Treatment Of Recurrent Brain Tumors Research Articles

Multimodality Dosimetric Evaluation for the Treatment of Recurrent Brain Tumors

GammaTile Surgically Targeted Radiation Therapy (STaRT) are bioresorbable collagen tiles containing four Cesium-131 radioactive seeds which are permanently implanted into the operative bed immediately following the surgical resection of a brain tumor. Alternative radiation treatment approaches for recurrent brain tumors include external beam radiation therapy (EBRT) with either proton or photon (volumetric modulated arc therapy, or VMAT) radiation. The purpose of this study is to perform a comparative dosimetric study of these three modalities for cases of recurrent brain tumors. We hypothesize that GammaTile would be dosimetrically superior at sparing radiation dose to surrounding organs at risk. A total of 5 patients have received GammaTile StaRT therapy at our institute for recurrent brain tumors in 2021-2022. Out of these 5 patients, 3 were recurrent glioblastoma (GBM) and 2 were brain metastasis (brain-met) cases. All patients were previously treated with radiation. Typical prescription for GammaTile therapy is 60 Gy to the High Risk CTV (HR_CTV), specified by 5mm depth from the plane of the seeds. For recurrent GBM cases, the alternative methods of radiation are proton therapy and photon therapy using VMAT. The standard re-irradiation dose for proton and photon therapy is 35 Gy in 10 fractions prescribed to PTV (3 mm expansion of EBRT CTV). For brain-met cases, an alternate method is hypo-fractionation radiation therapy with Linac-based SBRT. Linac-based SBRT prescription depends on the volume of EBRT CTV. For one of the brain-met cases, the SBRT prescription was 30 Gy in 5 fractions, and for the other case it was 27 Gy in 3 fractions to PTV (2 mm expansion from EBRT CTV). Proton and photon plans were generated in a treatment planning system using a double scattering Mevion system and a VersaHD with agility head, respectively. All the physical doses were converted to biological effective dose (BED) for evaluation. The dosimetric quantities are summarized in table 1. These quantities were evaluated using HR_CTV and EBRT_CTV for GammaTile therapy and EBRT (proton/photon), respectively. GammaTile therapy reduces dose to normal brain tissue considerably. However, it may have more uncertainty in the dose delivered compared to proton and photon EBRT. It appears that all three treatment modalities are adequate for treating recurrent brain tumors. However, GammaTile therapy may allow to deliver higher dose to the targets while reducing the irradiation to adjacent normal tissue.

Abstract 5422: Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors.

Abstract Glioblastomas (GBMs) are characterized by a very aggressive behavior and a heterogeneous presentation that includes proliferative, invasive, and necrotic areas. The rapid expansion of GBMs frequently outgrowths the blood supply, originating hypoxic and necrotic regions, which induces metabolic changes in the tumor cells. In a survival adaptation response, tumor cells adjust their glucose metabolism to an anaerobic glycolysis, even in the presence of oxygen. This is known as the Warburg effect and it is enhanced in Brain Tumor Stem Cells (BTSCs), the cellular sub-population considered to be responsible for the tumor origin and recurrence. Glycolysis inhibition can be achieved using glucose analogues like 2-deoxyglucose (2DG). We have previously demonstrated that 2DG treatment of BTSCs induces a decrease in cell proliferation and an increase in cell death and neuronal differentiation. Nevertheless, some BTSC cells are able to survive glycolysis inhibition and recover their aggressive phenotype which might be related to brain tumor recurrence. Here we studied the tumorigenic behavior of human GBM-derived primary BTSCs after recovery from glycolysis inhibition. We observed that cells which were pretreated with 2DG and subsequently allowed to recover for 72h in glucose-containing media, exhibited a more aggressive phenotype; including an increased migration, invasion, and proliferation capability; as well as MMP2 and nestin overexpression. Some of these features recapitulate what occurs in recurrent brain tumors. In studying the potential molecular mechanisms responsible for this behavior, we observed an increased expression of glucose-6-phosphatase isoform α (G6PC) in our primary GBM cells when compared to normal brain. Moreover, 2DG treatment induced an increase in the expression of this isoform. G6PC is a key glucose homeostasis enzyme not previously reported in brain tissue. In addition, when G6PC was inhibited, either pharmacologically (with chlorogenic acid) or genetically (with shRNA), we observed that the recovery capacity of GBM cells was significantly reduced. This was evident by a decrease in their proliferation, migration, and invasion ability, as well as by a decrease in HIF1α, pSTAT3 protein, MMP2 gene expression. In summary, we report for the first time the expression of G6PC in GBM cells. This specific isoform is not expressed in normal brain parenchyma, which makes it a very attractive target for anticancer therapy. Our results suggest a role of G6PC in promoting a mechanism of GBM cell recovery from glycolysis inhibition. By unraveling these mechanisms we describe an important therapeutic target that could impact the recurrence ability of brain tumors. Citation Format: Sara Abbadi, Hugo Guerrero-Cazares, Ameer Abutaleb, Chris L. Smith, William Ruff, Jennifer Schiller, Andre Levchenko, Alfredo Quinones-Hinojosa. Human GBM-derived brain tumor stem cells resist glycolysis inhibition through Glucose 6 phosphatase: a potential clinical implication in the treatment of recurrent brain tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5422. doi:10.1158/1538-7445.AM2013-5422

