Glioblastoma in the elderly: Current and future trends

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1 Critical Reviews in Oncology/Hematology 60 (2006) Glioblastoma in the elderly: Current and future trends Alba A. Brandes a,, Alessia Compostella b, Valeria Blatt b, Alicia Tosoni b a Department of Medical Oncology, Bellaria Hospital, Via Altura 3, Bologna, Italy b Department of Medical Oncology, Istituto Oncologico Veneto, IRCCS, Padova, Italy Accepted 30 June 2006 Contents 1. Epidemiology Prognostic factors Treatment Supportive care Surgery Radiotherapy Chemotherapy Conclusions Reviewers References Biography Abstract Data from a prospective trial large enough to provide a reliable analysis of outcome and prognostic factors in elderly patients with glioblastoma (GBM) are not yet available in the literature. Extensive tumor removal appears to offer patients the best possible chance of a speedy neurological recovery. Adequate radiotherapy (RT) should always be given to elderly patients if they have undergone gross total debulking and have maintained a good performance status. It is, however important to bear in mind that the risk of long-term cognitive impairment may be higher in patients on high-dose RT and that a short course of accelerated RT can achieve the same survival. Rather than being ruled out on principle, chemotherapy should be considered on the basis of an accurate assessment of the factors that might compromise the individual patient s tolerance to drugs administered. Temozolomide appears to be the best available chemotherapy in this population of patients Elsevier Ireland Ltd. All rights reserved. Keywords: Chemotherapy; Elderly; Glioblastoma; Radiotherapy 1. Epidemiology The importance of cancer treatment in elderly patients has recently come to the fore due to the progressive increase in life expectancy in the western world. The annual agestandardized mortality from brain tumors has almost doubled for men, being 15.7/100,000 between 1978 and 1985 and 28.4/100,000 between 1986 and 1992 [1]. The study of cancer in elderly patients calls for a definition of the Corresponding author. Tel.: ; fax: address: aa.brandes@yahoo.it (A.A. Brandes). population under study. The age at which patients are considered elderly varies in the literature. In geriatric medicine, a limit of 65 years is often considered for elderly patients, whereas in the European literature on cancer in the elderly an age limit of 70 years is often used. Some authors advocate a distinction between the young old (65 74 years), the older old (75 84 years) and the oldest old (85 years or older) [2,3]. However, the aging process varies from individual to individual and is poorly reflected on a chronological basis. Investigations on the treatment of high-grade gliomas in the elderly are scarce [4] and patients in this age category /$ see front matter 2006 Elsevier Ireland Ltd. All rights reserved. doi: /j.critrevonc

2 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) are often excluded from clinical trials focusing on novel treatments [5], thus being deprived of state-of-the-art investigational treatments. It has not yet been reliably established whether or not the incidence of primary brain tumors is increasing in the elderly population, although this issue has been widely debated in recent decades. According to a report from the National Cancer Institute, the incidence of primary malignant brain tumors in the elderly markedly increased between the 1973/1974 and 1985 time periods [6]. The increasing incidence brain tumors in the elderly was recently attributed to an improvement in the detection rate of cancer, thanks to the more widespread use of magnetic resonance imaging (MRI) and computed tomography scanning (CT) techniques in this age category [7]. However, some investigators disagree with this explanation [8]. Improvements in treatments for the more common illnesses and the consequently longer life expectancy may have prolonged the time for brain, breast and colon cancers to develop and become symptomatic [5]. Clinicians and pathologists will thus encounter an increasingly large number of elderly GBM patients, although the statistics reported may vary, depending on referral patterns and social issues influencing the access that elderly patients have to medical care. In a large cohort of 1003 patients, approximately 9% of all GBMs were identified in patients aged years [9]. Thus, although GBMs are known to be tumors affecting old patients, they do not necessarily develop in the older old category. However, as the population of subjects aged more than 75 years continues to rise, these data may need to be re-appraised. 