|Ahead of print
Factors affecting survival in glioblastoma patients below and above 65 years of age: A retrospective observational study
Berrin B Yavuz, Gul Kanyilmaz, Meryem Aktan
Department of Radiation Oncology, Meram Medical School, Necmettin Erbakan University, Konya, Turkey
|Date of Submission||09-Jan-2019|
|Date of Decision||18-Mar-2019|
|Date of Acceptance||03-Apr-2019|
Berrin B Yavuz,
Department of Radiation Oncology, Meram Medical School, Necmettin Erbakan University, Konya
Source of Support: None, Conflict of Interest: None
Background: The purpose of this study is to identify the differences with respect to survival and prognostic factors in a comparison between radiotherapy-receiving glioblastoma (GBM) patients above and below 65 years of age.
Methods: The results of 157 patients with GBM were analyzed retrospectively. Patients were divided into two groups as those below and above 65 years of age. A comparison was drawn with respect to each group's demographic characteristics, treatment methods, and findings.
Results: Out of a total of 157 patients, 53 patients (33.8%) were above 65 years of age. Karnofsky performance status (KPS) was weaker among older patients (P = 0.002). On the other hand, with respect to radiotherapy dose, among older patient group, greater hypofractionation and whole-brain radiotherapy was applied (P = 0.003) compared with younger patients. The survival rates for 1, 2, and 5 years among patients aged <65 years were 63%, 30%, and 3%, respectively, and in patients aged ≥65 years were 43%, 13%, and 0%, respectively. In univariate analyses, a comparison between patients below and above 65 years of age revealed that values higher than 80 KPS (P = 0.002), applying total excision (P < 0.001), receiving concurrent chemotherapy (P = 0.004), receiving conventional radiotherapy (P < 0.001), and adjuvant chemotherapy (P < 0.001) were effective factors on overall survival rates.
Conclusion: In the patient group above 65 years of age, the patient should be attentively selected before opting for a specific treatment, age alone should not be the sole determinant factor. Rather, by considering the KPS scores, potential aggressive treatment options should also be applied.
Keywords: Glioblastoma, older patient, radiotherapy, survival
Key Message: 1. The frequency of glioblastoma increases with age. Understanding treatment standards and prognostic factors is critical in this specific age group
2. Treatment standards for older patients are not definite. Still, before deciding to apply aggressive treatments on older patients too, it is suggested to make the decision not only by considering the patient′s age but also by taking into account his/her performance status and comorbidities.
|How to cite this URL:|
Yavuz BB, Kanyilmaz G, Aktan M. Factors affecting survival in glioblastoma patients below and above 65 years of age: A retrospective observational study. Indian J Cancer [Epub ahead of print] [cited 2020 Oct 30]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=297021
| » Introduction|| |
Glioblastomas (GBMs) are the most pervasive brain tumors among adults. They constitute 14.9% of all brain tumors and 47.1% of all malignant central nervous system tumors. Although they can also be observed among the pediatric population, incidence frequency rises along with age. Conducted studies state that age is the most salient prognostic factor. It is projected that in line with the climb in the older population worldwide, the total number of older GBM patients will also escalate. In a majority of studies, patients above 70 years of age were either excluded from the research or could not receive adequate treatment due to their age. Thus, it is critical to understand treatment standards and prognostic factors in this specific age group.
Among patients with GBM, survival rates are drastically low. Fewer than 5% of patients can survive for a period of 5 years, and when compared with younger ones, survival length is even shorter among older patients. According to analyses of the Central Brain Tumor Registry of the United States (CBTRUS), the 1-year survival rate among patients in 55-64 years of age is 46.1%, 65-74 years is 29.3%, and in patients above 75 years of age is 12.2%; whereas the five-year survival rates are 4.6%, 2.4%, and 1% respectively.
Currently, the standard treatment applied to GBMs involves a maximally-safe resection, concurrent radiotherapy (RT), and temozolomide treatment followed by adjuvant temozolomide. In the study by Stupp et al., RT and in addition to RT, concurrent and adjuvant temozolomide were applied. A comparison between groups showed that combined practice offered a survival advantage. In 2 years, the overall survival rate (OS) was measured as 10.9% against 27.2%. Median survival was measured as 14.6 months. Although the treatment offered subsequently to this study was standard care among GBMs, the patient group above 70 years of age were not included in this study. Keime-Gubert et al. compared the effects of supportive care and radiotherapy in a patient group above 70 years of age. In the group receiving RT, survival rate was 29.1 weeks. In the group that received supportive care, survival rate was 16.9 weeks. Although the treatment offered an advantage in survival rate, there was no decrease in quality of life either. Relevant studies also indicated that applying aggressive treatments helped to elevate the overall survival length of older patients.