Enhanced brain accumulation of pazopanib by modulating P-gp and Bcrp1 mediated efflux with canertinib or erlotinib

Primary objective of this investigation was to delineate the differential impact of efflux transporters P-glycoprotein (P-gp/Abcb1) and breast cancer resistance protein (Bcrp1/Abcg2) on brain disposition and plasma pharmacokinetics of pazopanib. In addition, this research investigated whether inhibition of these efflux transporters with clinically relevant efflux modulators canertinib or erlotinib could be a viable strategy for improving pazopanib brain delivery. In vitro assays with MDCKII cell monolayers suggested that pazopanib is a high affinity substrate for Bcrp1 and a moderate substrate for P-gp. Co-incubation with specific transport inhibitors restored cell accumulation and completely abolished the directionality of pazopanib flux. Brain and plasma pharmacokinetic studies were conducted in FVB wild type mice in the absence and presence of specific transport inhibitors. Drug levels in plasma and brain were determined using a validated high performance liquid chromatography method using vandetanib as an internal standard. In vivo studies indicated that specific inhibition of either P-gp (by zosuquidar or LY335979) or Bcrp1 (by Ko143) alone did not significantly alter pazopanib brain accumulation. However, dual P-gp/Bcrp1 inhibition by elacridar (GF120918), significantly enhanced pazopanib brain penetration by ~5-fold without altering its plasma concentrations. Thus, even though Bcrp1 showed higher affinity towards pazopanib in vitro, in vivo at the mouse BBB both P-gp and Bcrp1 act in concert to limit brain accumulation of pazopanib. Furthermore, erlotinib and canertinib as clinically relevant efflux modulators efficiently abrogated directionality in pazopanib efflux in vitro and their co-administration resulted in 2-2.5-fold increase in pazopanib brain accumulation in vivo. Further pre-clinical and clinical investigations are warranted as erlotinib or canertinib may have a synergistic pharmacological effect in addition to their primary role of pazopanib efflux modulation as a combination regimen for the treatment of recurrent brain tumors.

Tegwondo: Development of a novel near-continuous dose-dense temozolomide regimen for the treatment of recurrent brain tumors

