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Correlation Between O⁶-Methylguanine-DNA Methyltransferase and Survival in Inoperable Newly Diagnosed Glioblastoma Patients Treated With Neoadjuvant Temozolomide

Olivier L. Chinot, Maryline Barrié, Stephane Fuentes, Nathalie Eudes, Sophie Lancelot, Philippe Metellus, Xavier Muracciole, Diane Braguer, L'Houcine Ouafik, Pierre-Marie Martin, Henry Dufour, Dominique Figarella-Branger

From the Unité de Neuro-Oncologie, Service de Neurochirurgie, Service de Pharmacie, Service de Radiothérapie, Laboratoire de Transfert d'Oncologie Biologique, Service d'Anatomie Pathologique et de Neuropathologie, Centre Hospitalier Universitaire Timone, Assistance Publique–Hôpitaux de Marseille, and Université de la Méditérranée, Faculté de Médecine de Marseille, and Laboratoire de Cancérologie Expérimentale, Institut National de la Santé et de la Recherche, Equipe Mixte 0359, Centre National de la Recherche Scientifique 2737, Laboratoire de Biopathologie de l'Adhésion et de la Signalisation, Faculté de Médecine de Marseille, and Université de la Méditérranée, Marseille, France

Address reprint requests to Olivier Chinot, MD, Université de la Méditérranée, Faculté de Médecine de Marseille, Assistance Publique-Hôpitaux de Marseille, Unité de Neuro-Oncologie, Centre Hospitalier Universitaire Timone, 264 rue Saint Pierre, 13385 Marseille Cedex 05, France; e-mail: olivier.chinot{at}mail.ap-hm.fr

	ABSTRACT

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Purpose: This phase II study evaluated the efficacy and safety of a 7-day on/7-day off regimen of temozolomide before radiotherapy (RT) in patients with inoperable newly diagnosed glioblastoma.

Patients and Methods: Patients received temozolomide (150 mg/m²/d on days 1 to 7 and days 15 to 21 every 28 days; 7 days on/7 days off) for up to four cycles before conventional RT (2-Gy fractions to a total of 60 Gy) and for four cycles thereafter or until disease progression. The primary end point was tumor response. Tumor tissue from 25 patients was analyzed for O⁶-methylguanine-DNA methyltransferase (MGMT) expression.

Results: Twenty-nine patients with a median age of 60 years were treated, and 28 were assessable for response. Seven (24%) of 29 patients had a partial response, nine patients (31%) had stable disease, and 12 patients (41%) had progressive disease. Median progression-free survival (PFS) time was 3.8 months, and median overall survival (OS) time was 6.1 months. Patients with low MGMT expression, compared with patients with high MGMT expression, had a significantly higher response rate (55% v 7%, respectively; P = .004) and improved PFS (median, 5.5 v 1.9 months, respectively; P = .009) and OS (median, 16 v 5 months, respectively; P = .003). The most common grade 3 and 4 toxicities were thrombocytopenia (20%) and neutropenia (17%).

Conclusion: This dose-dense temozolomide regimen resulted in modest antitumor activity with an acceptable safety profile in the neoadjuvant setting, and expression of MGMT correlated with response to temozolomide. However, this treatment approach seems to be inferior to standard concomitant RT plus temozolomide.

	INTRODUCTION

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Patients with glioblastoma (GBM) have a poor prognosis, with a median survival time from diagnosis of approximately 12 to 15 months.¹ Complete surgical resection is often impossible; therefore, both radiotherapy (RT) and chemotherapy are often used to eliminate residual tumor. Recently, the role of chemotherapy for the treatment of GBM has changed dramatically as a result of a cooperative group study conducted by the European Organisation for Research and Treatment of Cancer and the National Cancer Institute of Canada.² This study showed that concomitant RT plus temozolomide followed by six cycles of temozolomide significantly prolonged survival compared with RT alone. Consequently, the concomitant RT plus temozolomide regimen has become the new standard of care for patients with newly diagnosed GBM. However, the benefit of this regimen has not been clearly demonstrated in patients with a poor Karnofsky performance score (KPS; ie, < 70) or in patients who receive biopsy only.³

Patients for whom debulking surgery is not feasible have a poor prognosis and limited treatment options. Therefore, this patient population provides a unique opportunity for testing neoadjuvant therapy and evaluating tumor response. Several studies using either single-agent or combination chemotherapy regimens administered for one to four cycles before RT have demonstrated objective response rates ranging from 23% to 48%.^4-8 Similar response rates were achieved with single-agent temozolomide administered for 5 days in every 28-day cycle (standard 5-day regimen)^9,10 or temozolomide in combination with carmustine.¹¹

It has been hypothesized that dose-dense temozolomide regimens may improve antitumor activity. The total cumulative dose achieved with the 7-day on/7-day off schedule at 150 mg/m²/d is theoretically 2.1-fold higher than the cumulative dose achieved with the standard 5-day regimen with only a modest increase in hematologic toxicity.¹² Tolcher et al¹³ have shown that dose-dense temozolomide regimens effectively deplete cellular O⁶-methylguanine-DNA methyltransferase (MGMT) activity; MGMT is a key enzyme in the DNA repair process that specifically removes cytotoxic O⁶-methylguanine adducts, thus mediating resistance to temozolomide.¹⁴ High expression of MGMT confers resistance to alkylating agents and is associated with poor survival.

