Radiol Oncol 2018; 52(2): 167-172. doi: 10.2478/raon-2018-0010 167 research article Glioblastoma in patients over 70 years of age Uros Smrdel1, Marija Skoblar Vidmar1, Ales Smrdel2 1 Department of Radiotherapy, Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Faculty of Computer and Information Science, University of Ljubljana, Slovenia Radiol Oncol 2018; 52(2): 167-172. Received 11 November 2017 Accepted 18 November 2017 Correspondence to: Assist. Uroš Smrdel, M.D., Ph.D., Department of Radiotherapy, Institute of Oncology Ljubljana, Zaloška cesta 2, 1000 Ljubljana, Slovenia. Phone: +386 1 5879 504; Fax: +386 1 5879 400; Email: usmrdel@onko-i.si Disclosure: No potential conflicts of interest were disclosed. Background. Glioblastoma has in last 20 years seen the steady increase of incidence, which is most prominent in the group of older patients. These older than 70 years have significantly poorer prognosis than other patients and are considered a distinct group of glioblastoma patients. Modified prognostic factors are being used in these patients and this information is lately supplemented with the genetic and epigenetic information on tumour. The therapy is now often tailored accordingly. The aim of our study was to analyse the current treatment of the glioblastoma patients over 70 years of age to determine the impact of clinical prognostic factors. Patients and methods. Among patients treated at the Institute of Oncology Ljubljana between 1997 and 2015, we found that 207 were older than 70 years. We analysed their survival, clinical prognostic factors (age, performance status) treatment modalities (extent of surgery, radiation dose, chemotherapy). Results. Median survival of patients older than 70 years was 5.3 months which was statistically significant inferior to the survival of younger patients (p < 0.001). The clinical prognostic factors that influenced survival the most were performance status (p < 0.001), extent of surgical resection (p < 0.001), addition of temozolomide (p < 0.001) and ad- dition of radiotherapy (p = 0.006). Patients receiving concomitant radiochemotherapy with temozolomide followed by adjuvant temozolomide, had same median survival as patients receiving adjuvant temozolomide after completion of radiotherapy. Conclusions. The increase of the number of older patients with glioblastoma corresponds to the increase in the life expectancy but in Slovenia also to the increased availability of diagnostic procedures. Clinical prognostic markers are helpful in decision on the aggressiveness of treatment. Radiotherapy and temozolomide have the biggest impact on survival, but the radiotherapy dose seems to be of secondary importance. In selected patients, chemotherapy alone might be sufficient to achieve an optimal effect. Patients that were fitter, had more aggressive surgery, and received temozolomide fared the best. The scheduling of the temozolomide seems to have limited impact on survival as in our study, there was no difference weather patients received temozolomide concomitant with radiotherapy or after the radiotherapy. Thus far, our findings corroborate the usefulness of recursive partitioning analysis (RPA) classes in clinical decisions. Key words: glioblastoma; age group over 70 years; elderly; prognostic factors; treatment Introduction Glioblastoma is the most common primary brain tumour. And while it accounts in Slovenia only for around 1.5 % of all tumours, it is also responsible for 2.5 % of cancer related deaths. The incidence of glioblastoma is slowly increasing, but marked increase of the incidence in the older population; especially in the over 70 year of age has been not- ed.1-7 Unlikely many other tumours, the natural histo- ry of glioblastoma is also changing with the age of the patients. While prognosis in the patients under 50 is relatively favourable, with significant portion of the patients living past 2 years after the diagno- sis, quite opposite is true for those over 70. In this Radiol Oncol 2018; 52(2): 167-172. Smrdel U et al. / Glioblastoma in elderly168 group, the median survival is well under a year, and it has not changed significantly in recent times. Along with the improved knowledge of the molec- ular and genetic characteristic of the glioblastoma, which show that the majority of tumours in elderly belong to the so called primary glioblastoma sub- group, with the characteristic mutation profile, and short disease history. These tumours are character- ized on the genetic level by the mutation of EGFR, Rb2, and amplification of MDM2, gain in chromo- some 7 and LoH of chromosome 10.8-10 Patients with these tumours have short history between