Mid-term treatment-related cognitive sequelae in glioma patients

Purpose: Cognitive functioning represents an essential determinant of quality of life. Since significant advances in neuro-oncological treatment have led to prolonged survival it is important to reliably identify possible treatment-related neurocognitive dysfunction in brain tumor patients. Therefore, the present study specifically evaluates the effects of standard treatment modalities on neurocognitive functions in glioma patients within two years after surgery. Methods: Eighty-six patients with World Health Organization (WHO) grade 1-4 gliomas were treated between 2004 and 2012 and prospectively followed within the German Glioma Network. They received serial neuropsychological assessment of attention, memory and executive functions using the computer-based test battery NeuroCog FX. As the primary outcome the extent of change in cognitive performance over time was compared between patients who received radiotherapy, chemotherapy or combined radio-chemotherapy and patients without any adjuvant therapy. Additionally, the effect of irradiation and chemotherapy was assessed in subgroup analyses. Furthermore, the potential impact of the extent of tumor resection and histopathological characteristics on cognitive functioning were referred to as secondary outcomes. Results: After a median of 16.8 (range 5.9-31.1) months between post-surgery baseline neuropsychological assessment and follow-up assessment, all treatment groups showed numerical and often even statistically significant improvement in all cognitive domains. The extent of change in cognitive functioning showed no difference between treatment groups. Concerning figural memory only, irradiated patients showed less improvement than non-irradiated patients (p = 0.029, η2 = 0.06). Resected patients, yet not patients with biopsy, showed improvement in all cognitive domains. Compared to patients with astrocytomas, patients with oligodendrogliomas revealed a greater potential to improve in attentional and executive functions. However, the heterogeneity of the patient group and the potentially selected cohort may confound results. Conclusion: Within a two-year post-surgery interval, radiotherapy, chemotherapy or their combination as standard treatment did not have a detrimental effect on cognitive functions in WHO grade 1-4 glioma patients. Cognitive performance in patients with adjuvant treatment was comparable to that of patients without. Keywords: Glioma; NeuroCog FX; Neuropsychological assessment; Prospective; Treatment-related neurotoxicit

Limited role for extended maintenance temozolomide for newly diagnosed glioblastoma

Objective: To explore an association with survival of modifying the current standard of care for patients with newly diagnosed glioblastoma of surgery followed by radiotherapy plus concurrent and 6 cycles of maintenance temozolomide chemotherapy (TMZ/RT -> TMZ) by extending TMZ beyond 6 cycles. Methods: The German Glioma Network cohort was screened for patients with newly diagnosed glioblastoma who received TMZ/RT -> TMZ and completed >6 cycles of maintenance chemotherapy without progression. Associations of clinical patient characteristics, molecular markers, and residual tumor determined by magnetic resonance imaging after 6 cycles of TMZ with progression-free survival (PFS) and overall survival (OS) were analyzed with the log-rank test. Multivariate analyses using the Cox proportional hazards model were performed to assess associations of prolonged TMZ use with outcome. Results: Sixty-one of 142 identified patients received at least 7 maintenance TMZ cycles (median 11, range 7-20). Patients with extended maintenance TMZ treatment had better PFS (20.5 months, 95% confidence interval [CI] 17.7-23.3, vs 17.2 months, 95% CI 10.2-24.2, p = 0.035) but not OS (32.6 months, 95% CI 28.9-36.4, vs 33.2 months, 95% CI 25.3-41.0, p = 0.126). However, there was no significant association of prolonged TMZ chemotherapy with PFS (hazard ratio [HR] 5 0.8, 95% CI 0.4-1.6, p = 0.559) or OS (HR 5 1.6, 95% CI 0.8-3.3, p = 0.218) adjusted for age, extent of resection, Karnofsky performance score, presence of residual tumor, O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation status, or isocitrate dehydrogenase (IDH) mutation status. Conclusion: These data may not support the practice of prolonging maintenance TMZ chemotherapy beyond 6 cycles. Classification of evidence: This study provides Class III evidence that in patients with newly diagnosed glioblastoma, prolonged TMZ chemotherapy does not significantly increase PFS or OS

Differential Retinoic Acid Signaling in Tumors of Long- and Short-term Glioblastoma Survivors

