Temozolomide Concomitant and Adjuvant to Radiotherapy in Elderly Patients With Glioblastoma

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1 Temozolomide Concomitant and Adjuvant to Radiotherapy in Elderly Patients With Glioblastoma Correlation With MGMT Promoter Methylation Status Alba A. Brandes, MD 1 ; Enrico Franceschi, MD 1 ; Alicia Tosoni, MD 1 ; Francesca Benevento, MD 1 ; Luciano Scopece, MD 1 ; Valeria Mazzocchi, MD 1 ; Antonella Bacci, MD 2 ; Raffaele Agati, MD 2 ; Fabio Calbucci, MD 3 ; and Mario Ermani, MD 4 BACKGROUND: A recent randomized study conducted on newly diagnosed glioblastoma (GBM) patients demonstrated that concomitant and adjuvant temozolomide added to standard radiotherapy had a survival advantage compared with radiotherapy alone. The overall survival benefit of this aggressive treatment, however, was attenuated in older or poor performance status patients. The aim of the present study was to verify the activity and the toxicity of temozolomide administration concurrent and adjuvant to radiotherapy as first-line treatment for elderly GBM patients, and to explore correlations between clinical outcome and O6 methylguanine-dna methyltransferase (MGMT) promoter methylation status. METHODS: Newly diagnosed GBM patients 65 years were considered eligible. Treatment comprised radiotherapy (60 Gy in 30 fractions over 6 weeks) plus continuous daily temozolomide (75 mg/m 2 /day), followed by 12 maintenance temozolomide cycles (150 mg/m 2 once a day for 5 consecutive days every 28 days) if MRI showed no enhancement suggesting a tumor; otherwise, chemotherapy was delivered until complete response or unequivocal progression. RESULTS: A total of 58 patients (34 males; median age, 68 years; range, years) were enrolled. Sixteen patients (43%) presented MGMT promoter methylated and 21 unmethylated (57%) status. The median progression-free survival and median survival time (MST) were 9.5 months (95% confidence interval [CI], ) and 13.7 months (95% CI, months), respectively. Mental status deterioration grade 3-4 was detected in 25% of patients. Leukoencephalopathy was diagnosed in 10% of patients. CONCLUSIONS: The overall and progression-free survival of patients given concomitant and adjuvant temozolomide are greater than in those given radiotherapy alone; however, this regimen incurs a greater deterioration in mental status. Further randomized trials should, therefore, be conducted to investigate the efficacy and against the toxicity of this regimen as first-line therapy in patients with GBM. Cancer 2009;115: VC 2009 American Cancer Society. KEY WORDS: glioblastoma, elderly, radiotherapy, temozolomide. Of primary central nervous system malignancies, 40% are glioblastoma (GBM), which, among older patients, accounts for the majority of primary brain tumors. 1 The elderly population is growing, and the Corresponding author: Alba A. Brandes, MD, Bellaria-Maggiore Hospital-Azienda USL Bologna, Medical Oncology, Via Altura 3, Bologna, Italy; Fax: (011) ; alba.brandes@yahoo.it 1 Department of Medical Oncology, Bellaria-Maggiore Hospital, Bologna, Italy; 2 Department of Neuroradiology, Bellaria-Maggiore Hospital, Bologna, Italy; 3 Department of Neurosurgery, Bellaria-Maggiore Hospital, Bologna, Italy; 4 Neurosciences Department, Statistics and Information Unit, Azienda University Hospital of Padova, Padova, Italy Received: September 2, 2008; Revised: December 28, 2008; Accepted: January 12, 2009 Published online: June 9, 2009 VC 2009 American Cancer Society DOI: /cncr.24406, Cancer August 1, 2009

2 Chemoradiation in Elderly GBM Patients/Brandes et al incidence of cancer, especially GBM, has increased in this age group over the past 20 years. It is particularly noteworthy that age has been recognized as a poor prognostic indicator in patients with malignant glioma. 2 Consequently, elderly patients are frequently treated suboptimally or left out of clinical trials. A combination regimen with standard radiotherapy (60Gy/30F) plus concurrent and adjuvant temozolomide, shown to have a survival advantage over radiotherapy alone, 3 has now become the standard treatment for GBM patients younger than 70 years. However, this combined treatment may not represent the optimal approach in patients older than 70. A subsequent trend benefit analysis demonstrated a decreasing benefit with increasing age, the hazard ratio being.80 for the year age group (P ¼.340). 