Temozolomide In Glioblastoma Research Articles

Pattern of Failure After Limited Margin Radiotherapy and Temozolomide for Glioblastoma

To evaluate the pattern of failure after limited margin radiotherapy for glioblastoma. We analyzed 62 consecutive patients with newly diagnosed glioblastoma treated between 2006 and 2008 with standard fractionation to a total dose of 60 Gy with concurrent temozolomide (97%) or arsenic trioxide (3%). The initial clinical target volume included postoperative T2 abnormality with a median margin of 0.7 cm. The boost clinical target volume included residual T1-enhancing tumor and resection cavity with a median margin of 0.5 cm. Planning target volumes added a 0.3- or 0.5-cm margin to clinical target volumes. The total boost planning target volume (PTV(boost)) margin was 1cm or less in 92% of patients. The volume of recurrent tumor (new T1 enhancement) was categorized by the percent within the 60-Gy isodose line as central (>95%), infield (81-95%), marginal (20-80%), or distant (<20%). For comparison, an initial planning target volume with a 2-cm margin and PTV(boost) with a 2.5-cm margin were created for each patient. With a median follow-up of 12 months, radiographic tumor progression developed in 43 of 62 patients. Imaging was available for analysis in 41: 38 (93%) had central or infield failure, 2 (5%) had marginal failure, and 1 (2%) had distant failure relative to the 60-Gy isodose line. The treated PTV(boost) (median, 140 cm(3)) was, on average, 70% less than the PTV(boost) with a 2.5-cm margin (median, 477 cm(3)) (p < 0.001). A PTV(boost) margin of 1cm or less did not appear to increase the risk of marginal and/or distant tumor failures compared with other published series. With careful radiation planning and delivery, it appears that treatment margins for glioblastoma can be reduced.

Personalized cancer therapy coming of age: clinical highlights in 2009 and future directions.

Brigette BY Ma Author for correspondence: LKS Specialist Clinic, Department of Clinical Oncology, Prince of Wales Hospital, Shatin, New Territories, Hong Kong SAR, China Tel.: +852 2632 2118 Fax: +852 2648 7097 brigette@clo.cuhk.edu.hk and State Key Laboratory in Oncology in South China, Hong Kong SAR, China and Sir YK Pao Centre for Cancer, Hong Kong SAR, China and Hong Kong Cancer Institute, Hong Kong SAR, China and Chinese University of Hong Kong, Hong Kong SAR, China

Selection of chemotherapy for glioblastoma expressing O6-methylguanine-DNA methyltransferase

The therapeutic benefit of nitrosoureas or temozolomide for glioblastoma is limited mainly by O(6)-methylguanine-DNA methyltransferase (MGMT) expression. The aim of this study was to evaluate the effectiveness of various anticancer drugs for MGMT-positive glioblastoma. Seventy-four glioblastoma patients were administered various anticancer drugs according to drug sensitivity testing. For the individualization, drug-induced apoptosis was quantified by flow cytometry in the primary culture of surgically resected tumor cells. The MGMT protein expression was analyzed by immunohistochemistry. The median survival of the patients receiving the individualized chemotherapy was 19.4 months (95% CI, 15.9-22.1). The patients with negative MGMT immunostaining had significantly longer survival than those with positive MGMT immunostaining [median survival, 22.3 months (95% CI, 17.6-27.0) vs. 15.1 months (95% CI, 13.4-16.8); p=0.0188]. For MGMT-positive tumors, the platinum agents and the taxanes were more frequently selected for administration than the other categories of anticancer agents. The patient survival period of MGMT-positive glioblastomas treated with the platinum agents or the taxanes [median survival, 20.1 months (95% CI, 18.0-22.7)] was significantly longer than that of MGMT-positive tumors treated with nitrosoureas (p=0.0026), and was equivalent to that of MGMT-negative glioblastomas (p=0.3047). These results suggest that the platinum agents and the taxanes offer the best probability to be effective against immunohistochemically MGMT-positive glioblastomas.