the onset of the first symptoms and the situation leading to the diagnosis. Quite often, for some time, the patient’s mental deterioration is be- ing assigned to other conditions and only quick de- terioration in the period of some weeks is the signal prompting the start of diagnostic process.11 The treatment of the elderly patients is in many aspects identical to the treatment of other glio- blastoma patients12, with the exemption, that since many of them are co-morbid and in poorer perfor- mance status as the younger ones, there is some reluctance in offering them all treatment modali- ties. Accordingly, fewer patients have gross total removal of the tumour, and fewer are receiving chemotherapy. Nevertheless, they are not a single homogeneous group. Though age is being recog- nized as a single most important factor in survival of glioblastoma patients, the glioblastoma peak in- cidence in the 6th decade of life, lead for a consider- able time to neglect regarding the influence of the patients age in the oldest category. So Radiation Therapy Oncology Group (RTOG) has introduced the most widely used classification of glioblastoma patients using the already recognized clinical pa- rameters, dividing them into groups based on age under or over 50, performance status, surgery, ra- diotherapy dose level and mental status.13,14 This, so called recursive partitioning analysis (RPA) classification has proved to be a useful tool in pre- dicting prognosis of the patients and also a tool to help clinician deciding upon the treatment of- fered to the patient. This classification though has a major drawback, not differentiating the patients in the oldest age group. Therefore RPA analysis regarding only patients over 70 has been made. It has proved that these patients also fall into four distinct groups regarding survival.14 In this anal- ysis, the main focus has been given to the extent of resection, dividing the patients on the basis of surgical resection versus the biopsy into two dis- tinct groups. The group where reception has been performed has been divided further on the basis of the patients’ age (1 < 75.5; 2 >75.5) and the bi- opsy group regarding the performance status (3 ≥ Karnofskyperformance status [KPS] 70; 4 < KPS 70). The patient, which had a resection and were younger than 75.5 years, don’t fare worse than the patients in group 5 of RTOG RPA analysis, but oth- er fare worse, especially those biopsied and in poor performance status. As the incidence of the glioblastoma in elderly has risen, the interest in these patients has grown and two large studies, NOA 08 in Germany and Nordic in Scandinavia, had shown that there is a chance, that the same effect on survival might be achieved with less aggressive approach.15,16 The re- sults of these studies had proven that in elderly, the same survival benefit might be achieved solely with the chemotherapy using temozolomide. The effect of temozolomide is primarily marked in pa- tients, which have methylated methylguaninem- ethyltransferase (MGMT) promoter region, thus disabling the tumour cells to repair the alkylation of tumour DNA. In Slovenia, we are also noting the increase of the number of elderly glioblastoma patients.5,6 Our strategy so far has been to assign patients either to radical treatment with radiochemotherapy with adjuvant temozolomide, palliative radiotherapy or supportive care. Since the methylation status in patients over 70, is now routinely determined, and the patients are now being offered treatment also on the basis of it, we have analysed our results of the past years, with the aim of obtaining our popu- lation data, so that it could serve as a benchmark for assessment of the further treatment strategies in this group of patients. Patients and methods Between the 1997 and the end of 2015, 1019 pa- tients, diagnosed with glioblastoma have been re- ferred to the Institute of Oncology Ljubljana. They represent the majority of the patients who were di- agnosed with the glioblastoma in Slovenia in this time period. The only exceptions are the patients that have died or were not fit enough for referral. Among these patients, we have searched for those, which were older than 70 years at the time of diagnosis. For these, we calculated their survival, compared it to the survival of the younger patients and then made the analysis of the survival and pa- tients and treatment relating factors. We also deter- mined RPA classes for those older than 70 accord- ing to classes described by Scott et al.14 Radiol Oncol 2018; 52(2): 167-172. Smrdel U et al. / Glioblastoma in elderly 169 For the statistical analysis we used SPSS soft- ware