|Year : 2017 | Volume
| Issue : 1 | Page : 362-367
Survival and prognostic factors for glioblastoma multiforme: Retrospective single-institutional study
M Ghosh, S Shubham, K Mandal, V Trivedi, R Chauhan, S Naseera
Department of Radiation Oncology, Mahavir Cancer Sansthan, Patna, Bihar, India
|Date of Web Publication||1-Dec-2017|
Dr. K Mandal
Department of Radiation Oncology, Mahavir Cancer Sansthan, Patna, Bihar
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults. The standard management has been maximum surgical resection followed by adjuvant radiotherapy with concurrent chemotherapy followed by adjuvant chemotherapy. Although the survival rate of patients with GBM has improved with recent advancements in treatment, the prognosis remains generally poor. The median survival rates are in the range of 9–12 months and 2-year survival rates are in the range of 8%–12%. MATERIALS AND METHODS: A single-institution retrospective review of 61 patients of GBM from 2012 to 2014. Data regarding patient factors, disease factors, and treatment factors were collected and survival has been calculated. RESULTS: A total of 61 patients with GBM were analyzed. GBM is commonly seen in sixth decade of life. Male to female ratio is 2.6:1. The right side of the brain is commonly involved with right frontal lobe being the most common site. The median follow-up was 4.6 months. The median survival of our patients was 8 months. The 1-year and 2-year survival rates were 20% and 3.27%, respectively.CONCLUSIONS: The overall survival and prognosis in patients with GBM remains poor despite of constant research and studies. Concurrent chemoradiotherapy followed by adjuvant chemotherapy with temozolomide should be used after maximal resection to improve the survival.
Keywords: Glioblastoma multiforme, prognostic factors, survival, temozolomide
|How to cite this article:|
Ghosh M, Shubham S, Mandal K, Trivedi V, Chauhan R, Naseera S. Survival and prognostic factors for glioblastoma multiforme: Retrospective single-institutional study. Indian J Cancer 2017;54:362-7
|How to cite this URL:|
Ghosh M, Shubham S, Mandal K, Trivedi V, Chauhan R, Naseera S. Survival and prognostic factors for glioblastoma multiforme: Retrospective single-institutional study. Indian J Cancer [serial online] 2017 [cited 2020 Mar 31];54:362-7. Available from: http://www.indianjcancer.com/text.asp?2017/54/1/362/219544
| » Introduction|| |
Primary brain tumors comprise approximately 2% of all malignant disease. With the incidence of 5/100,000 persons, more than 17,000 cases are diagnosed every year in the US with approximately 13,000 deaths. In adults, high-grade gliomas are the most common type of primary brain tumors among these majority are Grade IV gliomas, i.e., glioblastoma multiforme. The term glioblastoma multiforme (GBM) was introduced by Cushing in nineteenth century. The subtypes are primary and secondary glioblastoma, affecting patients of different age and developing through different pathways., Differences between primary and secondary glioblastoma shown in [Table 1].
The genetic basis and molecular pathways for the development of primary and secondary glioblastoma are different, but no morphological differences are seen. The exact etiology of GBM is not known. GBM generally occurs spontaneously, familial gliomas have also been noted in 1% of cases. Genetic disorders associated with GBM are tuberous sclerosis, Turcot syndrome, multiple endocrine neoplasia Type IIA, and neurofibromatosis Type I.