Pattern of Failure after Limited Margin Radiotherapy and Temozolomide for Glioblastoma

More conformal radiation therapy for glioblastoma (GBM) has the potential to reduce acute and late toxicity, but also may result in more marginal and/or distant recurrences (∼10% in modern series). In 2006, based on improvements in neuroimaging, image registration, and daily localization (kV-kV matching), we adopted a policy of reduced margins in radiation planning for patients with GBM. This review examined the pattern of tumor failure in these patients. 62 consecutively treated newly diagnosed GBM patients treated with standard fractionation between 2006 and 2008 were included in analysis. The initial clinical target volume (CTV) included postoperative T2 abnormality with a median margin of 0.7 cm (range 0.5-1.3 cm). The boost CTV included residual T1 enhancing tumor and resection cavity with a median margin of 0.5 cm (range: 0-1 cm). CTVs were modified to respect barriers to tumor progression (e.g., bone). Planning target volumes (PTVs) were created by adding a uniform 0.3 or 0.5 cm margin to CTVs. Total margin for the boost PTV was ≤1 cm in 92% of patients. Prescribed doses were 46 or 54 Gy (initial PTV) and 60 Gy (boost PTV). All patients received either concurrent temozolomide (97%) or arsenic trioxide (3%). New T1 enhancement comprised the volume of recurrent tumor (Vrecurr), delineated on the MRI at progression and fused to the treatment plan. The Vrecurr was categorized relative to the percent within the 60 Gy isodose line (IDL) as infield (>80%), marginal (20-80%), or distant (<20%). For comparison, a boost PTV using RTOG margins (2.5 cm) was created for each patient. With a median follow-up of 10.5 months, 37 of 62 patients developed radiographic tumor progression. The median time to progression was 7 months. 15 patients had not yet progressed while 7 died of other causes and 3 died of presumed tumor progression but without imaging. 36 of 37 patients with progression had imaging available for pattern of failure analysis. 34 (94%) had infield failure, and 2 (6%) had marginal failure relative to the 60 Gy IDL. No distant failures were observed. The median treated boost PTV (median: 140 cm3, range: 30-394 cm3), was, on average, 70% less than the median RTOG-defined boost PTV (median: 477 cm3, range: 155-887 cm3) (p < 0.001). An anatomically modified boost CTV margin of 0.5 cm with 0.3 cm for PTV expansion does not appear to increase the risk of marginal and/or distant tumor failures when compared to other published series. The RTOG-defined boost PTV margin of 2.5 cm may not be required, as our experience suggests treatment margins can be safely reduced. Whether a reduction in treatment volume decreases toxicity is yet to be defined. Applicability of these results is limited to patients treated with similar quality image registration, immobilization, and localization.

MGMT methylation status may predict survival in elderly patients with newly diagnosed glioblastoma (GBM)

e13023 Background: Methylation of the MGMT gene promoter is associated with prolonged survival and response to temozolomide in GBM &lt; 70. However, it is unclear if MGMT is a useful prognostic biomarker in the elderly GBM population who traditionally are viewed as less responsive to treatment. Methods: We retrospectively reviewed MGMT promoter methylation status and clinical characteristics in patients 70 years or older with newly diagnosed GBM undergoing resection at our institution from 1998–2008. MGMT analysis was performed by extracting tumor genomic DNA for bisulfite conversion. MGMT methylation specific PCR (MSP) was then performed using PCR primer sets specific for methylated and unmethylated MGMT promoter sequence. The logrank test was used to compare mPFS and mOS in patients who had methylated (ME) MGMT vs. unmethylated (UN) MGMT. Results: Thirty-four patients were included in the analysis. Twenty patients (59%) were ME while 14 (41%) were UN. Patients were treated with multimodality treatment (radiation + chemotherapy), radiation alone, or chemotherapy alone. ME was associated with a significantly prolonged mPFS and mOS as noted in the table below which also summarizes the characteristics of the study population. Conclusions: MGMT methylation status is associated with prolonged PFS and OS in elderly patients with newly diagnosed GBM. Knowledge of MGMT status may help improve prognostication in this patient population. [Table: see text] [Table: see text]