package. We calculated demographic charac- teristics, frequencies of patients in the correspond- ing RPA groups, changes of frequencies during the analysed period and the frequencies of treatment characteristics. We used Kaplan-Maier analysis and Cox regression for survival analysis. We also performed a multivariate analysis using R. The sig- nificance level was at 0.05 for all statistics. Ethical considerations The study is retrospective analysis. It is a spinoff of an earlier analysis, which was approved by the Commission for Medical Ethics of the Republic of Slovenia. Results The median age of 1019 patients, treated for glio- blastoma at the Institute of the Oncology Ljubljana between 1997 and 2015, was 60 years (standard de- viation [SD] 11.8 years; min. 18 years, max. 86 years) (Table 1). Their overall survival was 10 months (SD 0.4 months). Of these patients, 207 were older than 70 years, and their median survival was 5.3 months TABLE 1. Patients’ and treatment characteristics Age (median) (SD) 73 years 3.7 years Gender Female Male 99 (47.8%) 108 (52.2%) Surgery No Biopsy 5 (2.5%) 69 (33.3%) Reduction 96 (46.4%) Gross total resection 37 (17.9%) Performance status WHO 0 3 (1.5%) I 53 (25.6%) II 65 (31.4%) III 70 (33.8%) IV 16 (7.7%) Radiotherapy 158 (76.3%) > 50 Gy 57 (27.5%) 40–50 Gy 33 (15.9%) ≤ 40 Gy 68 (32.8%) Temozolomide 62 (30.0%) SD = standard deviation FIGURE 1. Survival of patients with glioblastoma according to the age below and over 70). FIGURE 2. The number of patients older than 70 from 1997 to 2015). Radiol Oncol 2018; 52(2): 167-172. Smrdel U et al. / Glioblastoma in elderly170 (SD 0.4 months). When comparing the groups of the patients younger than 70 with those older, the difference in median survival between groups was statistically significant at p < 0.001, with median survival of those younger than 70 years 12 months (SD 0.5 months) (Figure 1). The number of patients older than 70 has in- creased over the observed years (Figure 2). The percent has risen from less than 10% in 1997 to more than 20% since the middle of 2000s. Of the 207 patients older than 70 years, 99 were females and 108 males (1 : 1.1). The majority of whom had a surgical resection (69 gross total re- sections and 96 reductions), while less had biopsy only. For 5 patients, multidisciplinary team (MDT) decided, that any kind of surgical intervention would be too risky, so the diagnosis was decided upon radiological criteria. Except for this group, in which patients were somewhat older, the groups were identical regarding age and performance sta- tus. The usual treatment following surgery was ra- diotherapy, 158 (76.3%) of patients were irradiated. Of those, who were not, majority were in poor per- formance status (WHO 3 and 4), some refused any further treatment and couple of them deteriorated rapidly. Only 2 of them received chemotherapy with temozolomide instead of radiotherapy. Of the 207 patients, 67 were deemed suitable for “radical” treatment, and they proceeded with con- ventional radiochemotherapy 60 Gy in 30 fractions in 6 weeks with concomitant temozolomide, fol- lowed by adjuvant temozolomide. Others received either radiotherapy alone, radiotherapy followed by temozolomide, lower dose radiotherapy (45 Gy) with temozolomide or supportive care. While overall survival for the group was 5 months, the median survival of those treated with radical intent was significantly higher (9.6 months, SD 1.5; p < 0.001) (Figure 3). Also, the patients in good performance status fared better, from 8 months for the patients in WHO performance status 1 to 1.5 months for pa- tients in performance status of 4 (p < 0.001). Extent of surgical resection also proved to have a significant impact on survival. When neurosur- geon described a gross total resection, median sur- vival was 7.1 months, in reduction 5.2 and in pa- tients with the biopsy only 2.8 months (p < 0.001). While patients over 70 fare worse than younger, the age does not seem to have such an impact in this group. RPA classes were calculated, based on age, per- formance status and extent of surgical resection. FIGURE 3. Survival of glioblastoma patients older than 70 according to intent of treatment. FIGURE 4. Survival of glioblastoma patients older than 70 according to prognostic recursive partitioning analysis (RPA) classes. Radiol Oncol 2018; 52(2): 167-172. Smrdel U et al. / Glioblastoma in elderly 171 The survival was as predicted best in those with re- section and younger than 75.5 years and worst for patients with biopsy in poor performance status (p < 0.001) (Figure 4). We also looked in the impact treatment modali- ties have on survival. Patients