2. Prognostic factors Advanced age is the most relevant prognostic factor for patients with GBM [4,10], although the reasons for its biologically aggressive behavior in the elderly are still unknown. Commonly applied prognostic factors, such as performance status and neurological status, assessed in recursive partitioning analysis (RPA) [10], should always be considered in elderly GBM patients. In a systematic analysis of 14 histological variables (such as necrosis, vascular proliferation and calcification) in tumor samples of elderly and younger GBM patients, none of these characteristics were found to be closely correlated with advanced age and length of survival [9]. An impaired immune defense due to the aging process [11] and increased mortality from non-tumor-related causes have been suggested as additional factors leading to a shorter survival, but they probably are of only marginal relevance in view of the highly growth rate of GBM. In recent years, a number of molecular and genetic alterations have been identified in human GBM, underlining their biological heterogeneity. In this setting, it is unclear whether the prognostic factor of older age is related to intrinsic properties of the tumor-type or to the characteristics of patients. However, differences between the genetic expression of younger and that of older GBM patients suggest that genetic events associated with age contribute to determining tumor behavior (Table 1). Chromosome 10 loss and 7p gain, assessed by means of comparative genomic hybridization or FISH, are predictive of a shorter survival in elderly GBM patients [12,13]. Kunwar et al. [13] also demonstrated that chromosome 7 deletion is associated with shorter survival both in younger and older GBM patients whereas the presence of a normal chromosome 7p is associated with a longer survival (p = 0.001). Gain of chromosome 7 was shown by comparative genomic hybridisation to closely correlate with the level of EGFR protein expression [13]. Results reported on the prognostic significance of EGFR amplification in survival are contradictory (Table 1). The influence of EGFR amplification on GBM patient outcome has recently been shown to differ according to the age of patients [14,15]. In contrast to its negative impact on survival in younger patients, EGFR overexpression has been shown to be associated with a better prognosis in GBM patients older than 55 [15] or 60 years [16]. Kleinschmidt et al. have studied the effects of EGFR amplification on survival in GBM patients older than 75 years [17]. EGFR amplification was detected in 25% of cases. Patient survival was significantly longer in those with (median 10.5 months) than in those without (median 2 months) EGFR gene amplification. Conversely, Quan et al. [18] found no correlation between EGFR amplification and survival in patients of different ages (<60 and >60 years). Korshunov et al. [12] demonstrated the unfavorable prognostic impact of EGFR amplification in patients in the age categories of <40 and 40 years. Kleinschmidt et al. [17] found, as did McKeever et al. [19], a very high mean MIB- 1 index in tumors from older patients (no differences being found on the basis of EGFR amplification status), but concluded that the MIB-1 score did not further predict duration of survival in individual patients. Likewise, Simmons et al. [15] showed only a trend toward a poorer survival in elderly GBM patients with high MIB-1 index (Table 1). Survivin is a member of the inhibitor-of-apoptosis protein family (IPF). A recent study upon the prognostic impact of survivin in GBMs has indicated that the survivin index does not correlate significantly with overall survival [20]. Survivin does not therefore appear to be useful as a prognostic factor in the clinical setting. YKL-40 is a secreted protein that has been reported to be overexpressed in gliomas, although its function is unknown. In the study Pelloski et al. [21], two groups of GBM patients who underwent subtotal (147) or gross total (140) resection were studied for imaging-assessed changes in tumor size in serial studies following radiation therapy. In both groups, higher YKL-40 expression was significantly associated with poorer radiotherapy response, shorter time to progression and shorter overall survival. These authors found that, despite a higher YKL-40 expression being associated with older age, YKL-40 remained an independent prognostic factor in multivariate analysis after adjustment for age. Cytogenetic profiles can supplement current histological criteria to improve the accuracy of survival predictions and may

