The Efficacy of Temozolomide Combined with Levetiracetam for Glioblastoma (GBM) After Surgery: a Study Protocol for a Double-Dlinded and Randomized Controlled Trial

Background: Temozolomide is applied as the standard chemotherapy agent in patients with glioblastoma (GBM) after surgery. However, the benefit of this treatment for patients is limited by the invasive growth of glioma and drug resistance. There are indications from fundamental experimental and retrospective studies that levetiracetam has the potential to improve the survival rate of GBM patients. However, it has yet to be ascertained whether the combination of temozolomide and levetiracetam is more effective than temozolomide chemotherapy alone. Therefore, we designed a randomized clinical trial to investigate the therapeutic effect of the new combined regime for the treatment of GBM.Methods/design: This is a double-blind and randomized clinical trial carried out in a single center. A total of 142 patients will be recruited and screened for the inclusion and exclusion criteria. Then, eligible participants will be enrolled and randomly allocated into an Experimental group or a Control group in a 1:1 ratio. Based on the administration of radiation therapy (RT), participants in the Experimental group will be prescribed levetiracetam plus temozolomide chemotherapy for 34 weeks while participants in the Control group will be prescribed placebo tablets plus temozolomide for the same duration. All patients will be followed-up for three years after intervention. Accordingly, the primary outcome will be progression-free survival (PFS). The secondary endpoints include overall survival (OS), the Karnofsky Performance Status (KPS), the objective response rate (ORR), and the incidence of adverse events. Discussion: The results of this trial are expected to provide high-level evidence regarding the clinical benefits of the combination of levetiracetam and temozolomide in the treatment of GBM.Trial registration: www.ChiCTR.org.cn, ID: ChiCTR-2100049941. Registered on 14thAugust 2021.

Non-functional pituitary carcinoma

We present as case to review and present the clinical features, diagnosis and treatment of non-functional pituitary carcinoma (NFPC). We operated on a case of NFPC. After surgery, gamma knife therapy, temozolomide chemotherapy and whole craniospinal irradiation, the patient still had poor tumor control and died 7 months after operation. FPC is very rare. It needs to be diagnosed with a combination of clinical suspicion, imaging and dynamic monitoring. It is necessary to find more effective methods to control the progress of tumor while routine treatment fails.

Aggressive Pituitary Macroadenoma Treated With Capecitabine and Temozolomide Chemotherapy Combination in a Patient With Nelson’s Syndrome: A Case Report

Nelson’s syndrome is considered a severe side effect that can occur after a total bilateral adrenalectomy in patients with Cushing’s disease. It usually presents with clinical manifestations of an enlarging pituitary tumor including visual and cranial nerve alterations, and if not treated, can cause death through local brain compression or invasion. The first therapeutic option is surgery but in extreme cases of inaccessible or resistant aggressive pituitary tumors; the off-label use of chemotherapy with capecitabine and temozolomide can be considered. However, the use of this treatment is controversial due to adverse events, lack of complete response, and inability to predict results. We present the case of a 48-year-old man diagnosed with Nelson’s syndrome with prolonged partial response and significant clinical benefit to treatment with capecitabine and temozolomide.

BIOM-08. DNA METHYLATION-BASED SUBGROUPING PREDICTS SURVIVAL BENEFIT FROM LOMUSTINE/TEMOZOLOMID COMBINATION THERAPY IN MGMT PROMOTOR-METHYLATED GLIOBLASTOMA

BACKGROUND The CeTeG/NOA-09 trial showed that lomustine/temozolomide chemotherapy prolongs survival for newly diagnosed MGMT-methylated glioblastoma patients. Previous reports on temozolomide monotherapy suggested, that the survival benefit of temozolomide in MGMT-methylated tumors may be restricted to the RTK II methylation subgroup and absent in RTK I and MES subgroups. To identify patients with a particularly strong benefit from CCNU/TMZ, we explored the association of methylation subgroups with outcome after lomustine/temozolomide therapy. METHODS All patients from the CeTeG/NOA-09 trial with sufficiently available tumor tissue (n = 98) underwent 850K methylation array analysis of their tumor and methylation subgroup annotation (Heidelberg brain tumor methylation classifier v11b4; calibrated score > 0.5 required). Overall survival (OS) was compared between a pooled cohort of tumors of the RTK I/MES subgroups and RTK II tumors. RESULTS In the CCNU/TMZ arm of CeTeG/NOA-09, OS was prolonged in RTK I/MES (n = 16; median not reached, 4-year OS 69%) as compared to RTK II patients (n = 14; median 20.6 months, 4-year OS 23%; p = 0.004 logrank test). In the standard temozolomide arm of CeTeG/NOA-09, OS tended to be shorter in RTK I/MES (n = 7; median 23.7 months, 4-year OS 17%) as compared to RTK II patients (n = 17; median 35.2 months; 4-year OS 38%, p = 0.15). CONCLUSION The CCNU/TMZ-dependent survival prolongation in patients with RTK I/MES tumors as opposed to RTK II seen in CeTeG/NOA-09 suggests that methylation-based subgrouping could be predictive for CCNU/TMZ efficacy in newly diagnosed MGMT-methylated glioblastoma.