Herein, we report the efficacy and safety of a 7-day on/7-day off regimen of temozolomide (before and after RT) in patients with inoperable newly diagnosed GBM. In addition, MGMT expression was assessed to determine correlation with response to temozolomide and survival.

	PATIENTS AND METHODS

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Patients
Adult patients (age 18 to 70 years) were eligible if they had histologically proven inoperable GBM as determined by gadolinium-enhanced magnetic resonance imaging (Gd-MRI), no prior history of RT or chemotherapy, a KPS of 60, and adequate laboratory values (absolute neutrophil count 1,500 cells/µL, platelet count 100,000/µL, hemoglobin 8 g/dL, serum creatinine and bilirubin levels < 1.5x the upper limit of normal, and AST and ALT levels 3x the upper limit of normal). The study protocol was approved by the local medical ethics committee, and all patients provided written informed consent.

Study Design
This prospective phase II study was conducted at a single center in Marseille, France. The primary objective was to evaluate objective response rate. Secondary objectives included assessment of progression-free survival (PFS), overall survival (OS), and safety. Patients received oral temozolomide at 150 mg/m²/d on days 1 to 7 and on days 15 to 21 of every 28-day cycle (7 days on/7 days off). Study treatment was administered for up to four cycles before RT (neoadjuvant) and for up to four additional cycles starting 1 month after RT (maintenance) until unacceptable toxicity or disease progression. RT was delivered after four cycles of temozolomide on response or stable disease or earlier if tumor progression occurred during neoadjuvant chemotherapy. Focal RT was delivered with a linear accelerator once daily at 2 Gy per fraction for 5 days a week for a total of 60 Gy. Treatment volumes were determined based on initial Gd-MRI scan, including contrast-enhanced lesions plus a 2- to 3-cm margin, depending on tumor volume and location. Repeat cycles of temozolomide were administered based on strict hematologic criteria that required an absolute neutrophil count of 1,500 cells/µL and a platelet count of 100,000/µL; otherwise, the subsequent treatment cycle was delayed until recovery, and blood cell counts were reassessed weekly. A treatment delay of 2 or more weeks required a decrease of temozolomide in increments of 25 mg/m²/d. Prophylactic antiemetics, such as 5-hydroxytryptamine-3, were administered each day of temozolomide treatment. Anticonvulsants were administered as needed, and corticosteroid dose was adjusted based on the neurologic condition of the patient.

Patient Evaluation
Complete physical and comprehensive neurologic examinations, KPS, Mini-Mental State Examination, laboratory tests, and Gd-MRI were performed at baseline within 14 days (28 days for imaging) of study entry. All tests, except for hematology and chemistry assessments, were performed after each 28-day cycle for the first four cycles and then before RT and 1 month after completion of RT. Overall tumor response was assessed according to the criteria of Macdonald et al¹⁵ and was based on consecutive Gd-MRI scans of patients who were under stable corticosteroid use for 7 days before imaging. All patient scans in which a response (complete or partial response) was observed were centrally reviewed by an independent radiologist.

Weekly blood tests were performed during the first two treatment cycles and every 2 weeks thereafter. During maintenance therapy, clinical evaluations were performed after each cycle, and Gd-MRI was performed at least every two cycles. Adverse events occurring during treatment or up to 30 days after treatment were recorded and graded according to National Cancer Institute Common Toxicity Criteria (version 3.0).

MGMT Analysis
Twenty-five of 30 tumor biopsy samples were available for MGMT analysis. The three remaining assessable patients had insufficient tumor biopsy material for analysis. Immunohistochemistry was performed according to the method of Mollemann et al.¹⁶ Briefly, tissue sections were incubated with a mouse monoclonal antibody (MT-1; Chemicon, Temecula, CA) at a dilution of 1:100 for 1 hour at room temperature. Cytoplasmic-only and granular nuclear reactivity were considered negative. High expression was defined as 35% of tumor cell nuclei expressing detectable MGMT protein; low expression was defined as less than 35% of nuclei expressing detectable MGMT.