Treatment standards for older patients are not definite. Still, before deciding to apply aggressive treatments on older patients too, it is suggested to make the decision not only by considering the patient's age but also by taking into account his/her performance status and comorbidities. Thus, the purpose of this study is to determine the findings of treatment and effective factors on survival rates by drawing a comparison between GBM patients above and below 65 years of age.
| » Materials and Methods|| |
We retrospectively reviewed the medical records of patients diagnosed with GBM and who received RT in our clinic between January 2010 and December 2017. Eight out of 169 patients were discharged since they had no pathologic diagnosis and four patients were excluded since they were below 18 years of age. A total of 157 patients were analyzed. Patients were categorized into two groups those below and above 65 years of age. The median length of the follow-up period was 12.4 (range 1.25 - 61.90) months. Prior to initiating the research, approval of Ethical Board was endorsed. Clinical data were collected from medical records of patients as follows: 1. Patients characteristics (age, sex, Karnofsky performance status (KPS) scores); 2. Treatment characteristics (type and extent of surgery, radiotherapy, radiotherapy dose and schemes, adjuvant and concurrent chemotherapy); 3. Treatment toxicities; 4. Follow-up data.
In this study, older age refers to patients aged 65 years and above. This cutoff value was determined on the basis of the subgroup analyses by Stupp who revealed that among patients younger than 65 years of age, median survival tended to escalate. The KPS scores range from 0 to 100; a higher score means a patient is better able to carry out daily activities. Patients with KPS value of 80 or higher are able to carry out normal activity and do not need special care. Therefore, patients were divided into two groups: KPS value of 80 and above, and KPS value below 80. The KPS value was marked as the recorded performance score of the patients when they first applied to receive RT. Measurable side effects among patients were graded through The Radiation Therapy Oncology Group (RTOG)-Acute Radiation Morbidity Scoring Criteria.
In conventional RT, a 50 Gy and higher dose is applied in a fraction size of 1.8-2.0 Gy. In hypofractionation and whole-brain radiotherapy, it was 30-42.5 Gy RT in 10-16 fraction. RT started within 6 weeks after the operation. Before RT, magnetic resonance imaging (MR) was administered to all patients. In supine position, simulation was performed using a computer tomography (CT) simulator. To ensure stabilization, a suitable thermoplastic mask was applied to all patients. CT was imaged through sections of 3-5 mm. Through CT images, pre-operative and post-operative MR images were fused. On the MR, gross tumor volume (GTV) was identified as contrasting volume. By applying 1.5-2 cm onto this volume, clinical target volume (CTV) was formed and contours were restricted with anatomical structures. By adding 0.5 cm of margin to CTV, the planning tumor volume (PTV) was shaped.
The plan was to administer 3-dimensional conformal radiotherapy on patients receiving whole-brain RT. For patients receiving hypofractionation and conventional treatment, it was projected to apply intensity modulated radiation therapy (IMRT) technique. As regards the type of post-operative treatment that patients would receive, the clinician would make a decision based on performance status of the respective patient. All patients were treated with the Eclipse Treatment Planning System (Varian Medical Systems Inc., Palo Alto, CA).
In the application of concurrent temozolomide, the dose was 75 mg/m2/day. Throughout RT process, it was administered 7 days in a row. As the adjuvant treatment after RT, a dose of 150-200 mg/m2/day was administered 1-5 times daily for a period of every 28 days. In the daily application of temozolomide, the rates were 6-12 doses or application continued until some radiological progression could be detected.
During the treatment process, through applying complete blood count, biochemistry tests and physical examination once a week became viable to analyze any given potential side effects and the overall health condition of the patient. Potential side effects were then registered. After RT, the patient was followed up through a clinical examination and MR once in every 3 months.
The first endpoint of this research was to determine the survival rates among age groups in patients who underwent radiotherapy with a diagnosis of GBM in our clinic. The second primary endpoint of this study was to evaluate prognostic factors in patients with GBM.
Descriptive statistics was harnessed to identify characteristics of the patient and the treatment, to unveil findings of the treatment, and to compute any incidences of toxicity. Mean, median, proportional values, and standard deviations were respectively measured. OS was used to indicate the length between time of diagnosis and time of death or final checkup. Chi-square test was carried out to compare the categorical variables. Kaplan-Meier analysis was performed to estimate survival analysis. In univariate analysis, survival curves of subgroups were compared with the two-sided long-rank analysis. Cox proportional regression analysis was performed for prediction of 95% confidence intervals and hazard ratios. All the variables with statistical significance (P < 0.05) in univariate analysis were added as covariates in multivariate analysis. Version 13.0 of Statistical Package for Social Sciences Software (SPSS Inc.; Chicago, IL, USA) was utilized in the whole statistical analysis.