Clinical presentations of newly diagnosed GBM depend on the size, tumor location, and anatomical structures of involved brain. Patients often present with headaches, dizziness, nausea, lethargy, seizures, hemiparesis, visual loss, stroke-like symptoms, memory problems, or personality change. Seizure is the presenting symptom in as many as 30%–50% of patients with high-grade glioma. Computerized tomography (CT) scan findings of GBM are heterogeneous hyperdense ring with a hypodense core and there is surrounding hypodense signal tracking closely along subcortical white matter tracts indicating cerebral vasogenic edema. The imaging modality of choice for brain tumors is a contrast-enhanced magnetic resonance imaging (MRI), including T1-/T2-weighted and fluid-attenuation inversion recovery sequences. Gliomas appear as a contrast-enhancing mass, with a thickened ring of enhancement and a hypointense core, which corresponds to central necrosis. The margins of the tumor may be irregular or poorly defined, with spread of the tumor along white matter tracts or transcallosally into the opposite hemisphere.,
The standard management of malignant gliomas has been maximum surgical resection followed by adjuvant radiotherapy (RT). After the publication of Stupp's sentinel paper  in 2005, postoperative concurrent chemoradiotherapy followed by adjuvant chemotherapy with temozolomide (TMZ) has become the new standard of care. Despite this multidisciplinary approach, the prognosis for the patients with GBM remains poor.
| » Materials and Methods|| |
We retrospectively analyzed the case records of 61 patients with histological diagnosis of GBM from 2012 to 2014. The following data were collected from medical records of the patients: (1) patients characteristics (Karnofsky performance status [KPS], age, sex, gender, and religion); (2) tumor characteristics (site of tumor, location of tumor, and size of tumor); (3) presenting symptoms; (4) details of treatment (type of surgery and postoperative treatment); (8) follow-up data.
The clinical characteristics of the patients are given in [Table 2]. The age of the patients ranged from 15 years to 68 years. There were 44 males and 17 females, showing male preponderance. Forty-six (75.4%) patients had KPS more than 70 and remaining 15 (24.59%) patients had KPS below 70.
Details about the tumor were collected from the preoperative imaging (contrast-enhanced CT or MRI). Thirty-one (50.81%) patients had right-sided tumor, 24 (39.34%) had left-sided tumor, and 6 (9.83%) had midline tumor. Lobar distribution was as shown in [Table 3]. Frontal and frontoparietal lobe was most commonly involved. Twenty-one (34.42%) patients had tumor <4 cm in size whereas 40 (65.57%) patients had tumor ≥4 cm in size.
A spectrum of symptoms had been seen consisting of headache, vomiting, weakness, neurological symptoms, and visual symptoms. With most common symptom being headache (49.18%) followed by vomiting (44.26%) and weakness (29.5%).
Sixteen (26.22%) patients underwent complete surgical resection whereas 45 (73.77%) patients underwent subtotal resection including biopsy. Postoperative treatment included concurrent chemoradiotherapy followed by adjuvant chemotherapy with TMZ. Adjuvant RT was delivered either on linear accelerator or Co-60 teletherapy unit. CT simulation was done in all patients for treatment planning. In linear accelerator, three-dimensional RT or intensity-modulated RT technique was used to deliver a radical dose of 60 Gy in 30#. Radiotherapy dose refers to the actual dose delivered rather than the planned dose. Concurrent chemotherapy consisted of oral TMZ in a dose of 75 mg/m 2 day 1 to day 7 for 6 weeks with radiotherapy. Adjuvant chemotherapy consisted of oral TMZ in a dose of 150–200 mg/m 2 day 1 to day 5, 28 days cycle for 6 cycles. Routine complete blood count, kidney function test, liver function test, and serum electrolytes had been done and chemotherapy had been given only if the mentioned parameters were within normal limits details of treatment are given in [Table 4].
After the completion of treatment, first follow-up was done after 11/2 months and then after every 3 monthly follow-up was continued for 2 years. Two-year follow-up data had been recorded.
Survival duration was calculated from date of surgery to date of death or date of last contact. Data of patients who were alive at the end of study were censored from survival analysis. Statistical analysis was done using Graphpad Prism 6 (GraphPad Software, Inc.). Overall survival was calculated using Kaplan-Meier method and prognostic factors were determined by log-rank test, a P < 0.05 is considered to be statistically significant.
| » Results|| |
The overall 1-year and 2-year survivals for the entire cohort were 19.15% and 3.27%, respectively [Figure 1].