3 258 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) Table 1 Molecular prognostic factors in elderly GBM patients Molecular factor Author Method Patients age Influence on outcome EGFR amplification Kleinschmidt et al. [17] FISH >75 years Associated with longer OS (p = 0.04) Batchelor et al. [14] PCR <46 years Associated with reduced survival (HR 2.19, p = 0.039) >46 years Associated with longer survival (HR 0.74) Simmons [15] IHC >55 years Associated with longer survival (HR 0.5, p = 0.02) <55 years Trend toward a reduced survival (HR 1.7, p = 0.12) Smith [16] FISH >60 years Associated with longer survival <60 years Associated with reduced survival Quan [18] FISH >60 years No association <60 years No association Korshunov [12] FISH <40 years Associated with reduced survival (p = 0.03) 40 years Associated with reduced survival (p = 0.001) CDKN2A/p16 Batchelor [14] PCR >70 years Associated with reduced survival (HR 11.48) <70 years Associated with reduced survival (HR 1.33, p = 0.024) 1p36 Batchelor [14] LOH >60 years Associated with longer survival (HR 0.10) <60 years Marginally associated with longer survival (HR 0.91, p = 0.071) p53 Batchelor [14] SSC >70 years Associated with reduced survival (HR 7.54) SEQ <70 years Associated with longer survival (HR 0.84, p = 0.001) Simmons [15] IHC >55 years No association SSC <55 years No association SEQ MIB-1 Simmons et al. [15] IHC >55 years Associated with reduced survival (HR 1.3, p = 0.03) <55 years Trend toward a worse survival (HR 1.2, p = 0.09) YKL-40 Pelloski et al. [21] IHC NR Association with survival Gain of chromosome 7 Korshunov et al. [12] FISH <40 years No association 40 years Associated with reduced survival (p = ) Deletion of 10q23/PTEN Korshunov et al. [12] FISH <40 years No association 40 years Associated with reduced survival (p = ) therefore provide a more objective method than histology for classifying malignant gliomas. 3. Treatment Most studies report an average survival of 4 8 months in elderly patients with GBM [22,23]. The significantly diminished survival, compounded by a poor functional status in many cases, thus throws doubt upon any decision to undertake aggressive therapy (e.g. surgical resection, radiotherapy and chemotherapy) in this subgroup of patients with a confirmed diagnosis of GBM. Advocates of aggressive therapy using one or more of the post-biopsy treatment modalities argue that an older patient should not be denied standard care, which may prolong survival [5], while others maintain that aggressive, heroic treatment does not necessarily achieve a significantly improved outcome, only worsening quality of life [24]. 4. Supportive care Any decision to administer the best possible supportive care may be fraught with difficulties. Corticosteroids are the mainstay in treatment of brain edema and intracranial hypertension. However, as elderly patients often have diabetes, chronic gastritis, osteoporosis, hyperlipemia and cataract, dexamethasone should be administered cautiously in this patient category. In these patients, anti-epileptic drugs (AED) may markedly affect vigilance and lead to insomnia, thus severely compromising social interactions and exacerbating any cognitive defects. Few data are available concerning the role of supportive treatments alone in elderly glioma patients, because these approaches are usually reserved for patients with a dismal prognosis who are not enrolled in clinical trials. The treatment of peri-tumoral edema using steroids and mannitol combined with physiotherapy probably has a marginal effect on survival, but it may have a positive impact on quality of life. 5. Surgery Thanks to the recent, significant progress made in neurosurgery, elderly patients can be selected to undergo biopsy or resection: CT and MRI allow a more accurate preoperative diagnosis of brain lesions. Until recently, however, these techniques were not optimally utilized for elderly patients with brain lesions [25] and most studies in the literature also

4 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) predated the development of image-guided surgical resection techniques that allow for safer resection of brain tumors. With the availability of newer surgical techniques, a greater percentage of elderly GBM patients may be considered candidates for neurosurgical procedures. Thus, the elderly patient population treated over the past decade may differ from series reported on in former studies. In the literature there is a shortage of data on the benefits and risks of surgery in elderly patients with glioma. In a German series of 44 brain tumor patients ( 80 years), 43% improved after surgery, 34% remained stable and 23% worsened; the perioperative mortality was 11% [26]. Concomitant cerebrovascular and systemic chronic diseases were clearly associated with a poorer outcome, unlike tumor location and volume. Kelly et al. analyzed surgical outcome in a younger age class group (patients over 65 years) and found that postoperative mortality was only slightly higher than biopsy-related mortality: 2.5% versus 2.2% [27]. These authors [27] compared the outcome of stereotactic volumetric resection in 40 GBM patients aged 65 years with the outcome following bioptic procedures in 88 other patients; the two groups had comparable median ages and KPS. Survival in the former group was almost two-fold that in the latter: 6.3 months versus 3.6 months. In their retrospective study on 102 patients 70 years, Mohan et al. [22] reported a significant impact on survival on comparing complete versus partial resection versus biopsy (17.3 months versus 7.2 months versus 3.4 months, respectively), while Pierga et