Statistical Analysis
PFS was measured from date of study entry to first sign of radiologic or clinical disease progression, whichever came first. OS was measured from date of study entry to date of death or last follow-up. PFS and OS were estimated using the Kaplan-Meier method. The results of the log-rank test, which was used to compare PFS and OS between groups, are reported separately for the intent-to-treat (ITT) and assessable populations. Correlation between MGMT and response rate was calculated using the ² test. P .05 was considered significant.

	RESULTS

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Patient Characteristics
A total of 30 patients (20 men and 10 women) with a median age of 60 years were enrolled between June 2002 and July 2004, and 29 patients were eligible to receive treatment (ITT population; Table 1). One patient was ineligible after giving consent because of unacceptable hepatic function. Another patient was lost to follow-up without evidence of disease progression after initiation of treatment cycle 2 and was not assessable for response. Twenty-eight patients were assessable for response, and all patients were assessable for survival and safety. Tumor materials from 30 patients were available for central histopathologic review. All patients had confirmed GBM. At the time of initial diagnosis, two patients had undergone partial surgical resection, and 28 patients were diagnosed on the basis of stereotactic biopsy. By recursive partitioning analysis classification, 17 patients were class V, and three patients were class VI. Median time from diagnosis to study entry was 12 days (range, 6 to 12 days). No patient received prior RT or chemotherapy.

At the time of analysis, the median follow-up time was 6 months (range, 0.9 to 19 months) for the entire population. In the ITT population, median PFS time was 3.8 months (95% CI, 3.4 to 4.2 months), and median OS time was 6.1 months (95% CI, 0.9 to 11.3 months). Twelve- and 18-month survival rates were 28% (95% CI, 14.2% to 47.9%) and 14% (95% CI, 11.3% to 43.9%), respectively. The 12-month PFS rate was 7%, and all patients had disease progression at 18 months. Results for the ITT and assessable patient population were similar. At the time of analysis, a total of three patients (10%) were alive. The median follow-up time for these patients was 11.7 months (range, 4.2 to 11.9 months).

MGMT Analysis
MGMT expression was low in normal brain and restricted to endothelial cells and a few oligodendrocytes (< 10%). Expression of MGMT in tumor cells and positive control cells was mainly visible in nuclei, although some cytoplasmic expression might have occurred. Of 25 tumor biopsy samples available for MGMT analysis, low MGMT expression (< 35% of tumor cells) was detected in 11 patients, and high MGMT expression was detected in 14 patients (Table 3). RT was started in 10 patients (91%) with low MGMT expression, and all 10 patients completed RT. In contrast, among patients with high MGMT expression, nine patients (64%) started RT, and six patients (43%) completed RT. The objective response rate was 55% in the 11 patients with low MGMT expression compared with 7% in the 14 patients with high MGMT expression (P = .004). Analysis of MGMT expression as a continuous variable (percentage of tumor cells) showed a trend toward lower MGMT expression in patients with stable disease or objective response compared with patients with progressive disease (Fig 1). Patients with low MGMT expression, compared with patients with high MGMT expression, also had significantly longer PFS (5.5 v 1.9 months, respectively; P = .009; Fig 2A) and OS (16 v 5 months, respectively; P = .003; Fig 2B).

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Correlation of O6-methylguanine-DNA methyltransferase (MGMT) expression (percentage of tumor cells as a continuous variable) and clinical response.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Kaplan-Meier estimates of (A) progression-free survival and (B) overall survival according to O6-methylguanine-DNA methyltransferase (MGMT) expression.

	DISCUSSION

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In the present study, the 7-day on/7-day off temozolomide regimen was feasible and well tolerated in patients with unresectable GBM, and the toxicity profile was similar to that observed in patients with recurrent GBM treated with this schedule of temozolomide.^12,22 Furthermore, this regimen demonstrated antitumor activity with a 24% objective response rate after three treatment cycles. In comparison, studies investigating neoadjuvant temozolomide using the standard 5-day regimen to treat unresectable GBM have demonstrated response rates ranging from 23% to 48% after four treatment cycles.^9,10,18 Therefore, the response rate observed in the present study compares favorably to that observed with the standard 5-day regimen in a similar patient population. Although it is difficult to compare studies, these results do not suggest any increased antitumor activity with the 7-day on/7-day off regimen compared with the 5-day regimen. However, in a similar patient population treated with a neoadjuvant combination of temozolomide and carmustine, promising results were observed in terms of response rate (42.5%), median PFS time (7.4 months), and survival time (12.7 months).¹¹ The relatively short median survival time observed in the present study compared with other published reports may be explained, in part, by the fact that our patients did not receive concomitant RT plus temozolomide, as in the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial,² and they had poor prognosis based on recursive partitioning analysis classification.