4 The aim of the present study was, therefore, to verify the activity and the toxicity of a combined regimen using temozolomide concurrent and adjuvant to radiotherapy as first-line treatment for elderly patients with GBM. Moreover, because epigenetic silencing of the O6 methylguanine-dna methyltransferase (MGMT) DNA repair gene by promoter methylation has been strongly associated with longer survival in adult patients with GBM given alkylating agents, 5 a further endpoint was to investigate MGMT methylation status in an elderly population. MATERIALS AND METHODS Eligibility Criteria for eligibility were as follows: histological diagnosis of GBM; no prior chemotherapy or radiotherapy; age 65 years; Karnofsky performance score (KPS) 70; stable or decreasing dose of corticosteroids for at least 2 weeks before start concomitant treatment; neutrophils 1500/lL and platelets 100,000/lL; normal liver function (bilirubin <1.5 fold the upper limit of the normal range) alkaline phosphatase and transaminases <2.5 the upper limit of the normal range; serum creatinine <150 mmol/l. A Mini Mental State Examination (MMSE) score of at least 27 was required. Patients with active infection or other uncontrolled diseases, psychiatric disturbances, and/or a history of cancer other than resected nonmelanoma skin cancer or carcinoma in situ of the uterine cervix were ineligible. The study, approved by the Institutional Review Board of Padova, was conducted according to the principles of the Declaration of Helsinki and the rules of Good Clinical Practice. All patients signed a form giving their full informed consent to participate in the study. Treatment Regimen Radiotherapy comprised a conventionally fractionated regimen, a total dose of 60 Gy being delivered in 6 weeks, in a once daily schedule of 2Gy per fraction for a total of 30 fractions. During radiotherapy, temozolomide was administered continuously at a daily dose of 75 mg/m 2. After a 4-week resting period, temozolomide was administered as maintenance therapy once a day for 5 consecutive days every 28 days at a dose of 150 mg/m 2. A maximum of 12 maintenance cycles were administered if MRI showed no enhancement suggesting a tumor; otherwise chemotherapy was delivered until complete response or unequivocal progression. Dose Modifications Patients were closely monitored for toxicity throughout cycles, and all adverse events being recorded and graded according to the common toxicity criteria of the National Cancer Institute, version 3.0. ( forms/ctcaev3.pdf). Hematology was performed weekly, while complete biochemistry was assessed once per cycle, preferably on Day 28. No dose reduction was allowed during the concomitant treatment. Chemotherapy was given if neutrophils were 1500/lL, and platelets 100,000/lL; otherwise, treatment was delayed for a maximum of 3 weeks until adequate recovery. If blood counts analyzed throughout 3 weeks were still unsatisfactory, then treatment was stopped. In cases of G3 hematological toxicity at nadir or reversible G3 nonhematologic toxicity (except for nausea/vomiting), TMZ was reduced by 25%. If G4 hematologic or G3 nonhematologic toxicity reappeared notwithstanding dose reductions, or if any type of nonhematologic G4 toxicity was observed, chemotherapy was interrupted. The use of growth factors to maintain high Cancer August 1,

3 blood counts and to administer chemotherapy at fixed intervals was proscribed. Patients were kept at the lowest corticosteroid dosage allowed in relation to their neurological status. All patients underwent assessment of cognitive function with a MMSE at baseline and at intervals coinciding with MRI scans. Efficacy Measures Progression-free survival was evaluated from the start of chemotherapy to progression; median survival (MST) was calculated from the start of treatment to death for any reason. Progression-free survival at 6 months (progressionfree survival-6) and at 12 months (progression-free survival -12) and MST were calculated by using the Kaplan- Meier method 6 ; differences in progression and overall survival were evaluated by the log-rank test for statistical significance. Patients were evaluated for response using clinical and neurological examinations (performed monthly before each cycle) and MRI or CT neuroimaging performed at 3 weeks after the end of radiotherapy, and every 2 cycles, or earlier if indicated, according to Macdonald criteria. 