al. [28] and Chang et al. [29] reported a 5 6 month survival advantage with tumor resection versus no resection. These authors, however, believed that their findings were influenced by a strong selection bias. Conversely, surgery was not found to impact on survival in other studies [30,31] in which prognostic factors probably had a different distribution pattern. In a small, recent Finnish randomized clinical trial [32], 23 patients >65 years with malignant glioma (83% with GBM) were randomly assigned to biopsy only or surgical resection followed by RT. The median survival time was significantly longer in patients who underwent resection than in those who underwent biopsy, being 5.6 months and 2.8 months, respectively. Compared to biopsy, resection is also associated with improved quality-of-life in older GBM patients. Based on the results of this unique randomized study, it is reasonable to consider that the widest possible resection is the optimal goal of neurosurgery. However, the decision to operate on elderly patients with brain tumors should be based upon a careful consideration of the patient s condition and any comorbidities, the operability of the tumor and the availability of post-operative care units. 6. Radiotherapy Radiation therapy has a survival advantage over supportive care; it can also improve and control existing compromised symptoms in elderly GBM patients, as observed by Bauman et al. [33], Meckling et al. [31] and Thomas et al. [34], in cohorts of more than a hundred patients [31,33 35]. These authors found an improvement in symptoms ranging from 18 to 38%, a disease stabilization of up to 78%, only a small percentage of patients having clinical deterioration. The study conducted by Marijnen et al. [36] on 202 GBM patients over 70 years of age treated between 1990 and 2000, demonstrated that irradiated patients survived significantly longer than non-irradiated patients (10.6 months versus 1.9 months), radiotherapy being the only prognostic factor for survival (HR 8.9). Radiotherapy is standard therapy in elderly GBM patients and any new strategies should be tested against this golden standard. In fact, the French randomized study [35] comparing radiotherapy ( Gy, 50.4 Gy) with best supportive care in 84 patients over the age of 70 years, showed that radiotherapy was followed by a longer progression-free survival time (14 weeks versus 7 weeks), while the overall survival time in patients receiving radiotherapy was 6.5 months, compared with 4 months with best supportive care only (p = 0.004). No patients in this series had severe clinical adverse reactions related to radiotherapy and preliminary data on quality of life evaluation indicated a benefit from radiotherapy. The elderly appear to be more susceptible to radiationinduced brain atrophy and, ultimately, dementia, due to the presence of pre-existing vascular changes and the higher incidence of diabetes mellitus, which predisposes them to vascular injury and arteriosclerosis [37]. However, few studies performed between the 60s and the 80s have demonstrated radiation-induced late effects in elderly populations. Stylopoulos et al. [38] showed that glioma survivors over 40 years of age presented a more rapid decline in clinical and cognitive status than younger patients. Maire et al. [39] found a close correlation between younger age and the preservation of adult intellectual ability. Asai et al. [40] found cerebral atrophy in 56% of cases. This condition was strongly correlated with age: in patients aged 50 years or more, the incidence was 72.9% while in patients aged less than 50 it was 39.2% (p = 0.005). The incidence of radiation-induced brain atrophy was correlated with irradiation volume, being found in 73.3% of whole brain irradiated patients and in 47.5% of patients on regional irradiation (p = 0.025). Nevertheless, in recent years, radiation technology has dramatically changed and no new data on radiotherapy-induced late effects are available. On analyzing the prognostic influence of some factors, emerges that the median survival after minimal debulking was less than 26 weeks in patients with high-grade gliomas and KPS < 60 and age >60 years [41]. The median survival of patients with high-grade astrocytomas and the best possible supportive care is 14 weeks. In patients with negative prognostic factors, the survival period following RT is slightly longer than the time required for the treatment itself. Therefore, some clinicians believe that RT should be avoided in these cases. Findings from one randomized trial have demonstrated that RT adds roughly 6 months median survival