| » Results|| |
Characteristics of the patient group and the treatment
Out of a total of 157 patients, 53 (33.8%) patients were aged 65 years and above. In the patient group below 65 years of age, male patients constituted a rate of 65.4%, while the male population was 69.8% in patient group aged 65 years and above. [Table 1] shows a comparison of the characteristics of the patient and the treatment with respect to age group during the diagnosis stage. KPS was comparatively lower among older patients (P = 0.002). As the characteristics of treatment applied to both groups were analyzed, it became feasible to apply high concurrent CT doses to two patient groups (P = 0.365). Still, with respect to RT dose, higher levels of hypofractionation and whole-brain RT were administered to older patient group compared with the younger group (P = 0.003). 9.4% of older patients failed to complete the treatment while all of the younger patients could reach the end of the treatment (P = 0.004). In terms of acute toxicity, grade 3-4 toxicity was measured in 2.6% level. There was no statistically significant difference in toxicity with respect to age groups.
|Table 1: Characteristics of the patient and treatment with respect to age group|
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Survival analysis and findings
Median survival was 16.92 months in the group below 65 years of age and 9.65 months in older age group. The survival rates for 1, 2, and 5 years among patients aged <65 years were 63%, 30%, and 3%, respectively, and in patients aged ≥65 years were 43%, 13%, and 0%, retrospectively [Figure 1]. In univariate analyses, the comparison between patient groups below and above 65 years of age revealed that a KPS value higher than 80 (P = 0.002), applying total excision (P < 0.001), receiving concurrent chemotherapy (P = 0.004), receiving conventional RT (P < 0.001), and adjuvant chemotherapy (P < 0.001) were effective factors on the OS.
|Figure 1: (a) Overall survival curves for patient groups < 65 years of age. (b) Overall survival curves for patient groups ≥ 65 years of age|
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The findings of the multivariate analysis are exhibited in [Table 2]. As shown in the analysis, applying total excision, performance status, and administering adjuvant CT were effective factors on the OS of all patient groups. Among younger patients, receiving adjuvant CT and total excision were vital OS predictors but in older patients receiving adjuvant CT and conventional RT were the criteria for OS.
|Table 2: Findings of multivariate analysis for overall survival rates with respect to age groups|
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| » Discussion|| |
GBMs are the most pervasive malignant brain tumors and irrespective of the advancements in modern medical treatments, survival rates are still dramatically low. There is an evident parallelism between age climb and frequency of lower survival rates. Although exact causes of this incidence among older patients are not certain, a higher number of comorbidities, fewer functional reserves, and a more aggressive tumor biology among older people are recognized as the potential reasons for the lower survival rates.,
Age is the most common prognostic factor in GBMs.,,, As age increases, prognosis becomes worse. Morgan et al. made a comparison between groups below and above 65 years of age and determined that among older patients, survival is significantly lower than the younger patients (7.2 months vs. 11.2 months). Although in young patients there is a definite standard care, treatment has not yet been clarified for older patients. In a randomized 3-phase study organized by European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC), standard treatment was defined as a maximally-safe resection and adjuvant CT followed up by temozolomide and concurrent RT. However, the patient group above 70 years of age was not included in their study. In this study that compared single RT and concurrent chemoradiotherapy + adjuvant temozolomide application, the two years OS rate was measured as 27.2% in a combined practice while the rate was 10.9% in single RT (P < 0.001). Although in all subgroups concomitant CT provided a survival advantage, this advantage was comparatively smaller in 65-70 age group. In both groups alike, acute toxicity was acceptable. On the other hand, in the study by ANOCEF, a comparison was drawn in 70 years old and older patients with respect to RT and standard care. During 21-week median follow-up, survival in RT branch was measured as 29.1 weeks while in standard-care group, it was measured as 16.9 weeks (P = 0.002). No decrease was observed in RT-dependent cognitive functions and quality of life. In this study that applied 50 Gy RT as well, 15% of the patients tended to quit the treatment. Roa et al., on the other hand, reported to discontinue the treatment among 26% of patients in 30 fraction of 60 Gy dose. In our study, however, there was no tendency to discontinue in patients below 65 years, whereas 9.4% of patients above 65 years of age failed to complete the treatment. In NOA-08(phase 3, randomized) study, patients aged 65 years and above with a malignant glioma were analyzed and a comparison was made between temozolomide and RT. In this study, temozolomide was applied as dose-dense temozolomide (100 mg/m2/day, 1 week on, 1 week off) and RT was administered as 1.8-2 Gy/fraction dose in 60 Gy. Although there is no statistically significant difference between both groups in terms of survival advantage, there was still a stronger advantage in the group that received temozolomide and O-6 methylguanine DNA methyltransferase (MGMT) methylated.