Absence of MGMT promoter methylation in endometrial cancer

Objective O 6-methylguanine-DNA methyltransferase (MGMT) acts to repair DNA damaged by alkylation of guanine residues. MGMT promoter methylation and gene silencing is seen in a variety of cancers and pre-cancerous changes [Ogino S, Meyerhardt JA, Kawasaki T, et al. CpG island methylation, response to combination chemotherapy, and patient survival in advanced microsatellite stable colorectal carcinoma. Virchows Arch 2007;450:529–37; Rodriguez MJ, Acha A, Ruesga MT, Rodriguez C, Rivera JM, Aguirre JM. Loss of expression of DNA repair enzyme MGMT in oral leukoplakia and early oral squamous cell carcinoma. A prognostic tool? Cancer Lett 2007;245:263–8; Ishii T, Murakami J, Notohara K, et al. Oesophageal squamous cell carcinoma may develop within a background of accumulating DNA methylation in normal and dysplastic mucosa. Gut 2007;56:13–9]. The loss of MGMT activity and promoter methylation is associated with increased sensitivity to alkylating agents and is a favorable prognostic indicator in gliomas [Weaver KD, Grossman SA, Herman JG. Methylated tumor-specific DNA as a plasma biomarker in patients with glioma. Cancer Invest 2006;24:35–40; Esteller M, Garcia-Foncillas J, Andion E, et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350–4; Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997–1003]. We sought to determine if MGMT promoter methylation plays a role in endometrial cancer. Methods One hundred and twenty primary endometrial cancers were analyzed for MGMT promoter methylation by combined bisulfite restriction analysis (COBRA). The cohort included 77 endometrioid endometrial cancers, 43 endometrial tumors of adverse histologic type, and 6 endometrial cancer cell lines. Twenty-one endometrioid and mixed endometrioid ovarian cancers were also analyzed. A subset of the primary tumors was analyzed for MGMT expression by immunohistochemistry. Results No MGMT promoter methylation was seen in the 120 endometrial cancers evaluated or the 6 endometrial cancer cell lines. One of the 21 endometrioid ovarian cancers showed methylation. Immunohistochemistry revealed moderate to high level expression of MGMT in the primary endometrial tumors. Conclusion MGMT promoter methylation is an infrequent event in endometrial cancer. MGMT expression and the ability to repair damaged alkylguanine residues could in part explain the limited response of endometrial tumors to alkylating chemotherapy.

Radiotherapy and temozolomide in glioblastoma: Predictive factors of response to the treatment

Radiotherapy and temozolomide in glioblastoma: Predictive factors of response to the treatment

Pseudo-progression Following Concurrent Radiotherapy and Temozolomide for Glioblastoma

Radiotherapy with concurrent temozolomide (RT/TMZ) followed by adjuvant temozolomide is the current standard of care for patients with newly diagnosed glioblastoma. Pseudo-progression following RT/TMZ has recently been recognized. The aims of this study are to confirm the incidence of pseudo-progression, to determine the effect on prognosis, and to explore the implications regarding early follow-up imaging.

Temozolomide in glioblastoma: results of administration at first relapse and in newly diagnosed cases. Is still proposable an alternative schedule to concomitant protocol?

To evaluate if timing of chemotherapy with Temozolomide (TMZ) was able to modify the outcome of glioblastoma (GBM), we analyzed two comparable series of supratentorial GBM patients, treated with surgery and radiotherapy, in which the administration of TMZ has been performed in the first group at first relapse and in the second group in newly diagnosed cases. The end-points were the median survival, the time tumor progression (TTP) and also the Karnofsky (KPS) scale and the Mini Mental State Examination (MMSE) scale at follow-up. From December 1999 to December 2001 30 patients with recurrent GBM received TMZ until progression. From January 2002 to January 2004 38 newly diagnosed patients received a first cycle of TMZ immediately after surgery, and additional cycles after completing radiotherapy until recurrence. In order to obtain a greater drug exposure we adopted a once-daily 10 days schedule of TMZ every 28 days as follows: 150 mg/m(2)/day (day 1-5) and 75 mg/m(2)/day (day 6-10). The first group had a median overall survival of 14 months and a median TTP of 6. The second group had a median survival of 16 months and a median TTP of 10. The difference of TTP was statistically significant (P < 0.001), while the overall survival was not. The values of KPS and MMSE at 12 months demonstrated a better quality of life in the second group (P < 0.01). Our regimen permitted to cover the therapeutic "window" between surgery and the beginning of radiotherapy in newly diagnosed cases and is well tolerated by the patients with limited side effects. We will propose as alternative option when the concomitant radio-chemotherapic protocol is not feasible.

Interpretation of Early Imaging after Concurrent Radiotherapy and Temozolomide for Glioblastoma

Interpretation of Early Imaging after Concurrent Radiotherapy and Temozolomide for Glioblastoma

2080: Concurrent Hypofractionated Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost Technique and Temozolomide for Glioblastoma

2080: Concurrent Hypofractionated Intensity-Modulated Radiation Therapy With Simultaneous Integrated Boost Technique and Temozolomide for Glioblastoma

MGMT Gene Silencing and Benefit From Temozolomide in Glioblastoma

MGMT Gene Silencing and Benefit From Temozolomide in Glioblastoma

MGMTGene Silencing and Benefit from Temozolomide in Glioblastoma

Epigenetic silencing of the MGMT (O6-methylguanine-DNA methyltransferase) DNA-repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.