5 Table 2 Radiotherapy ± chemotherapy in malignant glioma in the elderly Author Pts (age limit) Median age (range) KPS GBM (%) Surgery Radiotherapy Chemotherapy (% of Median survival (months) patients) Newall et al. [69] 18 ( 63 yrs) NR (63 75) Mean 50 (30 90) resection 30 Gy None biopsy WB Ampil et al. [70] 23 ( 65 yrs) Mean 69 yrs (65 80) Median 50 (40 70) resection Gy in F None biopsy WB + boost 4 if surgery, 4 if biopsy 1 none 39.1% no radiotherapy Bauman et al. [33] 29 ( 65 yrs, but Mean 69.2 yrs Mean NR 30 Gy in 10 F None 6 some younger) 15 biopsy WB Kelly et al. [27] 128 ( 65 yrs) Mean 71.4 yrs (65 83) Mean 84.2 (60 100) volumetric resection 88 biopsy Gilbert et al. [59] 17 ( 65 yrs) NR Mean resection 11 biopsy Meckling et al. [31] 103 ( 70 yrs) Median 75.6 yrs ( ) 62.2% with moderate to severe neurological deficits Hoegler and Davey [30] resection 15 biopsy 22 no surgery at all Dose not reported 18% of pts no radiotherapy 60 Gy ± brachytherapy or radiosurgery Gy in 35 F (median) (40.3% limited fields 59.7% WB) 35% of pts no radiotherapy None if resection, 3.6 if biopsy, p = if radiotherapy, 1.6 if no radiotherapy, p = 0 (.000) BCNU + DDP, before radiotherapy, with 76% of response. (100%) 2 pts (drugs not reported) (2%) radiotherapy significantly improves survival (p < 0.001) 2.3 if >80 years, with or without radiotherapy 25 ( 70 yrs) Median 73 yrs (70 78) Median 70 (30 90) resection 37.5 in 15 F limited fields CCNU in 2 pts 8 10 biopsy 20% of pts no radiotherapy (8%) 5.5 if KPS 70, 10.4 if KPS>70(p = ) Mohan et al. [22] 102 ( 70 yrs) Mean 74.5 yrs (70 87) Mean 70.5 (50 100) resection >55 Gy (56.8% of pts) BCNU or PCV in 16 pts biopsy <55 Gy (18.7% of pts) WB ± boost in 35.3% of pts limited field in 40.2% of pts) 24.5% of pts no radiotherapy (15.7%) 7.2 if KPS 70, 1.3 if KPS < 70, p = if RT >55 Gy; 4.5 if RT < 55 Gy, 1.2 if no RT (p = ) 17.3 if total resection; 7.2 if partial resection; 3.4 if only biopsy (p = ) 8 if chemotherapy, 4.9 if no chemotherapy 260 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) Villa et al. [71] 85 ( 65 yrs) 70 yrs (65 81) 60 (30 100) resection Gy limited fields BCNU or PCV in 10 pts biopsy 49.4% of pts no radiotherapy (11.8%) 10.5 if radiotherapy; 1.9 if no radiotherapy 11.4 if total resection; 10 if partial resection or biopsy (p = 0.08) 12.8 if age 70, 7.9 if age >70 (p = 0.008) 11.2 if KPS 70, 7.7 if KPS<70(p = 0.06)

6 Pierga et al. [28 30 ( 70 yrs) 73 yrs (70 79) Mean 66 (30 100) resection 45 Gy in 25F limited fields BCNU or PCV in 12 pts 8.4 overall 14 biopsy 4 no surgery (40%) 9.3 if KPS 70; 5.6 if KPS < 70 (p = 0.05) 10.5 if total resection; 5.6 if no resection 13.5 with chemotherapy, 6.3 without chemotherapy Brandes et al. [65] 79 ( 65 yrs) Mean 69 yrs (65 76) 80 (60 90) 100 All resection 59.4 Gy in 33F limited fields PCV in 32 pts (40.5%) Temozolomide in 23 (29.2%) Chang et al. [29] 59 ( 44 yrs) 65 yrs (44 82) 70 (30 100) resection 13 biopsy 2 none 50 Gy in 20F limited fields BCNU or PCV or Temozolomide Adjuvantly in 15 pts (25.4%) At relapse in 9 pts (15%) Piribauer et al. [72] 54 ( 65 yrs) NR (60 100) resection 51 Gy (17F) or 66 Gy (33F) CCNU 8.6 overall (65 83) 14 biopsy Limited fields concomitantly and after radiotherapy (100%) Muacevic and Kreth [73] 123 ( 65 yrs) 69 yrs (65 73) 70 (40 90) resection 65 biopsy Glantz et al. [61] 86 ( 70 yrs) 73.8 yrs (70 91) 67.7 (40 90) 97.5 All with histological diagnosis 12.5 overall 11.2 without chemotherapy, 12.7 with PCV, 14.9 with Temozolomide (p = ) 7 10 with chemotherapy, 4 without chemotherapy (p = 0.044) 12 if total resection, 6 if subtotal or biopsy (p = ) 60 Gy limited fields None 5.6 overall 8.4 with resection plus completed radiotherapy, 7.9 if biopsy plus completed radiotherapy (p > 0.05) 2.8 if radiotherapy not completed 60 Gy (33F) 37.2% of pts no radiotherapy, but only chemotherapy Temozolomide in 32 pts (37.2%) Chinot et al. [60] 32 ( 70 yrs) 75 (70 81) 70 (60 80) resection None Temozolomide biopy Roa et al. [44] 47 ( 60 yrs) Mean 72.4 yrs 70 (60 80) resection 60 Gy (30F) None biopsy 48 ( 60 yrs) Mean 71 yrs 70 (60 80) resection 45 Gy (15F) None biopsy Lutterbach and Ostertag [48] 5 overall 6 with temozolomide alone, 4.1 with radiotherapy alone (p = 0.198) HR for death = if KPS 80 (p <.0001) 96 ( 60 yrs) 67 yrs (60 81) 60% resection 42 Gy (12F) None 7.3 (hypofractionated RT 39 biopsy 60 Gy (30F) 5.6 conventional RT yrs, years; WB, whole brain; NR, not reported; PTS, patients, KPS, Karnofsky performance score; GBM, glioblastoma multiforme. A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006)

7 262 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) compared to surgery alone in adult patients [42], while in a subsequent study it was calculated that the additional benefit of delivering a full dose RT (60 Gy/30 F) course compared to a shorter course of treatment (45 Gy/20 F) may be quantified at around two months in adults [43]. In the randomized prospective clinical trial on GBM patients of over 60 years of age, performed by Roa et al. [44], patients received either a standard (60 Gy in 30 fractions over 6 weeks), or short-term (40 Gy in 15 fractions over 3 weeks) RT, without chemotherapy. The primary end-point of the trial was overall survival. Of the 100 patients randomly assigned, 95 were eligible and analyzable. The median survival times and 1-year