13016 Background: We report on activity and feasibility of a rechallenge of recurrent gliomas with temozolomide (TMZ) in a dose- dense 21/28-day regimen and development of a novel 5/7-day schedule. Methods: 40 recurrent glioma-patients received TMZ 100mg/m2 with individual dose adaptation: 21 pts. received 148 cycles day 1–21/28 (18 WHO IV [GBM], 3 WHO III). GBM-pts. had a mean age of 54.4y, median KPS was 60%. Patients with critical blood counts (∼50%) were switched to a 1–5/7-day regimen. Better tolerability led us to treat 19 subsequent patients initially day 1–5/7: 13 GBM, 2 WHO-III, 4 WHO-II; 55.5 y, KPS 70%, total 61 cycles. All malignant gliomas were pretreated with temozolomide. Results: Nausea and fatigue were less frequent than with the 5/28-day schedule. Blood counts usually decreased continuously. Dosage was reduced in approx. 50% of patients and increased to up to 130 mg/m2 in 3 patients. Hematotoxicity grade ¾ (asymptomatic): 2/21 pts. (21/28-day) and 2/19 pts. (5/7-day); nonhematological ¾°: 4/21 Pts. (21/28), 0/19 (5/7). Efficacy of 21/28-day application in GBM was: 2 CR (11%), 2 PR (11%), 7 SD (39%) and 7 PD (39%) after at least 3 months. 38.8% were progression-free at 6 months. Survival after relapse was 34.8 weeks, overall 17.9 months. MGMT-status was available from 7 tumors: 2/4 pts. with unmethylated MGMT were progression-free after 12 months, but only 1/3 with methylated MGMT. Conclusions: Rechallenge of recurrent gliomas with dose-dense temozolomide at 100 mg/m2 and individual dose adaptation is feasible and active. 22% objective long-term responses demonstrate that this strategy is effective even with unfavorable prognostic criteria. Dose adaptation is most appropriate with a near-continuous application day 1–5/7, which is expected to cause permanent depletion of the alkylation-resistance factor MGMT. In fact, also patients with unmethylated MGMT had long-term responses, indicating that chemotherapy resistance may be overcome with this strategy. We therefore consider TEGWONDO (Temozolomide in the Goettingen WOrkiNgday Dose-dense regimen) to be active and feasible also in TMZ-pretreated patients with critical blood counts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Schering-Plough

Update of radiation therapy oncology group (RTOG) protocol 9005: Single dose radiosurgical treatment of recurrent brain tumors

Update of radiation therapy oncology group (RTOG) protocol 9005: Single dose radiosurgical treatment of recurrent brain tumors

Brain metastases in renal cell carcinoma. Results of treatment and prognosis

Brain metastases develop as a late manifestation of renal cell cancer (RCC) and pose an increasing challenge to urologists as a result of the more frequent prolonged survival of patients with advanced RCC. Therapeutic options, including surgical resection and radiotherapy, were analyzed retrospectively to assess survival and to identify factors influencing prognosis in a group of 90 patients treated either by brain metastasectomy (n = 64) or radiotherapy (n = 26). The analysis confirmed that the overall median survival was a disappointing 461 days and the 1-year survival rate was 31% for patients treated by surgical resection and 310 days and 15% respectively for patients treated by radiotherapy. However, a subgroup of patients who, benefitted significantly from aggressive treatment of metastases could be defined. The following favorable prognostic factors showed a trend toward improved survival: (1) metachronous appearance of brain metastases more than 1 year after nephrectomy (P < 0.0001), (2) good patient performance (Karnofsky > 70) (P < 0.0002), (3) patient's age under 50 years (P < 0.05), (4) solitary lesions (P < 0.05), (5) minimal or no neurological deficit (P < 0.05), and (6) the absence of/or minimal extracranial metastases (P < 0.05). No influence of lesion size and localization (infratentorial vs supratentorial) on survival was detected. Surgical treatment of recurrent brain tumors (n = 17) yielded and additional median survival advantage of 8 months as compared to untreated patients (n = 16). Our results suggest that, especially in patients with good prognostic criteria, a radical metastasectomy plus vigorous surgery of local recurrences and, if required, subsequent systemic immuno- or chemoimmunotherapy should be performed. In patients with poor prognosis, stereotactic radiosurgery is recommended for palliation and survival prolongation.

Fractionated regimens for stereotactic radiotherapy of recurrent tumors in the brain

Radiosurgery (single-fraction stereotactic radiotherapy) was initially developed to treat non-malignant arteriovenous malformations, but there is growing interest in its use for the treatment of recurrent brain tumors. We suggest that there are sound reasons to expect improved results for tumor radiotherapy, in terms of late effects, if a fractionated regimen is used. At present, no published guidelines are available for choosing appropriate doses for fractionated regimens. We present two sets of guidelines, based on experimentally derived radiobiological parameters: first, we estimate gamma-ray doses which, if delivered in various numbers of fractions, should produce equivalent early effects to 70 Gy of 125I X rays delivered at low dose rate; this latter regimen is currently used in RTOG interstitial brachytherapy trials. Second, we estimate doses for multi-fractioned stereotactic radiotherapy which may be advantageous alternatives to particular doses of single-fractioned radiosurgical therapy. As the appropriate hardware is available, the use of fractionated stereotactic radiotherapy deserves serious consideration for the treatment of recurrent tumors in the brain.