7 Neurological status was assessed by considering signs and symptoms possibly correlated with progression, as compared with the previous examination, and each variation in daily corticosteroids dosage was recorded. Patients were withdrawn if they had progressive disease, unacceptable toxicity, or retracted their consent DNA Extraction and Methylation-specific Polymerase Chain Reaction DNA from 10 lm paraffin sections of cerebral lesion was modified by sodium bisulfite, which converts unmethylated cytosine to uracil, according to the procedure of Herman et al. 8 Modified DNA was submitted for methylation-specific polymerase chain reaction (PCR) after a nested-pcr protocol. 9 Because the quality of DNA obtained from formalin-fixed, paraffin-embedded tumor tissue affects the success rate of methylation-specific PCR, in some cases MGMT methylation status was determined using an alternative nested methylation-specific PCR approach, a first pair of primers being used to obtain smaller amplicons (129bp), for which forward and reverse primers have been described. 8,9 Statistical Analysis The main endpoint of the present phase 2 study was to determine the progression-free survival at 6 months (progression-free survival-6). According to the 1 stage design, our study, with its sample size of n ¼ 53, had a 5% probability of rejecting (a) the hypothesis of a progression-free survival-6 of 30% (P 0 ) and a 90% probability of accepting (1-b) the hypothesis of a progression-free survival-6 of 50% (P 1 ). Overall survival and progression-free survival were calculated using the Kaplan-Meier method, 6 and differences in progression and survival in relation to prognostic factors were evaluated with the log-rank test. Multivariate analysis was performed using the Cox proportional hazard model. The significance level was set at P <.05. All calculations were performed using S-PLUS software (MathSoft, Seattle, Wash). RESULTS Patients Characteristics From June 2004 to November 2007, 58 patients (34 males, 24 females; median age, 68 years, range years); 29.3% of patients were aged 70 years, and the median KPS was 80 (range, ). Patients characteristics are reported in Table 1. All patients were evaluated for drug activity and toxicity. Methylation-specific PCR was performed in 37 of the 58 patients because adequate paraffin-embedded tumor tissue was not available in 21 cases. Among patients with methylation-specific PCR assessment, 16 (43%) presented MGMT promoter methylated and 21 unmethylated (57%) status. In this subgroup with available MGMT methylation status, 27 patients were 65 to 70 years of age, and 10 were >70 years old. Moreover, MGMT promoter was methylated in 11 of 27 (40.7%) patients aged <70 years and in 5 of 10 (50%) patients aged >70 years, but unmethylated in 16 of 27 (59.3%) patients aged <70 years and 5 of 10 (50%) patients aged >70 years (P ¼.61). Progression-free Survival All patients were followed up to disease progression. The progression-free survival-6 and progression-free survival- 12 was 78.8% (95% confidence interval [CI], 68.8%- 90%), and 35% (95% CI, 24%-51%), respectively. The 3514 Cancer August 1, 2009

4 Chemoradiation in Elderly GBM Patients/Brandes et al Table 1. Patients Characteristics Characteristics No. of Patients (%) Sex Women 24 (41) Men 34 (59) Age, y (71) (25) (4) KPS 70 7 (12) (33) (40) (15) Extent of resection at latest surgery Partial 35 (60) Radical 23 (40) Previous treatment Surgery 58 (100) Radiotherapy 0 Chemotherapy 0 median progression-free survival, which was 9.5 months (95% CI, ) overall, was 22.9 months (95% CI, ) versus 9.5 months (95% CI, ) in patients with MGMT promoter methylated status and with unmethylated MGMT promoter status, respectively; progression-free survival-6 was 86% (95% CI, 69.5%-100%) and 76% (95% CI, 60%-97%) in