Radiosurgery for central neurocytoma: long-term outcome and failure pattern

Despite the favorable outcomes of radiosurgery for central neurocytoma (CN), these results are based on case series that included a limited number of patients and short follow-up periods because of the scarcity of CN. Because CN is a benign tumor with an indolent clinical course, long-term follow-up and analysis of failure pattern are required for the establishment of the role of radiosurgery in the management of CN. Twenty consecutive patients (10 patients who received Gamma Knife radiosurgery (GKRS) as a primary treatment and 10 patients who received GKRS as a secondary treatment) with a radiological follow-up period ≥36 months were included in this study. The mean radiological follow-up duration was 100 months (range 43–149 months). The mean tumor volume was 10.4 cm³ (range 0.4–36.4 cm³) and the mean marginal dose was 15.4 Gy (range 9–20 Gy). Local control failure was found in six patients at the last radiological follow-up. Overall actuarial local control rates were 89.5 % at 5 years and 83.1 % at 10 years. The primary GKRS group included two cases with local failure, with cyst formation or local recurrence. In contrast, in the secondary GKRS group, local control failure was found in four cases (including three cases with an “out-of-field recurrence” pattern) and occurred earlier compared with the primary GKRS group. Our study suggests that GKRS could be a primary or secondary treatment option for CN. However, long-term radiological follow-up is mandatory. In particular, more careful consideration during margin delineation and planning procedure is required in the secondary GKRS group.     

A practical scoring system to determine whether to proceed with surgical resection in recurrent glioblastoma

Background

To determine the benefit of surgical management in recurrent glioblastoma, we analyzed a series of patients with recurrent glioblastoma who had undergone surgery, and we devised a new scale to predict their survival.

Methods

Clinical data from 55 consecutive patients with recurrent glioblastoma were evaluated after surgical management. Kaplan–Meier survival analysis and Cox proportional hazards regression modeling were used to identify prognostic variables for the development of a predictive scale. After the multivariate analysis, performance status (P = .078) and ependymal involvement (P = .025) were selected for inclusion in the new prognostic scale. The devised scale was validated with a separate set of 96 patients from 3 different institutes.

Results

A 3-tier scale (scoring range, 0–2 points) composed of additive scores for the Karnofsky performance status (KPS) (0 for KPS ≥ 70 and 1 for KPS < 70) and ependymal involvement (0 for no enhancement and 1 for enhancement of the ventricle wall in the magnetic resonance imaging) significantly distinguished groups with good (0 points; median survival, 18.0 months), intermediate (1 point; median survival, 10.0 months), and poor prognoses (2 points; median survival, 4.0 months). The new scale was successfully applied to the validation cohort of patients showing distinct prognosis among the groups (median survivals of 11.0, 9.0, and 4.0 months for the 0-, 1-, and 2-point groups, respectively).

Conclusions

We developed a practical scale to facilitate deciding whether to proceed with surgical management in patients with recurrent glioblastoma. This scale was useful for the diagnosis of prognostic groups and can be used to develop guidelines for patient treatment.     

Temozolomide Salvage Chemotherapy for Recurrent Anaplastic Oligodendroglioma and Oligo-Astrocytoma

Objective

To evaluate the efficacy of temozolomide (TMZ) chemotherapy for recurrent anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA).

Methods

A multi-center retrospective trial enrolled seventy-two patients with histologically proven AO/AOA who underwent TMZ chemotherapy for their recurrent tumors from 2006 to 2010. TMZ was administered orally (150 to 200 mg/m²/day) for 5 days per 28 days until unacceptable toxicity occurred or tumor progression was observed.

Results

TMZ chemotherapy cycles administered was median 5.3 (range, 1-41). The objective response rate was 24% including 8 cases (11%) of complete response and another 23 patients (32%) were remained as stable disease. Severe side effects (≥grade 3) occurred only in 9 patients (13%). Progression-free survival (PFS) of all patients was a median 8.0 months (95% confidence interval, 6.0-10.0). The time to recurrence of a year or after was a favorable prognostic factor for PFS (p<0.05). Overall survival (OS) was apparently differed by the patient''s histology, as AOA patients survived a median OS of 18.0 months while AO patients did not reach median OS at median follow-up of 11.5 months (range 2.7-65 months). Good performance status of Eastern Cooperative Oncology Group 0 and 1 showed prolonged OS (p<0.01).

