grade tumors live longer, it is important to increase availability of cognitive interventions to improve HRQOL and outcomes. This iPad based approach provides in-home access to cognitive training and compensation strategies for patients with brain tumors.

Abstract

OBJECT

Under-enrollment in clinical trials significantly limits valid analyses of clinical interventions and generalizability of findings. Often it results in premature study termination, with estimates of 22% to 50% of clinical trials terminated due to poor accrual. Currently, there are limited reports addressing the influence of race/ethnicity and socioeconomic status on clinical trial enrollment in patients with adult glioma. The goal of this study was to determine if these factors impact clinical trial participation for glioma patients.

METHODS

852 adult patients were identified from the UCSF Tumor Board Registry and analyzed to determine the rate of therapeutic clinical trial consideration, tumor board recommendation, and study enrollment based on clinical reports in their electronic medical records.

RESULTS

At initial diagnosis, 30.7% and 18.0% of glioma patients were recommended and enrolled in a therapeutic clinical trial, respectively. At recurrence, 38.7% and 25.3% of patients were recommended and enrolled in a clinical trial, respectively. Nineteen percent of the study population belonged to a NIH-designated underrepresented minority group; Asian/Pacific-Islander comprising 10.3% overall. On univariate analysis, only in-state location, distance to the hospital, and WHO grade were associated with consideration, recommendation, and enrollment at initial diagnosis and recurrence. Minority status, insurance type, median household income, and percent below poverty were not associated with clinical trial recommendation or enrollment.

CONCLUSION

Race and socioeconomic status did not impact clinical trial consideration, tumor board recommendation, or study enrollment. Our results do not support the premise that provider decisions are impacted by biases based on minority or socioeconomic status.

Abstract

BACKGROUND

Analysis of tumors via next-generation sequencing is now routinely used in clinical practice. The UCSF500 NGS panel became available starting in June 2015. In Dec 2017, a glioblastoma precision medicine initiative started at our institution to sequence all newly-diagnosed WHO grade IV diffuse gliomas. We review our experience over a 3-year period.

METHODS

The UCSF500 Cancer Panel assesses approximately 500 cancer-associated genes for mutations, copy number alterations, and structural rearrangements, including fusions. The test can be run on tumor DNA alone or compared with normal DNA, allowing for discrimination of germline variants. Sequencing results are analyzed by a neuropathologist with genomics expertise (D.A.S.). Results from the 165 adult WHO grade IV diffuse glioma cases sequenced to date were analyzed, including 136 glioblastomas, IDH-wildtype; 19 glioblastomas, IDH-mutant; and 10 diffuse midline gliomas, H3 K27M-mutant.

RESULTS

Among the 136 IDH-wildtype glioblastomas, the most common alterations were in TERT, EGFR, CDKN2A, PTEN, NF1, TP53, PIK3R1, PDGFRA, CDK4, MDM2, LZTR1, and STAG2. Among the 19 IDH-mutant glioblastomas, the most common additional alterations were in TP53, ATRX, CDKN2A, and PDGFRA. Paired germline sequencing was performed on 71 patients, ten of which were found to harbor a germline mutation associated with increased cancer risk, including the CHEK2, MSH2, and NF1 genes. Somatic hypermutation was present in nine cases, four at initial resection and five at recurrence with a temozolomide-associated mutational signature. Among the four treatment-naïve glioblastomas with hypermutation, two were Lynch syndrome-associated in patients with damaging germline mutations in MSH2, and two were sporadic tumors that harbored somatic mutations in mismatch repair genes. CONCLUSIONS: Genomic profiling in adult glioblastoma patients results in identification of potentially actionable genetic alterations and also previously unknown germline mutations associated with increased cancer risk. A subset of glioblastomas (approximately 5%) harbor somatic hypermutation, indicating potential utility of immune checkpoint inhibition.