We also correlated response with MGMT expression using immunohistochemistry, which we considered the most appropriate method for the small quantities of tumor material obtained by stereotactic biopsy. The optimal method for MGMT analysis remains a matter of debate; contradicting results have been reported regarding the correlation between MGMT promoter methylation and MGMT protein expression.^16,23,24 Given interpatient variability in tumor density and the potential for contamination with endothelial cells (which constitutively express MGMT), there is a risk of unrepresentative results when determining MGMT status by promoter methylation assay. Furthermore, in the MGMT methylation analysis performed by Hegi et al,²⁰ the assay success rate from biopsy material was low, suggesting that technical difficulties were encountered.

The reported cutoff values used to characterize low versus high or negative versus positive MGMT expression by immunohistochemistry vary considerably; some studies have used a cutoff value ranging from 5% to 20% of cells to define a positive expression pattern,^10,25 and others have defined three to four levels of expression with various cutoffs.^16,23 In our preliminary experience, technical factors influenced the level of detection of MGMT; therefore, median MGMT expression varied. Because of this heterogeneity, we chose the median expression level (ie, 35%) as the cutoff. This is consistent with published reports showing that methylated and unmethylated MGMT promoters are nearly equally distributed in GBM (45% methylated and 55% unmethylated).²⁰

When response to temozolomide was correlated with MGMT expression, an objective response rate of 55% was observed in patients whose tumors had low MGMT expression compared with an objective response rate of 7% in patients with high MGMT expression. In addition, PFS and OS were significantly prolonged by 3.6 months (P = .009) and 11 months (P = .003), respectively, in patients with low versus high MGMT expression; however, this result may be confounded by differences in the extent of RT in these subgroups. Nevertheless, these results are consistent with those reported by Hegi et al,²⁰ who demonstrated a greater survival benefit from temozolomide in patients who had a methylated MGMT promoter (ie, low MGMT expression as a result of epigenetic silencing) compared with patients who had an unmethylated MGMT promoter. Although patients with a low percentage of MGMT-positive tumor cells frequently responded in the present study, 45% did not respond, suggesting that these tumors may have other mechanisms of resistance to temozolomide.¹⁰ The observation that few patients with high MGMT expression responded suggests that the 7-day on/7-day off regimen may not effectively deplete MGMT in tumor tissue. Studies are ongoing to assess this further.

Among patients with MGMT data available for analysis, RT was started and completed in 91% of patients with low MGMT expression. In contrast, among patients with high MGMT expression, only 64% started RT, and 43% completed RT. These results suggest that neoadjuvant chemotherapy may be feasible for inoperable GBM patients expressing low levels of MGMT without compromising subsequent treatment with RT, whereas patients with high MGMT expression are less likely to respond and more likely to experience progression before or during RT.

In summary, although results from the present study suggest that the 7-day on/7-day off regimen of neoadjuvant temozolomide is active for treating patients with inoperable GBM, the advantage of this dose-dense schedule is not clear compared with the standard 5-day schedule. This study also provides further evidence that MGMT expression correlates with response to temozolomide. Future studies are needed to prospectively incorporate the molecular analysis of MGMT such that subgroups of patients who may respond to more intensive therapy can be identified.

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Olivier L. Chinot, Schering-Plough Stock: N/A Honoraria: Olivier L. Chinot, Schering-Plough Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Collection and assembly of data: Olivier L. Chinot

Data analysis and interpretation: Olivier L. Chinot, Maryline Barrié, Stephane Fuentes, Nathalie Eudes, Sophie Lancelot, Philippe Metellus, Xavier Muracciole, Diane Braguer, L'Houcine Ouafik, Pierre-Marie Martin, Henry Dufour, Dominique Figarella-Branger

Manuscript writing: Olivier L. Chinot, Maryline Barrié, L'Houcine Ouafik, Dominique Figarella-Branger

Final approval of manuscript: Olivier L. Chinot, Maryline Barrié, Stephane Fuentes, Nathalie Eudes, Sophie Lancelot, Philippe Metellus, Xavier Muracciole, Diane Braguer, L'Houcine Ouafik, Pierre-Marie Martin, Henry Dufour, Dominique Figarella-Branger

	ACKNOWLEDGMENTS

 
We thank Claire Senay for drafting the manuscript and Jean Cougnard and Anderson Loundou for the statistical analysis.

	NOTES

 
Supported by the Foundation Lionel Perrier, the Fondation Nelia and Amadeo Barletta, and the Institut National du Cancer Project No. RS019 (coordinated by D.F.-B.).

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted May 18, 2006; accepted October 19, 2006.

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