Conclusion

For recurrent AO/AOA after surgery followed by radiation therapy, TMZ could be recommended as a salvage therapy at the estimated efficacy equal to procarbazine, lomustine, and vincristine (PCV) chemotherapy at first relapse. For patients previously treated with PCV, TMZ is a favorable therapeutic option as 2nd line salvage chemotherapy with an acceptable toxicity rate.     

C-MET overexpression and amplification in gliomas

We investigated c-Met overexpression and MET gene amplification in gliomas to determine their incidence and prognostic significance. c-Met immunohistochemistry and MET gene fluorescence in situ hybridization were carried out on tissue microarrays from 250 patients with gliomas (137 grade IV GBMs and 113 grade II and III diffuse gliomas). Clinicopathological features of these cases were reviewed. c-Met overexpression and MET gene amplification were detected in 13.1% and 5.1% of the GBMs, respectively. All the MET-amplified cases showed c-Met overexpression, but MET amplification was not always concordant with c-Met overexpression. None of grade II and III gliomas demonstrated c-Met overexpression or MET gene amplification. Mean survival of the GBM patients with MET amplification was not significantly different from patients without MET amplification (P=0.155). However, GBM patients with c-Met overexpression survived longer than patients without c-Met overexpression (P=0.035). Although MET amplification was not related to poor GBM prognosis, it is partially associated with the aggressiveness of gliomas, as MET amplification was found only in grade IV, not in grade II and III gliomas. We suggest that MET inhibitor therapy may be beneficial in about 5% GBMs, which was the incidence of MET gene amplification found in the patients included in this study.     

MGMT promoter gene methylation in pediatric glioblastoma: analysis using MS-MLPA

Purpose  

Promoter methylation of the O⁶-methylguanine-DNA-methyltransferase (MGMT) gene is widely recognized as an important predictive factor in the treatment of glioblastoma (GBM) patients with temozolomide. However, data regarding the methylation status of the MGMT promoter in pediatric GBM are yet to be elucidated.     

O<Superscript>6</Superscript>-methylguanine DNA methyltransferase status determined by promoter methylation and immunohistochemistry in gliosarcoma and their clinical implications

O⁶-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3–14.5 months] and 8.3 months (95% CI, 7.4–9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.     

Temozolomide during and after radiation therapy for WHO grade III gliomas: preliminary report of a prospective multicenter study

This prospective study was performed to determine the efficacy, safety, and tolerability of concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy with temozolomide (TMZ) in the treatment of patients with WHO grade III gliomas. Thirty-three adult patients with WHO grade III glioma and aged >17 years were enrolled from three institutions between 2003 and 2008. The median age was 41 years (range, 17?C60 years). The pathological diagnoses were anaplastic astrocytomas in 21 patients and anaplastic oligodendrogliomas in 12 patients. The preoperative Karnofsky performance scale score was >60 for all patients. The patients received fractionated focal irradiation in daily fractions of 2 Gy administered five days per week for six weeks, for a total of 60 Gy, in combination with continuous daily TMZ, followed by six cycles of adjuvant TMZ. The median dose of radiotherapy was 59.4 Gy (range, 28.8?C61.2 Gy) and the duration of CCRT was 7.0 weeks (range, 3.1?C8.3 weeks). A median of 6.2 cycles (range, 2?C12 cycles) of TMZ chemotherapy were performed during the period of adjuvant chemotherapy. The response rate was 61% and the tumor-control rate was 82%. Mean progression-free survival (PFS) was 48.7 months (95% CI, 36.0?C61.4) and the 12, 24, and 36-month PFS was 74%, 60%, and 50%, respectively. Mean overall survival (OS) was 66.4 months (95% CI, 56.4?C76.4) and the 12 and 24-month OS was 97% and 77%, respectively. The extent of surgical resection was a significant prognostic factor for PFS and OS (hazard ratio, 0.24; 95% CI, 0.02?C0.73; and hazard ratio, 0.12; 95% CI, 0.01?C0.88, respectively; P < 0.001). However, there was no significant difference in the PFS and OS of patients regarding loss of heterozygosity in chromosomes 1p and 19q and methylation of O ⁶-methylguanine-DNA methyltransferase promoter, because of the small number of patients available. Only five cases (15%) receiving CCRT with TMZ and three cases (9%) receiving adjuvant chemotherapy had hematological toxicity greater than grade 3. All these patients, however, tolerated the therapy well enough to continue treatment. No opportunistic infections were noted. This protocol for WHO grade III gliomas was relatively safe and tolerable. It showed the possibility of achieving favorable results compared with those of historical controls. A randomized controlled study with a long-term follow-up may be mandatory to evaluate its efficacy.