receiving radiother- apy had a better survival, 6.1 months with radio- therapy and 3 months without (p = 0.006). And so is true for the addition of temozolomide with 10.4 months with the temozolomide and 3.8 without (p < 0.001). However, it seems, that concomitant temozolomide is no better than other schedules, as the survival remains the same, (10.3 and 10.6 months respectively, p = 0.64) in patients receiving concomitant temozolomide followed by adjuvant and adjuvant only. In multivariate analysis, the significant impact on survival is retained by extent of operation (p < 0.001, HR 1.5 for biopsy), performance status (p < 0.006, hazard ratio [HR] 1.2 for WHO performance status > 1), and temozolomide (p < 0.001 HR 0.6 for temozolomide). Discussion In the last decade, we are observing a surge in the number of glioblastomas in the elderly population. This is being observed worldwide, and we demon- strated it for Slovenia. In our analysis, the rise is seemingly greater than in other reports. The rise is surely coming from the fact that the lifespan has extended considerably from the old threescore and ten. In Slovenia in the observed period, the life ex- pectancy was 74.6 years in 1997, but in the 2015 it was 81.1 years.17 The other thing, we can assume could be responsible for the increase we are observ- ing is the availability of diagnostic procedures for instance according to Organisation for Economic Cooperation and Development (OECD) data, the number of CT scanners in Slovenia has risen from 18 in 2004 to 28 in 2016, and this can be seen also in the number of MRI scanners (2004–2010; 2016– 2017)18, thus diagnosis has become much more af- fordable. Admittedly, the direct proof of the later is lacking, but it is a plausible hypothesis. In the analysis, we have shown that the median survival is worse for the elderly patients. But the therapeutic nihilism is ill warranted19, as with the appropriate treatment we can at least approach the median survival of some patients to the median survival of those in more favourable groups. The impact of good surgery in elderly is marked20, so it is the impact of radiotherapy and chemothera- py, the key is probably to tailor the postoperative therapy to individual patients. After surgery, all patients deserve a good radiotherapy if they are fit to receive it; more questionable is this approach in those which were only biopsied, or even had a diagnosis of malignant glioma established only by radiology. But even in those, some kind of pallia- tive radiotherapy might result in better symptom control.21 Data, which has been published has shown, that there has been no significant detri- mental effect of radiotherapy on cognitive status22, but the tests used have only limited sensitivity for more subtle changes. In the period we are describ- ing, routine MGMT methylation testing haven’t been performed in Slovenia23, so the impact of alkylating agents is harder to determine, but the inclusion of temozolomide in treatment schedule, has resulted in improved median survival even in unknown methylation status. Interesting find was that the patients receiving concomitant chemoradiotherapy and adjuvant chemotherapy had identical survival to those re- ceiving radiotherapy followed by adjuvant temo- zolomide. This may be due to the fact, that more fragile patients haven’t been exposed to such ag- gressive treatment, which might produce detri- mental effect, but had benefited from systemic therapy as the performance improved. Of course, with the routine MGMT methylation assessment, with which we have started in 2016, group benefit- ing the most from temozolomide might be singled out, so we will not be giving the potentially non effective therapy to frail, while we will be able to avoid radiotherapy in those, where chemotherapy alone would suffice for the best palliative effect. Conclusions Glioblastoma is becoming ever more important problem in the population of patients aged over 70 years. While we are not able to cure these pa- tients, we are able at least in the portion of them to prolong the survival and ameliorate the symp- toms. The means we have at disposal towards this goal are essentially the same as the means we are utilising in the younger patients, the poorer perfor- mance status, arising not only due to the tumour related factors, but also due to the patients’ co- morbidity in elderly patients is forcing us to use them right. Up until now, the clinical prognostic factors have been our sole tool, with which we have accomplished our goals with a measure of success. The epigenetic and possibly even genetic Radiol Oncol 2018; 52(2): 167-172. Smrdel U et al. / Glioblastoma in elderly172 markers will hopefully improve our decision mak- ing capabilities and maybe improve the lot of some of these patients. References 1. Cancer Research UK. Brain cancer (C71): 2010-2011. One-, five- and ten- year net survival (%), adults aged 15-99, England & Wales. [cited 2017 Avg 15]. Available at: http://info.cancerresearchuk.org/cancerstats/faqs/#How. 2. Arora RS, Alston RD, Eden TO, Estlin EJ, Moran A, Geraci M, et al. Are re- ported increases in incidence of primary CNS tumours real? An analysis of longitudinal trends in England, 1979–2003. Eur J Cancer 2010; 46: 1607-16. doi: 10.1016/j.ejca.2010.02.007 3. Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 2012; 14(Suppl 5): v1–49. doi: 10.1093/ neuonc/nos218 4. Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, et al. CBTRUS statistical report: primary brain and central nervous aystem tumors diagnosed in the United States in 2008-2012. Neuro Oncol 2015; 17(Suppl 4): iv1-62. doi: 10.1093/neuonc/nov189 5. Cancer incidence in Slovenia 1997-2006. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2000-2009. 6. Cancer in Slovenia 2007-11. Ljubljana: Institute of Oncology Ljubljana, Epidemiology and Cancer Registry, Cancer Registry of Republic of Slovenia; 2010-2014. 7. Smrdel U, Kovac V, Popovic M, Zwitter M. Glioblastoma patients in Slovenia from 1997 to 2008. Radiol Oncol 2014; 48: 72-9. doi: 10.2478/ raon-2014-0002 8. Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre P-L, et al. Genetic pathways to glioblastoma: a population-based study. Cancer Res 2004; 64: 6892-9. doi: 10.1158/0008-5472.CAN-04-1337 9. Steinfeld AD, Donahue B, Walker I. Delay in the diagnosis of glioblastoma multiforme: is age a factor? Cancer Invest 1996; 14: 317-9. 10. Crespo I, Vital AL, Gonzalez-Tablas M, Patino M del C, Otero A, Lopes MC, et al. Molecular and genomic alterations in glioblastoma multiforme. Am J Pathol 2015; 185: 1820-33. doi: 10.1016/j.ajpath.2015.02.023 11. De Groot JF, Aldape KD CH. High-grade astrocytomas. In: Schiff D, On B, edi- tors. Principles of neuro-oncology. New York: McGraw Hill; 2005. p. 259-88. 12. Biau J, Dalloz P, Durando X, Hager MO, Ouédraogo ZG, Khalil T, et al. [Elderly patients with glioblastoma: state of the art].[French]. Bull Cancer2015; 102: 277-86. doi: 10.1016/j.bulcan.2015.02.002 13. Li J, Wang M, Won M, Shaw EG, Coughlin C, Curran WJ, et al. Validation and simplification of the Radiation Therapy Oncology Group recursive partition- ing analysis classification for glioblastoma. Int J Radiat Oncol Biol Phys 2011; 81: 623-30. doi: 10.1016/j.ijrobp.2010.06.012 14. Scott JG, Bauchet L, Fraum TJ, Nayak L, Cooper AR, Chao ST, et al. Recursive partitioning analysis of prognostic factors for glioblastoma patients aged 70 years or older. Cancer 2012; 118: 5595-600. doi: 10.1002/cncr.27570 15. Arvold ND, Reardon DA. Treatment options and outcomes for glioblastoma in the elderly patient. Clin Interv Aging 2014; 9: 357-67. doi: 10.2147/CIA. S44259 16. Lönn S, Klaeboe L, Hall P, Mathiesen T, Auvinen A, Christensen HC, et al. Incidence trends of adult primary intracerebral tumors in four Nordic coun- tries. Int J Cancer 2004; 108: 450-5. doi: 10.1002/ijc.11578 17. Statistical Office, Republic of Slovenia. Births and deaths. [Internet]. [cited 2017 Nov 19]. Available at: http://www.stat.si/StatWeb/Field/Index/17/95 18. OECDiLibrary. Health at a glance 2017. [Internet]. OECD Publishing; 2017 [cited 2017 Nov 19]. Available at: http://www.oecd-ilibrary.org/social- issues-migration-health/health-at-a-glance-2017_health_glance-2017-en 19. Fiorentino A, De Bonis P, Chiesa S, Balducci M, Fusco V. Elderly patients with glioblastoma: the treatment challenge. Expert Rev Neurother 2013; 13: 1099-105. doi: 10.1586/14737175.2013.840419 20. Reardon D, Arvold N. Treatment options and outcomes for glioblastoma in the elderly patient. Clin Interv Aging 2014; 9: 357-67. doi: 10.2147/CIA. S44259 21. Zouaoui S, Darlix A, Fabbro-Peray P, Mathieu-Daudé H, Rigau V, Fabro M, et al. Oncological patterns of care and outcomes for 265 elderly patients with newly diagnosed glioblastoma in France. Neurosurg Rev 2014; 3: 415-23. doi: 10.1007/s10143-014-0528-8 22. Keime-Guibert F, Chinot O, Taillandier L, Cartalat-Carel S, Frenay M, Kantor G, et al. Radiotherapy for glioblastoma in the elderly. N Eng J Med 2007; 356: 1527-35. doi: 10.1056/NEJMoa065901 23. Smrdel U, Popovic M, Zwitter M, Bostjancic E, Zupan A, Kovac V, et al. Long- term survival in glioblastoma: methyl guanine methyl transferase (MGMT) promoter methylation as independent favourable prognostic factor. Radiol Oncol 2016; 50: 394-401. doi: 10.1515/raon-2015-0041