Koichiro Kawasaki

Phase II trial of gefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR-mutant lung adenocarcinoma

BACKGROUND Brain metastases (BM) are a common in patients with lung cancer. Although whole-brain radiation therapy (WBRT) is the standard therapy, it may have a risk of decline in cognitive function of patients. In this study, we evaluated the efficacy of gefitinib alone without radiation therapy for the treatment of patients with BM from lung adenocarcinoma. MATERIALS AND METHODS Eligible patients had BM from lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutations. Gefitinib was given at 250 mg orally once a day until tumor progression or unacceptable toxicity. RESULTS Forty-one patients were enrolled. The response rate was 87.8%. No patient experienced grade ≥4 toxicity. The median progression-free survival time was 14.5 months (95% CI, 10.2-18.3 months), and the median overall survival time was 21.9 months (95% CI, 18.5-30.3 months). In compared with L858R, exon 19 deletion was associated with better outcome of patients after treatment with gefitinib in both progression-free (p = 0.003) and overall survival (p = 0.025). CONCLUSION Favorable response of BM to gefitinib even without irradiation was demonstrated. Exon 19 deletion was both a predictive and prognostic marker of patients with BM treated by gefitinib.

Phase 2 Trial of Hypofractionated High-Dose Intensity Modulated Radiation Therapy With Concurrent and Adjuvant Temozolomide for Newly Diagnosed Glioblastoma

PURPOSE/OBJECTIVES To assess the effect and toxicity of hypofractionated high-dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m(2)/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. RESULTS No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. CONCLUSIONS Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial.

Levetiracetam versus phenytoin for seizure prophylaxis during and early after craniotomy for brain tumours: a phase II prospective, randomised study

Objective Phenytoin (PHT) is routinely used for seizure prophylaxis in patients with brain tumours during and after craniotomy, despite incomplete evidence. We performed a prospective, randomised study to investigate the significance of prophylactic use of levetiracetam (LEV), in comparison with PHT, for patients with supratentorial tumours in the perioperative period. Methods Patients were randomised to receive LEV, 500 mg/body every 12 h until postoperative day 7, or PHT, 15–18 mg/kg fosphenytoin followed by 125 mg PHT every 12 h until postoperative day 7. The primary end point was the occurrence of seizures, and secondary end points included the occurrence of haematological and non-haematological adverse events. Results One hundred and forty-six patients were randomised to receive LEV (n=73) or PHT (n=73). The incidence of seizures was significantly less in the LEV group (1.4%) compared with the PHT group (15.1%, p=0.005), suggesting benefit of LEV over PHT. The observed OR for being seizure free in the LEV prophylaxis group relative to the PHT group was 12.77 (95% CI 2.39 to 236.71, p=0.001). In a subgroup analysis of patients who did not have seizures before craniotomy, similar results were demonstrated: the incidence of seizures was 1.9% (LEV) and 13.8% (PHT, p=0.034), and OR was 8.16 (95% CI 1.42 to 154.19, p=0.015). LEV was completed in all cases, although PHT was withdrawn in five patients owing to liver dysfunction (1), skin eruption (2) and atrial fibrillation (2). Conclusions Prophylactic use of LEV in the perioperative period is recommended because it is safe and significantly reduces the incidence of seizures in this period. Trial registration number UMIN13971.