survival rates of patients on the two different regimens were similar; 5.1 months and 9% for standard RT and 5.6 months and 15% for short-term RT, respectively. All patients had died at 2 years. Short course RT thus appears to be a reasonable treatment option for older GBM patients. However, in this study all patients had an unfavorable prognosis, the median KPS being only 70 in both treatment arms. Moreover, biopsy alone was performed in 39% of patients and only 9% of patients underwent gross total resection, compared to biopsy in 17% and gross total resection in 19% of 645 patients treated in three consecutive RTOG clinical trials [45] (Table 2). In this study, the median survival time was 6.6 months with biopsy alone, compared to 11.3 months with resection. A similar observation was recently made by the Glioma Outcomes Project [46] in a group of 565 patients with malignant glioma (primarily GBM) diagnosed between 1997 and This observational database, used to evaluate the efficacy of resection compared with that of biopsy, demonstrated a median survival of 45.3 and 21 weeks after resection and biopsy, respectively (p < ). Likewise, our previous study median survival was 14 months in patients with good performance status who underwent surgery followed by full dosage RT and adjuvant temozolomide [47]. Lutterbach and Ostertag [48], whose findings were in agreement with the above, analyzed data on 96 GBM patients aged 60 years, who underwent hypofractionated (42 Gy in 12 fractions over a period of 2.5 weeks) or conventionally fractionated radiotherapy (60 Gy in 30 fractions over a period of 6 weeks). The median age in this subgroup was 67 years and 60% of the patients had a Karnofsky performance status of 70. Gross total or subtotal resection was performed in 59% of the patients. As in the study by Roa et al. [44], no chemotherapy was administered. The median overall survival was 7.3 months for the hypofractionated group (n = 50) and 5.6 months for the conventionally fractionated group (n = 46; log-rank test p = 0.2). Survival in the two groups was 60% versus 49% at 6 months and 26% versus 18% at 12 months, respectively (Table 2). 7. Chemotherapy The administration of chemotherapy in elderly patients is a widely debated issue. The pharmacokinetics of the drugs to be used should always be borne in mind when administering chemotherapy to elderly patients and some general considerations should also be made [49]. Patients in this age group often have a decrease in gastrointestinal motility, splanchnic blood flow and secretion of digestive enzymes, together with mucosal atrophy and the reduced absorption of oral chemotherapy such as temozolomide and lomustine [50]. Changes in body weight can also influence drug distribution. Decreases in the liver/mass flow and the oxidative metabolism affect hepatic drug metabolism. Cytochrome P450 shows a clearance decrease of 20 25% in healthy elderly subjects with respect to younger subjects [51] and this may result in a decreased first-pass metabolism of drugs, such as anti-epileptics, the level of which greatly affects the metabolism of some chemotherapic agents (e.g. procarbazine and irinotecan). Renal drug excretion is altered in the presence of kidney function impairment and cardiopulmonary changes must be considered when planning surgery and the administration of drugs incurring cardiopulmonary toxicity. Stem cell reserve, which appears to be compromised in the aged, may be responsible for the relative increase in hematological toxicity found in this age group [52]. Chemotherapyinduced neutropenia also appears to be more common and associated with a higher risk of infectious complications, more hospitalizations and a higher mortality in the elderly [53,54]. The PCV regimen (procarbazine, CCNU and vincristine) has been administered in recurrent GBM patients with a progression free survival at 6 months of % and a survival rate at 1 year of %. However, these studies reported a common grade III IV hematological toxicity (25.6%), which makes this treatment unsuitable for elderly GBM patients. Data from 12 randomized clinical trials, analyzed in a recent meta-analysis [55], showed that adjuvant chemotherapy improves survival in patients with malignant glioma, although the average benefit (2 months) is modest. Twentyeight percent of the 3004 patients considered in this analysis were more than 60 years of age and, even when this age class was considered separately, the survival advantage following adjuvant chemotherapy maintained its statistical significance. Yet, the number of individuals 70 years, who should be regarded as truly elderly, is not specified in the analysis. A retrospective analysis performed on the MSKCC database [56] reported a significant survival advantage with adjuvant nitrosoureas only in patients aged 65 years or less. No survival benefit was detected in patients aged more than 65 years, although no firm conclusion could be drawn due to the paucity of long-term survivors in this age class. Thus, the role of adjuvant chemotherapy remains controversial in the elderly, whose glioma cells are less chemosensitive than those of younger patients both in vitro [57] and in vivo [58]. Although none of the studies performed in the elderly in recent years were randomized, a modest trend to improved survival is apparent in patients who receive chemotherapy after radiotherapy [47]. According to Pierga et al. [28], in patients given reduced-dose BCNU or PCV after RT, sur-