patients with methylated and unmethylated MGMT status, respectively. At log-rank test evaluation, no significant correlation was found between progression-free survival and sex (P ¼.3), type of surgery (P ¼.27), or age less or older than 70 years (P ¼.4), whereas KPS (P <.001) was a significant prognostic factor. Among patients with methylation-specific PCR determination, a significant difference was found between progression-free survival in relation to MGMT promoter methylated or unmethylated status (P ¼.005) (Fig. 1). At multivariate analysis, MGMT methylation status and KPS (P <.005) retained significance (P <.005). FIGURE 1. Progression-free survival in relation to MGMT promoter methylation status. Thick line, MGMT methylated patients; thin line, MGMT unmethylated patients (P <.01). The median overall survival was 13.7 months (95% CI, ). The median survival, which was not reached in methylated MGMT promoter status cases, was 13.7 months (95% CI, ) in unmethylated MGMT promoter status cases. At 2 and 3 years, 31.4% (95% CI, 19.6%-50%) and 16% (95% CI, 6%-43.4%) of patients were alive. The percentage of methylated MGMT promoter status patients alive at 2 and 3 years was 83 (95% CI, 63%-100%), and 69 (95% CI, 44%-100%), respectively; while in patients with unmethylated MGMT promoter status, these figures were 56 (95% CI, 36%-84%) and 38 (95% CI, 19%-75%), respectively. At log-rank test evaluation, no significant correlation was found between survival and sex (P ¼.12), type of surgery (P ¼.21), or age less or older than 70 years (P ¼.37), whereas KPS (P <.01) and MGMT promoter status (P ¼.05) were significant prognostic factors (Fig. 2). Overall Survival FIGURE 2. Survival according to MGMT promoter methylation status. Thick line, MGMT methylated patients; thin line, MGMT unmethylated patients (P ¼.05). Cancer August 1,

5 Table 2. Toxicity per Patient Toxicity Grade 1-2 No. (%) 3-4 No. (%) Concomitant part, n ¼ 58 Neutropenia 1 (2) 2 (3) Lymphopenia 3 (5) 1 (2) Thrombocytopenia 4 (7) 3 (5) Transaminase elevation 4 (7) 1 (2) Thrombosis 0 3 (5) Constipation 8 (14) 1 (2) Nausea 2 (3) 0 Infection 3 (5) 0 Adjuvant part, n ¼ 48 Neutropenia 1 (2) 2 (4) Lymphopenia 5 (10) 1 (2) Thrombocytopenia 9 (19) 2 (4) Transaminase elevation 2 (4) 0 Thrombosis 0 3 (6) Constipation 4 (8) 0 Nausea 5 (10) 0 Infection 7 (15) 1 (2) Leukoencephalopathy 2 (4) 3 (6) Mental status 15 (31) 12 (25) At multivariate analysis, only MGMT methylation status retained significance (P <.01), thus proving to be the most important prognostic factor for survival in elderly patients with GBM. Toxicity Three patients (5%) interrupted concomitant phase for grade 4 hematological toxicity: in 2 of these patients, levels returned to normal in 3 weeks and temozolomide was continued as maintenance treatment, and 1 patient had persistent grade 2 hematological toxicity 6 months after discontinuation of concomitant treatment and no further chemotherapy was given. Ten patients (17%) discontinued treatment after the phase of concomitant therapy because of disease progression in6cases,andtoxicityin4(pulmonaryembolism,2cases; prolonged grade 4 hematological toxicity, 2 cases). Grade 2 and grade 3 mental status deterioration were detected in 15 (31%), and 12 (25%) patients, respectively. Patients with cognitive impairment had a median age of 66 years (range, 65-73); only 1 patient was (8%) older than 70 years of age. The median time from end of radiotherapy to mental state deterioration was 6 months. Grade 3 leukoencephalopathy was demonstrated in 3 patients (6%), with a median time from the end of radiotherapy to diagnosis of 14 months. Toxicities are listed in detail in Table 2. Among 12 patients that presented grade 3 mental deterioration, 9 (75%) had no comorbidities, 2 (17%) and 1 (8%) patients had 1 and 2 controlled comorbidities, respectively. DISCUSSION Radiotherapy could be considered current standard treatment for elderly GBM patients: In a recent randomized study, it has been demonstrated that, at a dose of 50 Gy (1.8 Gy per fraction), this regimen has a survival advantage over best supportive care (7.3 vs 4.2 months), without reducing quality of life or cognition. 