Performance status is one of the most important prognostic factors for survival in GBM patients. Kumar et al. demonstrated that the pre-treatment performance status is an independent prognostic factors. The median survival was 6.3 months and 7.97 months in patients with KPS <70 and KPS >70, retrospectively. In our study, KPS <80 was found to have a negative effect on prognosis.
The very first treatment in GBMs is a surgical operation. This operation aims to extend the survival rate, create new tissues for histopathological and molecular analysis, protect neurological functions, and diminish the need for steroid. To perform a maximally-safe resection, chronological age alone should not be viewed as a contraindication. It is suggested to perform a maximally-safe resection in patients having good performance levels.,, Almanaver in his metaanalysis examined resection width of patients older than 60 years of age and detected that compared with biopsy and subtotal resection, resection alone was more effective in increasing the OS (P < 0.001). In parallel with the increase in the width of resection, there was an improvement in survival rates, tumor recurrence rates, and functional healing. These advantages prevent high mortality and morbidity rates. In a different study that examined 103 patients above 65 years of age, the analysis focused on patients that received single operation, operation + RT, and operation + RT + CT and survival rates were recorded as 1.8 months, 4.4 months, and 15 months (P = 0.000), respectively. It was reported that older patients benefited from maximal treatment procedures and treatment options were clearly determined by performance and age factors. In a study that included 207 patients at the age of 70 and above, an analysis of operation resection revealed that OS rate was 7.1 months for gross total resection (GTR); it was 5.2 months for reduction and it was 2.8 months for biopsy (P < 0.001). Although there was an improved survival among patients on RT care, there was not an increased survival rate in patients receiving concurrent temozolomide. In a prospective PERNO study by Franceschi et al, a comparison was made between RT and chemoradiotherapy. Survival rates were measured as 11.6 months versus 9.3 months (P = 0.164). Age and width of resection were identified as vital prognostic factors. In our study, in the group that received total and subtotal/biopsy, the survival rate in the group below 65 years of age was 29.07 months and 13.79 months, respectively, but it was 13.89 months and 7.39 months in the patient group above 65 years of age (P < 0.001).
Among gliomas, RT is the basic main post-operative treatment but there is no consensus on the RT doses and schemes to apply to older patients. Hence, in a myriad of studies, comprehensive analyses were conducted on the use of hypofractionation RT and conventional RT, hypofractionation RT, and concurrent CT application. By applying hypofractionation RT, there was some decrease in the length of treatment and hospitalization. Comparison between older patients receiving whole-brain or conventional RT revealed that there was an improved OS by hypofractionation RT, whereas no increase was measured in toxicity. Likewise, in NORDIC research, patients aged 60 years and above were analyzed. Those patients were randomized with respect to temozolomide, standard 6-week RT, and hypofractionation RT branches. Survival rates were similar (8.4 months vs. 7.4 months) in temozolomide and hypofractionation RT groups. In patient at the age of 70 years and above, survival rates were higher than the conventional treatment in temozolomide and hypofractionation RT group. In this study, more positive findings were detected among patients using temozolomide MGMT methyl groups but among patients treated with RT, there was no difference detected whether or not MGMT methyl was applied. Perry et al. in their research included that patients aged 65 years and above compared hypofractionation RT and concurrent and adjuvant temozolomide with RT alone. In the combined branch, OS rate was longer (9.3 months vs. 7.6 months; P < 0.001). In each group, quality of life was identical and in older patients it was observed that hypofractionation RT was an appropriate treatment option. On the other hand, in our study, a comparison between patients below and above 65 years of age indicated that there was a positive effect on OS, particularly when receiving conventional RT (P < 0.001). In the same vein, in the first study that compared hypofractionation RT and conventional RT for the patients above age 65, when applied singly hypofractionation RT was associated with lower OS. Among older GBMs, the comorbidities among those receiving hypofractionation RT worsened, lower CT or decreased resection was identified, and survival rates lowered when hypofractionation RT was present (4.9 months vs. 8.9 months; P < 0.001).
In this research, KPS was lower among patients aged 65 years and above and compared with younger patients a higher hypofractionation RT and whole-brain RT were applied. The width of excision, performance status, receiving concurrent and adjuvant CT, and applying conventional RT were determined to be effective factors on OS. The most evident limitation of our research is that it was a retrospective study and lacked exact knowledge of the MGMT methylation state since during that period, it was not feasible to regularly work in the center.
| » Conclusion|| |
It is suggested that further studies be conducted to optimize treatment options for older patients. In a patient group above 65 years of age, the patient should be attentively selected before opting for a specific treatment; age alone should not be the sole determining factor. Instead, optional aggressive treatments could be applied after measuring the performance status of the patient. Applying conventional RT concomitant with concurrent and adjuvant chemotherapy in older GBM patients would elevate survival rates after performing a maximally-safe resection.
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Conflicts of interest
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[Table 1], [Table 2]