GBM most commonly occurred in sixth decade of life. 11% patients were aged <30 years. Median survival was maximum in 31–40 years age group and found to be decreased with increasing age [Figure 2]. Median survival for patients aged ≤50 years was 8.8 months, for patients aged >50 years, median survival was 4.55 months; P = 0.016 which was statistically significant [Figure 3].
Median survival was 8.5 months in patients with KPS >70 and it was 5.5 months in patients with KPS ≤70; P = 0.51, which was not statistically significant [Figure 4].
The male:female ratio was 2.6:1. The median survival of male patients was 7.5 months and for females, it was 8.8 months. The 2-year survival rates for male and female patients were 0% and 4.54%, respectively. These differences were not statistically significant with P = 0.68.
Median survival of the patients with complete resection and subtotal resection are 8 months and 7.2 months, respectively; P = 0.88 which is not statistically significant.
The median survival for patients with right-sided tumor was 8.2 months, for left-sided tumor was 8 months. The location of tumor did not have significant impact on survival as P = 0.67.
Median survival for the patients with frontal and fronto-parietal tumor was 8.6 months and for the other sites, it was 6.5 months; P = 0.55.
Fifty-nine patients had completed the planned treatment with 60 Gy of radiation dose. In two of the patients treatment was stopped at 50Gy due to poor tolerance to radiotherapy. The median survival was 9.05 months for patients who have taken concurrent chemotherapy and it was 4.7 months for patients who have not taken concurrent chemotherapy, P = 0.022 which is statistically significant [Figure 5].
|Figure 5: Survival comparing concurrent temozolomide/no concurrent temozolomide|
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Thirty-one (50.81%) patients who had been started postoperative RT within 30 days of surgery had a median survival of 8.8 months whereas 30 (49.18%) patients with gap more than 30 days had a median survival of 6.45 months; P = 0.414, which was statistically not significant [Figure 6].
The median survival for the patients who have taken adjuvant chemotherapy and those who have not taken adjuvant chemotherapy was 10.1 months and 4.8 months, respectively, with a significant P value of 0.0057 [Figure 7]. Among the patients who have taken adjuvant chemotherapy, 4 patients completed 6 cycles of chemotherapy having a median survival of 13.6 months. For the patients who have taken <6 cycles of chemotherapy, median survival was 9.5 months.
|Figure 7: Survival according adjuvant temozolomide/no adjuvant temozolomide|
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| » Discussion|| |
This was a single-institutional retrospective study with median follow-up of 4.6 months. The results of the present study closely resemble the results of various studies on GBM. It is the most malignant brain tumor with a dismal prognosis despite of multimodality treatment. Initial treatment was surgery in the form of maximum safe resection. The addition of RT to surgery improved the survival from 4 to 5 months to 9–12 months. After the sentinel study by Stupp et al. in 2005, the standard therapy for newly diagnosed GBM cases has changed. At present, the Stupp protocol, and postoperative RT with concurrent TMZ followed by adjuvant TMZ have become the standard of care. The median survival with chemoradiotherapy was 14.6 months compared to 12.1 months for RT alone. The 2-year and 5-year survival rates were 27.2% and 9.8% versus 10.9% and 1.9% for both the arms, respectively.
In GBM, various patient-related, tumor-related, and treatment-related factors effect the outcome. It is, therefore, important to analyze the impact of these (age, performance status, extent of surgery, concurrent TMZ, adjuvant chemotherapy) factors on the result.
The median age of our patients was 48 years, which was slightly younger than Stupps study, i.e., 56 years. In two of the Indian studies, the median age of the patients was 49.5 years and 50 years, which is consistent with our study., The reason for our patients being younger than western population is not known. One reason could be the shorter life span of people living in developing countries than those living in developed countries.