10 In a previous randomized trial conducted on GBM patients aged older than 60 years (median KPS, 70; previous surgical resection in 65%), no difference was found between standard (60 Gy/30F) and short course radiotherapy (45 Gy/15F) for survival, the MST being 5.1 versus 5.6 months, respectively. 11 The impact of adjuvant chemotherapy was analyzed in a trial conducted by Brandes et al, in which 79 elderly GBM patients with favorable prognostic factors (gross total resection and KPS 80) were treated with radiotherapy (60 of 30F) alone or the same radiotherapy followed by adjuvant procarbazine, lomustine, and vincristine (PCV), or the same radiotherapy followed by adjuvant temozolomide. Patients who received adjuvant temozolomide had a median overall survival and median progression-free survival of 14.9 months 10.7 months, respectively. 12 The EORTC/NCIC phase 3 randomized trial comparing temozolomide concomitant and adjuvant to standard radiotherapy versus radiotherapy alone (60Gy/30F) has demonstrated an overall and progression-free survival benefit over radiotherapy alone in patients younger than 70 years of age 3 : the trend benefit analysis showed a decreasing benefit with increasing age, with a hazard ratio (HR) of 0.63 for patients 50 to 60 years of age (P <.05), HR of 0.72 for patients 60 to 65 years of age (P ¼.096), and HR of 0.8 for patients 65 to 71 years of age (P ¼.340). 4 Two studies have analyzed the impact of concomitant and/or adjuvant treatment in the elderly population. 13,14 In the study conducted by Combs et al, GBM patients older than 65 years of age were treated with temozolomide concomitant with (81% received temozolomide at 50 mg/m 2, and 19% 75 mg/m 2 ) radiotherapy 3516 Cancer August 1, 2009

6 Chemoradiation in Elderly GBM Patients/Brandes et al Table 3. Studies on Elderly GBM Patients Author Treatment No. of Patients Median KPS Median Age Biopsy % OS, mo PFS, mo Keime-Guibert 10 BSC RT (50 Gy) Roa 11 RT (60 Gy) NR RT (45 Gy) NR Brandes 12 RT (60 Gy)!TMZ Combs 13 TMZ (50 mg/m2)þrt (60 Gy) 35 NR Minniti 14 TMZ (75 mg/m2)þrt (60 Gy)!TMZ Present study TMZ (75 mg/m2)þrt (60 Gy)!TMZ KPS indicates Karnofsky performance score; OS, overall survival; PFS, progression-free survival; BSC, best, supportive care; RT, radiotherapy; TMZ, temozolomide. (adjuvant chemotherapy prescribed in only in 5 cases for unspecified reason); the median OS was 11 months and the median progression-free survival only 4 months. No data on MGMT status were provided. In the study conducted by Minniti et al, patients aged over 70 were treated with temozolomide concomitant with radiotherapy followed by 6 cycles of adjuvant treatment; the median survival was 10.6 months and the median progression-free survival was 7 months. No data on MGMT status were provided (Table 3). In the present study, 58 GBM patients older than 65 years of age were treated with temozolomide concomitant with and adjuvant to standard radiotherapy; the median survival and the median progression-free survival were 13.7 and 9.5 months, respectively. The prognostic profile of this population was favorable: 71% of patients were 65 to 70 years of age; 92% had a KPS of , and all had undergone a previous surgical resection. These more favorable prognostic factors may explain the more satisfactory findings made in the present paper. Elderly GBM patients are considered less tolerant to treatment than younger patients; however, the survival in the elderly GBM patients with good prognostic factors treated in our study was similar to that of the adult population treated in the EORTC/NCIC trial 3 (13.7 vs 14.6 months); moreover, the percentages of patients alive at 2 years were 31% versus 26%, and different from other previous studies, age (<70 vs >70 years) does not seem to correlate to progression-free survival or OS in our study. On evaluating results in terms of MGMT promoter methylation status, 5 it emerges that the prognostic and predictive value of MGMT methylation is also maintained in the elderly population, being associated with a longer progression-free survival and OS. The dosage of temozolomide (150 mg/m 2 ) given to our patients during the maintenance period was lower than that (200 mg/m 2 ) given to the adult population; treatment was well tolerated and the therapy discontinuation rates and hematological toxicity profiles were similar. 