Epilepsy in patients with gliomas: Incidence and control of seizures

Brain tumor-related epilepsy (BTRE) is a unique condition that is distinct from primary epilepsy. The aim of this retrospective study was to clarify the epidemiology and results of treatment of BTRE in a single institution. From a database of 121 consecutive patients with supratentorial gliomas treated at Chiba Cancer Center from 2006-2012, the incidence and control of seizures before and after surgery were retrospectively evaluated. Epilepsy occurred in 33.9% of patients before surgery. All patients received prophylactic anti-epileptic drugs (AED) during surgery; however, seizures occurred in 9.1% of patients within the first postoperative week. During follow-up, seizures occurred in 48.3% of patients. The overall incidence of seizures was 73.7% in patients with World Health Organization Grade II gliomas, 66.7% in those with Grade III and 56.8% in those with Grade IV gliomas. Levetiracetam was very well tolerated. However, carbamazepine and phenytoin were poorly tolerated because of adverse effects. AED were discontinued in 56 patients. Fifteen of these patients (26.8%) had further seizures, half occurring within 3 months and 80% within 6 months of AED withdrawal. No clinical factors that indicated it was safe to discontinue AED were identified. The unpredictable epileptogenesis associated with gliomas and their excision requires prolonged administration of AED. To maintain quality of life and to safely and effectively control the tumor, it is necessary to select AED that do not adversely affect cognitive function or interact with other drugs, including anti-cancer agents.

Methionine Uptake and Required Radiation Dose to Control Glioblastoma

PURPOSE The purpose of this study was to retrospectively assess the feasibility of radiation therapy planning for glioblastoma multiforme (GBM) based on the use of methionine (MET) positron emission tomography (PET), and the correlation among MET uptake, radiation dose, and tumor control. METHODS AND MATERIALS Twenty-two patients with GBM who underwent MET-PET prior to radiation therapy were enrolled. MET uptake in 30 regions of interest (ROIs) from 22 GBMs, biologically effective doses (BEDs) for the ROIs and their ratios (MET uptake:BED) were compared in terms of whether the ROIs were controlled for >12 months. RESULTS MET uptake was significantly correlated with tumor control (odds ratio [OR], 10.0; P = .005); however, there was a higher level of correlation between MET uptake:BED ratio and tumor control (OR, 40.0; P < .0001). These data indicated that the required BEDs for controlling the ROIs could be predicted in terms of MET uptake; BED could be calculated as [34.0 × MET uptake] Gy from the optimal threshold of the MET uptake:BED ratio for tumor control. CONCLUSIONS Target delineation based on MET-PET was demonstrated to be feasible for radiation therapy treatment planning. MET-PET could not only provide precise visualization of infiltrating tumor cells but also predict the required radiation doses to control target regions.

The influence of carmustine wafer implantation on tumor bed cysts and peritumoral brain edema

The development of perifocal edema and tumor bed cyst has been reported after implantation of biodegradable carmustine wafers for the treatment of malignant gliomas. We retrospectively evaluated these changes in a series of patients; 19 consecutive patients with malignant glioma who received carmustine wafer implantation at our hospital from January 2013 through July 2013, and 28 patients who underwent surgery prior to our institutions initiation of carmustine wafer implantation, as historical controls. The volume of the tumor bed cyst and perifocal edema was calculated on MRI acquired at four time points: ⩽72hours after surgery for baseline, and at 1-4, 5-8, and 9-12weeks after surgery. The volume of the tumor bed cyst in the wafer group increased significantly relative to the control group at all time points (p=0.04). Opening of the ventricle was inversely correlated with enlargement of the tumor bed cyst in the wafer group (p=0.04). The change in the volume of perifocal edema in the wafer group was not significantly different (p=0.48), but exhibited a considerable increase in patients with anaplastic oligodendroglioma relative to glioblastoma patients in the wafer group (p=0.01). We demonstrated significant enlargement of the tumor bed cyst volume after carmustine wafer implantation, as well as the development of marked perifocal edema in patients with anaplastic oligodendroglioma.

Abstract 1808: Gene expression signature of malignant astrocytomas and its association with MGMT promoter methylation status.