DDRE-09. MULTI-INSTITUTION RETROSPECTIVE EXPERIENCE WITH LENVATINIB FOR PROGRESSIVE MALIGNANT GLIOMA

Despite treatment with radiation and temozolomide chemotherapy, malignant gliomas inevitably recur after treatment and have poor prognosis. Clinical trials should be offered when available, but effective treatment options for multiply recurrent tumors is sparse. In our multi-institutional retrospective cohort, we looked at recurrent malignant gliomas treated with Lenvatinib multi-kinase inhibitor. Patients consented to an IRB-approved study protocol that allows for longitudinal history review and analysis at our institution. Lenvatinib is a targeted therapy that is FDA approved for Differentiated Thyroid Cancer, Renal Cell Carcinoma, Hepatocellular Carcinoma, and Endometrial Carcinoma. Lenvatinib binds to tyrosine kinase receptors inhibiting kinase activity by VEGFR1-3, FGFR1-4, PDGFRa, FGF, KIT, and RET. In this cohort, patients received radiation and temozolomide chemotherapy, N=15, median age was 45.5, and 47% were male. At time of surgery 40% underwent biopsy, 40% had STR, and 20% had GTR. Glioblastoma was the most common tumor type at 87%, 6.7% were recurrent anaplastic astrocytoma, and 6.7% were recurrent glioma NOS. IDH mutation was seen in 13% of our cohort, and MGMT methylation was seen in 27%, all patients had available IDH and MGMT data. Patients were heavily treated, median number of recurrences was 3. Patient mean PFS was 2.7 months, and median OS was 24.0 months. Clincal Benefit Rate (PR+SD) to Lenvatinib in recurrent disease was 57%, with 29% Partial Responses and 29% Stable Disease as best radiographic response. This retrospective cohort supports further evaluation of the efficacy of Lenvatinib in recurrent malignant glioma in a clinical trial.

P14.41 Cost-effectiveness of FET PET for early treatment response assessment in glioma patients following adjuvant temozolomide chemotherapy

BACKGROUND In light of increasing healthcare costs, higher medical expenses should be justified socio-economically. Therefore, we calculated the effectiveness and cost-effectiveness of PET using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) compared to conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recent study in IDH-wildtype glioma patients suggested that after two cycles, FET-PET parameter changes predicted a significantly longer survival while MRI changes were not significant. MATERIALS AND METHODS To determine the effectiveness and cost-effectiveness of serial FET-PET imaging, we analyzed published clinical data and calculated the associated costs in the context of the German healthcare system.Based on a decision-tree model, FET-PET and MRI’s effectiveness was calculated, i.e., the probability to correctly identify a responder as defined by an overall survival ≥15 months. To determine the cost-effectiveness, the incremental cost-effectiveness ratio (ICER) was calculated, i.e., the cost for each additionally identified responder by FET-PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic (Monte Carlo simulation) sensitivity analyses. RESULTS Compared to MRI, FET-PET increases the rate of correctly identified responders to chemotherapy by 26%; thus, four patients need to be examined by FET-PET to identify one additional responder. Considering the respective cost for serial FET-PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by FET-PET. The sensitivity analyses confirmed the robustness of the results. CONCLUSION In contrast to conventional MRI, the model suggests that FET PET is cost-effective in terms of ICER values. Concerning the high cost of temozolomide, the integration of FET-PET has the potential to avoid premature chemotherapy discontinuation at a reasonable cost.

Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and their Implications for Therapy

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

Prognostic value of TP53 expression and MGMT methylation in glioblastoma patients treated with temozolomide combined with other chemotherapies

Objective To assess the recurrence interval and predictive significance of TP53 expression and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastomas treated with radiotherapy and combined chemotherapies, including temozolomide, lomustine, procarbazine and bevacizumab. Method We reviewed the clinical outcomes of 52 totally resected glioblastoma patients, who received conventional radiotherapy and temozolomide with other chemotherapeutic agents. Correlation of TP53 expression and MGMT promotor methylation with recurrence interval was analyzed using Kaplan Meier estimates. Results No significant association was found between MGMT promotor methylation and TP53 expression in glioblastomas (P-value = 0.158). Patients with non-methylated MGMT who received temozolomide chemotherapy with other chemotherapeutic agents showed significantly later recurrence (P-value = 0.007) compared with patients with non-methylated MGMT who received temozolomide alone. No significant difference was found in recurrence interval among glioblastoma patients with methylated MGMT who received temozolomide alone or with other chemotherapies (P-value = 0.667). Moreover, patients with non-TP53-expressing tumors who received temozolomide with other chemotherapies had significantly later recurrence (P-value = 0.04) compared with patients who received temozolomide alone. Conclusion Totally resected glioblastoma patients, with non-methylated MGMT or non-TP53-expressing tumors treated with radiotherapy and combined chemotherapies had a reduced chance of tumor recurrence and a more favorable outcome. Furthermore, both MGMT and TP53 are independent prognostic factors for glioblastoma.