3 However, the neurologic and neurocognitive sequelae found in the present study were important: deterioration in mental status, occurring in 56% of patients, led to significant disability and compromising quality of life. Of the patients, 6% had grade 3 leukoencephalopathy. The risk of cognitive impairment does not appear to be age related. Patients with cognitive impairment had a median age of 66 years (range 65-73); only 1 (8%) patient was older than 70 years of age. The median time of onset to the development of neurologic toxicity was 6 months, whereas time to progression was 9.5 months. These findings suggest that disease progression does not play an important role in neurotoxicity and that the burden of neurocognitive deficits is a crucial issue in elderly patients. However, it is possible that cognitive impairment was due to tumor progression and in many trials it was, in fact, the first indicator of tumor growth. However, lack of an untreated control arm makes it difficult to determine the specific contribution of the treatment to neurocognitive decline. Nevertheless, the neurocognitive decline, occurring after concomitant and adjuvant treatment in GBM patients, is multifactorial because of the disease itself and age-related comorbidity, and chemotherapy also Cancer August 1,

7 playing a role; moreover, concomitant treatment may exacerbate neurological deterioration in view of the activity of radioenhancers involved in concomitant chemotherapy. The real benefit of concomitant and adjuvant treatment over radiotherapy alone followed by adjuvant treatment has not yet been clearly demonstrated in the elderly population. Moreover, although it is known that this approach incurs long-term cognitive impairment, none of the trials reported in literature made pretreatment and post-treatment psychometric evaluations of their patients. A randomized study including specific testing should, therefore, be conducted to further investigate this aspect; it may yield data revealing that the real incidence of cognitive deficit in elderly GBM patients given concomitant radiochemotherapy is even higher than reported so far. Conflict of Interest Disclosures We are indebted to the Research and Development Unit of Azienda Ospedaliera di Padova and to the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO) for the research funding. References 1. Brandes AA, Compostella A, Blatt V, Tosoni A. Glioblastoma in the elderly: current and future trends. Crit Rev Oncol Hematol. 2006;60: Brandes AA, Monfardini S. The treatment of elderly patients with high-grade gliomas. Semin Oncol. 2003;30(6 suppl 19): Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352: Laperriere N, O Callaghan C, Ding K, et al. Rationale and design for a phase III randomized controlled trial in elderly patients with glioblastoma multiforme: NCIC CTG CE. 6 13th Biannual Canadian Neuro-Oncology Meeting Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352: Kaplan E, Meier P. Non parametric estimation for incomplete observation. J Am Stat Assoc. 1958;53: Macdonald DR, Cascino TL, Schold SC, Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol. 1990;8: Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB. Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA. 1996;93: Palmisano WA, Divine KK, Saccomanno G, et al. Predicting lung cancer by detecting aberrant promoter methylation in sputum. Cancer Res. 2000;60: Keime-Guibert F, Chinot O, Taillandier L, et al. Radiotherapy for glioblastoma in the elderly. N Engl J Med. 2007; 356: Roa W, Brasher PM, Bauman G, et al. Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. J Clin Oncol. 2004;22: Brandes AA, Vastola F, Basso U, et al. A prospective study on glioblastoma in the elderly. Cancer. 2003;97: Combs SE, Wagner J, Bischof M, et al. Postoperative treatment of primary glioblastoma multiforme with radiation and concomitant temozolomide in elderly patients. Int J Radiat Oncol Biol Phys. 2008;70: Minniti G, De Sanctis V, Muni R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma in elderly patients. J Neurooncol. 2008;88: Cancer August 1, 2009