Background: MGMT promoter methylation has been reported as a predictive marker, not only for response to temozolomide (TMZ), but also for the longer survival of the patients with malignant astrocytomas (MAs) regardless of treatment with TMZ. This led us to hypothesize that methylation status of MGMT in MAs could somehow associate with epigenetic modification of other cancer-related gene promoters resulting in alterations of gene expression profiles and acquisition of therapy- sensitive characters. In this study, to elucidate the molecular characteristics that contribute to chemosensitivity and prognosis in MAs, we conducted gene expression profiling of the tumors with or without MGMT promoter methylation. Materials and Methods: Forty-seven MAs including 5 anaplastic astrocytomas and 42 glioblastomas were enrolled in this study. Methylation status of MGMT gene promoter was evaluated by methylation-specific PCR and subsequent pyrosequencing. Gene expression profile was analyzed using 13,000 genes-cDNA microarray which was developed in our institute. Differentially expressed genes between MGMT-methylated and -unmethylated cases were picked up by statistical analysis (Wilcoxon test). Results: MGMT promoter methylation was found in 26 out of 47 cases. Among the 13,000 genes examined, 163 genes demonstrated statistically significant difference in expression between MGMT-methylated and -unmethylated cases. 22 genes demonstrated lower expression in MGMT-methylated cases, while the remaining 141 genes showed higher expression in methylated cases. When we classify the cases into two groups according to the expression profiles of these 163 genes, survival of the patients were clearly divided (median survival: 18.9m vs. 9.7m, p=0.039). Annotation analysis indicated that the 22 genes with lower expression in MGMT-methylated tumors include those which actively participate in tumor progression, invasion and metastasis, and one of these showed a significant prognostic power in 47 MAs examined (p=0.049). Validation of methylation status of these gene promoters is underway. Conclusion: We identified a gene expression signature strongly correlated with MGMT methylation in MAs, which might contribute to predict chemosensitivity of tumors as well as prognosis of the patients with MA in combination of MGMT methylation. Citation Format: Toshihiko Iuchi, Miki Ohira, Sana Yokoi, Hajime Kageyama, Yuzo Hasegawa, Koichiro Kawasaki, Tsukasa Sakaida, Akira Nakagawara. Gene expression signature of malignant astrocytomas and its association with MGMT promoter methylation status. [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 1808. doi:10.1158/1538-7445.AM2013-1808

Abstract 4592: Sox8 as a molecular marker of oligodendroglial tumors

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Backgournd: The precise diagnosis of oligodendroglial tumors from astrocytic tumors is required because the sensitivity to treatments and outcome of patients are different between these two types of gliomas. However, morphological diagnosis of these tumors is not always easy and sometimes different among pathologists. The aim of this study is to clarify the clinical significance of Sox8 as a molecular marker of oligodendroglial tumors. Materials and Methods: The expression level of Sox8 was evaluated by real-time PCR in 74 gliomas (OII: 7, OIII: 15, AIII: 5, GBM: 47), and was compared with morphological diagnosis and other molecular markers as follows: 1p/19q co-deletion evaluated by array CGH, methylation of MGMT gene promoter by methylation-specific PCR, and IDH-1 mutation by immunohistochemistry. For the evaluation of diagnostic value of Sox8-expression, tumors were divided into two groups owing to the expression level of Sox8 (threshold: 2000), and the clinical outcome of patients were compared between these two groups. Furthermore, these diagnostic significances of Sox8 were compared with those of Olig-1 and Olig-2. Results: The expression level of Sox8 was significantly higher in oligodendroglial tumors (p<0.0001), 1p/19q co-deleted tumors (p<0.0001) and tumors with mutant IDH-1 protein (p<0.0001). The frequency of MGMT methylation was higher in tumors with high Sox8-expression, although statistical significance was not proven. In oligodendroglial tumors, the survival of patients with tumors exhibiting high Sox8-expression was significantly better than those with low SOX8-expression (hazard ratio: 6.2, p=0.031). High-expression of Olig-2 (hazard ratio: 4.5, p=0.026) and 1p/19q co-deletion (hazard ratio: 5.1, p=0.020) were also correlated with favorable outcome of patients, but no significant correlation between the expression of Olig-1 and patients’ outcome was observed. Conclusions: Sox8 was highly expressed in 1p/19q co-deleted oligodendroglial tumors. In oligodendroglial tumors, the expression of Sox8 was the significant prognostic factor of patients’ survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4592. doi:1538-7445.AM2012-4592