Abstract The design and evaluation of immunotherapies in IDH-mutant lower grade gliomas (LGG) is hindered by a poor understanding of the LGG T-cell repertoire. We present data on the temporal evolution, intratumoral spatial distribution, and prognostic value of the T-cell repertoire in IDH-mutant LGGs. We performed immunogenomic profiling using T-cell receptor beta-chain sequencing of 163 glioma and peripheral blood samples from 33 immunotherapy-naive glioma patients (22 astrocytomas, 11 oligodendrogliomas). T-cell repertoire evolution was analyzed in a subset of 26 patients (69 samples) with matched primary (WHO grade II) and recurrent (WHO grade II-IV) glioma samples. T-cell repertoire diversity was defined as the number of unique T-cell clonotypes by V-gene, J-gene, and CDR3 nucleotide sequences. Malignant transformed (Grade III or IV) recurrent gliomas demonstrated increased T-cell repertoire diversity compared to their patient-matched primary tumors (p=0.0023), but grade II recurrences did not show the same increased diversity (p=0.26). This increase in T-cell repertoire diversity was greater in patients who underwent transformation in the context of TMZ-associated hypermutation compared to spontaneously transformed counterparts (p=0.035). In grade II primary astrocytomas (n=17), T-cell repertoire diversity above the median (186 unique T-cell clonotypes per sample) was associated with worse transformation-free (HR=4.2, p=0.045) and overall survival (HR=6.4, p=0.025). Next, we evaluated intratumoral immune heterogeneity in 7 patients by sampling from up to 10 distinct and maximally-separated intratumoral sites per LGG (64 samples). Eighty-two to 96% of unique clonotypes within a given tumor were present only within a single sampled site. Despite this heterogeneity, six LGG patients harbored T-cell clonotypes present tumor-wide across all sampled sites within a given tumor. Ten of 24 (42%) tumor-wide T-cell clonotypes were enriched in the glioma compared to matched peripheral blood, suggesting glioma-specificity. Taken together, T-cell receptor profiling in LGGs may have utility both as a prognostic biomarker and to identify glioma-specific T-cells.

Abstract Although the overall prognostic significance of maximal surgical resection of contrast-enhancing tumor in glioblastoma patients is well established, prior studies have not evaluated the combined importance of resection, molecular markers, patient characteristics, and chemoradiation. Incorporation of these factors may redefine the relative benefit of cytoreductive surgery and establish differing thresholds for extent of resection in varying clinical presentations. In the first study of its kind, we examine the interactive effects of volumetric extent of resection with molecular and clinical factors to develop a new roadmap for cytoreductive surgery. Based on a 20-year retrospective cohort of 850 glioblastoma patients who had initial surgery at UCSF, we employed survival models and recursive partitioning (RPA) to investigate multivariate relationships of overall survival (OS), both in the entire cohort as well as a subset diagnosed since 2005 (Stupp-era) with IDH1 mutation status available (n=470). For the entire cohort and the Stupp-era subset, the RPAs elucidate the combinatorial consequence of treatment, age, IDH1 status (in the subset), and resection of both enhancing and non-enhancing tumor. In the Stupp-era, temozolomide-treated patients that are IDH-wildtype and >65 clearly benefit from a reduction of the enhancing tumor (median OS: 10.1 vs 15.8 months). IDH-wildtype, temozolomide-treated patients under 65 benefit from reduction of both enhancing and non-enhancing tumor with a median survival similar to that of IDH-mutant, temozolomide-treated patients (combined median OS: 33.7 months). The patients faring worst are those that did not receive temozolomide that are >65 and/or have ≥0.3 cm3 residual enhancing tumor (median OS: 4 months). These risk models outperform all published prognostic models. This is the first study to combine resection of contrast-enhancing and non-enhancing tumor in conjunction with molecular and clinical information in a large single-institution study, and paves the way for rethinking surgical strategies for individual patients with newly diagnosed glioblastoma.