Although the prognosis of most glioblastoma patients is poor, 3%-5% patients show long-term survival of 36 months or longer after diagnosis. To study the differences in activation of biochemical pathways, we performed mRNA and protein expression analyses of primary glioblastoma tissues from 11 long-term survivors (LTS; overall survival ≥ 36 months) and 12 short-term survivors (STS; overall survival ≤ 6 months). The mRNA expression ratio of the retinoic acid transporters fatty acid-binding protein 5 (FABP5) and cellular retinoic acid-binding protein 2 (CRABP2), which regulate the differential delivery of retinoic acid to either antioncogenic retinoic acid receptors or prooncogenic nuclear receptor peroxisome proliferator-activated receptor delta, was statistically significantly higher in the tumor tissues of STS than those of LTS (median ratio in STS tumors = 3.64, 10th-90th percentile = 1.43-4.54 vs median ratio in LTS tumors = 1.42, 10th-90th percentile = −0.98 to 2.59; P < .001). High FABP5 protein expression in STS tumors was associated with highly proliferating tumor cells and activation of 3-phosphoinositide-dependent protein kinase-1 and v-akt murine thymoma viral oncogene homolog. The data suggest that retinoic acid signaling activates different targets in glioblastomas from LTS and STS. All statistical tests were two-side

Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before; albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation

Zotiraciclib (TG02) for newly diagnosed glioblastoma in the elderly or for recurrent glioblastoma:The EORTC 1608 STEAM trial

Background: Zotiraciclib (TG02) is an oral multi-cyclin dependent kinase (CDK) inhibitor thought to inhibit tumor growth via CDK-9-dependent depletion of survival proteins such as c-MYC and MCL-1 which are frequently overexpressed in glioblastoma. Methods: EORTC 1608 (NCT03224104) (STEAM) had a three parallel group (A,B,C) phase Ib, open-label, non-randomized, multicenter design in IDH wild-type newly diagnosed glioblastoma or anaplastic astrocytoma. Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), according to O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Group C explored single agent activity of TG02 at first relapse after temozolomide chemoradiotherapy with a primary endpoint of progression-free survival at 6 months (PFS-6). Tumor expression of CDK-9, c-MYC and MCL-1 was determined by immunohistochemistry.Results: The MTD was 150 mg twice weekly in combination with radiotherapy alone (group A) or temozolomide alone (group B). Two dose-limiting toxicities were observed at 150 mg: one in group A (grade 3 seizure), one in group B (multiple grade 1 events). Main toxicities included neutropenia, gastrointestinal disorders and hepatotoxicity. PFS-6 in group C was 6.7%. CDK-9, c-MYC and MCL-1 were confirmed to be expressed and their expression was moderately cross-correlated. High protein levels of MCL-1 were associated with inferior survival. Conclusions: TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.</p

Prospective cohort study of radiotherapy with concomitant and adjuvant temozolomide chemotherapy for glioblastoma patients with no or minimal residual enhancing tumor load after surgery

Survival of glioblastoma patients has been linked to the completeness of surgical resection. Available data, however, were generated with adjuvant radiotherapy. Data confirming that extensive cytoreduction remains beneficial to patients treated with the current standard, concomitant temozolomide radiochemotherapy, are limited. We therefore analyzed the efficacy of radiochemotherapy for patients with little or no residual tumor after surgery. In this prospective, non-interventional multicenter cohort study, entry criteria were histological diagnosis of glioblastoma, small enhancing or no residual tumor on post-operative MRI, and intended temozolomide radiochemotherapy. The primary study objective was progression-free survival; secondary study objectives were survival and toxicity. Furthermore, the prognostic value of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was investigated in a subgroup of patients. One-hundred and eighty patients were enrolled. Fourteen were excluded by patient request or failure to initiate radiochemotherapy. Twenty-three patients had non-evaluable post-operative imaging. Thus, 143 patients qualified for analysis, with 107 patients having residual tumor diameters ≤1.5 cm. Median follow-up was 24.0 months. Median survival or patients without residual enhancing tumor exceeded the follow-up period. Median survival was 16.9 months for 32 patients with residual tumor diameters >0 to ≤1.5 cm (95% CI: 13.3–20.5, p = 0.039), and 13.9 months (10.3–17.5, overall p < 0.001) for 36 patients with residual tumor diameters >1.5 cm. Patient age at diagnosis and extent of resection were independently associated with survival. Patients with MGMT promoter methylated tumors and complete resection made the best prognosis. Completeness of resection acts synergistically with concomitant and adjuvant radiochemotherapy, especially in patients with MGMT promoter methylation