8 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) vival was two-fold that of patients treated with RT alone (13.5 months versus 6.3 months), but patients were selected to receive chemotherapy on the basis of their KPS, which was found to be the only significant and independent prognostic factor. Notwithstanding frequent dose reductions and a mean of only 2.5 cycles per patient, 33% of patients had grade 3 4 hematological toxicity. The PCV regimen should therefore probably be avoided in this age class. Gilbert et al. [59], who used a combination of BCNU (40 mg/m 2 /day for 3 days) and cisplatin (40 mg/m 2 /day for 3 days) combined with RT (60.2 Gy) and surgery (RS in 35%, biopsy in 65%), reported a median survival of 51.1 weeks in 17 patients with mean age of 71 years. The prognostic factors in the patients in this small series were more favorable than those in series reported by Chinot et al. [60] and Glantz et al. [61] and less favorable (median age, 71.6 years; performance status, 78.8 and only 35% of the patients underwent tumor resection) than those in the series reported by ourselves [47]. Toxicity was high, being G3 4 in 40 out of 47 cases (Table 2). Temozolomide (TMZ) is an alkylating drug with a safe clinical tolerability profile [47,62]. In most TMZ trials, less than 10% of patients have grade 3 4 hematological toxicity [63]. Moreover, no more than 2% of stable or responsive patients suspend chemotherapy due to toxicity, unlike the 80% of patients treated with PCV [64]. As TMZ causes only transitory myelosuppression and its clearance is not influenced by advanced age or liver and renal dysfunction, it appears to be well suited for elderly patients. We conducted a prospective, non-randomized trial on 79 elderly GBM patients (>65 years) with positive prognostic factors enrolled consecutively from 1993 to 2000 [65]. All patients had undergone gross tumor resection (residual disease 2 cm) and had a postoperative KPS status of 60. The first 24 patients received full dose radiotherapy (59.4 Gy/33 fractions), another 32 patients were treated with the same radiotherapy regimen plus adjuvant PCV and the remaining 22 patients received the same radiotherapy regimen followed by TMZ. Adjuvant chemotherapy was started 4 weeks after the end of radiotherapy and continued up to progression or unacceptable toxicity. The three groups were comparable for median age, median KPS, percentage of radical resection and burden of comorbidities. Patients in the TMZ group had a significant increase in survival (14.9 months) compared to those who underwent RT alone (11.2 months, p = 0.002) but not to PCV chemotherapy (12.7 months, p = 0.09). At multivariate analysis, only KPS > 70 maintained statistical significance for survival, TMZ chemotherapy being very close to the significance level (p = 0.058). More recently, a combination regimen with standard radiotherapy (60 Gy/30 F) plus concurrent and adjuvant temozolomide has become the standard treatment for GBM patients younger than 70 years, demonstrating a survival advantage over radiotherapy alone [66]. However, this combined treatment may not be the optimal approach for patients over70ofage[67]. Based on these results and on the demonstration of no differences in the survival of elderly GBM patients treated with a 40 Gy/15 versus a 60 Gy/30 dose of RT, the EORTC and NCI Canada are planning a randomized trial phase III study of temozolomide and radiation (40 Gy/15 F) versus radiation alone (40 Gy/15 F) in the treatment of newly diagnosed GBM in elderly patients. In the absence of results from randomized studies on elderly populations, the choice of first line treatment should be based upon patient age (65 70 versus versus >75), presence and type of co-morbidities and performance status. Up-front TMZ ( mg/m 2 for 5 days every 4 weeks) was administered soon after surgery or biopsy to elderly GBM patients by Chinot et al. [60], who reported a response in 31% of cases. Interestingly, in 50% of patients an increase in KPS was observed and in 52% of cases the daily steroid dose was reduced. The overall survival was only 6.5 months, but these patients already had a poor prognosis: 75% of them had undergone biopsy alone, 44% had a KPS of 60 and up to 63% presented cognitive deficits. Glantz et al. [61] recently reported their experience on 32 patients who received TMZ alone instead of brain irradiation, for a median of 3.5 cycles (range 1 12 cycles) and found that five patients (15.6%) had myelosuppression requiring a delay in the next cycle or a dose reduction in five patients. Their median survival was 6 months, which was slightly longer than that of a similar cohort of 54 patients treated with full dose radiotherapy alone (4.1 months), although the difference was not of statistical significance (p = 0.198). At multivariate analysis, only KPS > 50 was of prognostic significance (p < ). TMZ chemotherapy instead of brain RT should be evaluated, especially in patients at an increased risk of damage from radiotherapy (e.g. previous ischemic events, initial signs of dementia). This therapeutic strategy is under evaluation in two ongoing randomized trials. One, the Nordic study, a three-armed randomized trial, aims to compare conventional radiotherapy (60 Gy in 30 fractions) to short term radiotherapy (34 Gy in 10 fractions) or chemotherapy alone (Temozolomide 200 mg/m 2 for 5 days every 28 for 6 cycles) after surgery or biopsy. The other, a German randomized phase III study on a one week on/one week off schedule of temozolomide versus involved-field radiotherapy (54 60 Gy, 1,8 2 Gy fractions) in elderly (>65 years) patients with newly diagnosed anaplastic glioma and glioblastoma, aims to compare the efficacy and safety of standard radiotherapy with that of a novel schedule of temozolomide. The administration of TMZ chemotherapy instead of brain radiotherapy appears worthy of evaluation, especially in patients at an increased risk of radiotherapyinduced damage, such as those with previous ischemic events or with initial signs of dementia. However, in the absence of randomised studies, this strategy can not be regarded as an alternative to standard irradiation in patients with a good neurological status who have undergone extensive surgery. There are no data in literature on salvage treatment after recurrence in elderly GBM patients. Clearly treatment for recurrence should be evaluated on the basis of: patient age, performance status, concomitant disease, site of recurrence and the patient s preferences.

9 264 A.A. Brandes et al. / Critical Reviews in Oncology/Hematology 60 (2006) Conclusions Due to the lack of randomized trials, in clinical practice elderly patients are often managed according to the treating physician s anecdotal experiences or intuitive assumptions drawn from literature on glioma in adults rather than on appropriate sound scientific data from geriatric neurooncological trials. A multidimensional geriatric evaluation of the aged individual with cancer should help oncologists to predict tolerability to radio- and chemotherapeutic treatments, prompt them to tailor treatment to the single patient and assist patients in cooperation with all other specialists involved in the care of elderly patients. We believe that an a priori opinion that all elderly patients with GBM must be treated less aggressively than younger patients to limit costs and spare resources is not justified because a cancer treatment plan should not be modified on the basis of age alone. Treatment opportunities are just as important to otherwise fit elderly individuals as they are to all cancer patients. More properly, a multidisciplinary evaluation of prognostic factors such as KPS, neurological and cognitive functions, size of residual tumor and presence and severity of co-morbidities should determine whether each patient is fit for standard or adapted treatments or whether he should receive palliative therapy only. Moreover, it is important to stress to patients, families and physicians that, if selected appropriately, elderly cancer patients can benefit from treatments proposed in the context of clinical trials. New and more specific indicators able to balance the benefits against the side effects of different radiotherapy doses and chemotherapy regimens should be used as an endpoint in future trials in elderly populations, such as for example Quality Adjusted survival parameters [68]. Since these data are not currently available, particular priority should be given to safeguarding the patient s physical independence, an issue with a great social impact. Further randomized studies are required to determine the clinical benefit of aggressive therapy in the elderly patient population and to define standard treatment. Novel classes of agents currently under evaluation in patients with malignant gliomas include some EGFR inhibitors (ZD1839 and Erlotinib). As long they have a relevant anti-tumor activity, all these drugs appear potentially appropriate for elderly patients, in view of the high prevalence of EGFR over-expression, their more specific mechanisms of action, being more cytostatic rather than cytotoxic and, above all, their expected lower toxicity, which makes them ideal candidates for co-administration with TMZ. Reviewers Prof. Dr. Rolf-Dieter Kortmann, Department of Radiooncology, University of Leipzig, Stephanstr. 9, DE Leipzig, Germany. 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