Studies have reported that decreased survival was associated with older age; similarly in our study, the survival had decreased with increasing age. There was a significant difference in survival between patients aged ≤50 years and >50 years. Curran et al. developed a set of classes from a recursive partitioning analysis (RPA) model. In RPA, the most important split was by age with age of 50 years being the break point. The median survival in patient of GBM with age <50 years and KPS of 80–90 was 18 months. Patients with age ≥50 years, low KPS, and abnormal mental status had median survival of 5 months. The Medical Research Council divided patients into three age groups of <45 years, 45–59 years, >59 years and observed median survival of 12 months, 9 months, and <5 months, respectively.
Indian study by Kumar et al. reported, median survival of 6.3 months for patients KPS <70 whereas it was 7.97 months in patients with KPS ≥70. Lutterbach et al. reported a median survival of 8.8 months for patients with KPS ≥70 versus 6.7 months for KPS <70. Lacroix et al. in a retrospective analysis of GBM patients reported median survival of 8.8 months in patients with KPS ≤70 vs 11.2 months for KPS >70. Performance status is one of the determining factors for overall survival. Although, in our study, median survival was more in patients with KPS >70 compared to those with KPS ≤70, it was not statistically significant as proven by above-mentioned studies.
In Stupps study, 83% patients had major debulking of tumor with 40% having complete excision. In our study, 26.22% of patients had complete excision and 73.77% had subtotal excision (debulking, decompression). Median survival for patients with complete excision was 8 months and 7.2 months for the patients with subtotal excision, respectively (P = 0.88). Jalali et al. from India reported median survival of 17 months and 6 months for patients with gross total resection and partial resection, respectively (P = 0.922). Impact of extent of resection of GBM is still not proven. Sanai et al. reviewed 28 high-grade glioma articles in terms of quality of evidence, expected extent of resection, and survival benefit. They concluded despite limitations in quality of data, evidence suggest that more extensive surgical resection is associated with longer life expectancy in patients of GBM. Slotman et al. reported median overall survival of entire cohort was 18.9 months and extent of resection was the only significant prognostic factor (P = 0.02) on multivariate analysis (age, gender, PS, RT target volume). A systematic review and meta-analysis by Brown et al. of 37 studies stated decreased mortality for GTR compared to STR at 1 year and 2 years. They concluded compared with STR, GTR substantially improves overall and progression-free survival (PFS), but the quality of the supporting evidence is moderate to low. Our study shows no significant impact of surgical resection on survival, contrary to the results of above-mentioned studies. The main reason for this is that we determine extent of resection from neurosurgeons operative notes rather than early postoperative MRI scans. Postoperative pre-RT scans (CT/MRI) are not routinely obtained due various constraints, financial, or availability of resources (CT/MRI).
In our study, concurrent chemotherapy was taken by 30 (49.18%) patients. Significant difference in median survival has been noted in patients who had taken concurrent TMZ compared to those who had not taken concurrent TMZ with a P = 0.022. Twenty patients had completed the 6 cycles of adjuvant chemotherapy with median survival 10.1 months versus 4.8 months in patients with <6 cycles of adjuvant chemotherapy (P = 0.0057). Song Tao et al. reported adjuvant concurrent chemotherapy with TMZ was associated with improved survival on both univariate and multivariate analyses (P = 0.003 and P = 0.03 respectively). The median survival and 2-year rate among the patients who had adjuvant concurrent chemotherapy than among the patients who did not was 16.4 months and 33.7% versus 9.2 months and 7.7%, respectively. In landmark phase-III multiinstitutional study of Stupp et al., the median survival was 14.6 months for patients treated with concurrent chemoradiotherapy versus 12.1 months with RT alone (P = 0.001). The long-term results and 5-year survival were published in 2009 by Stupp et al., the combination therapy maintained its survival advantage over 5 years (9.8 vs. 1.9%). Roldán Urgoiti et al. in their study to evaluate if adjuvant TMZ beyond 6 months improves survival as compared to the current standard of 6 months reported median survival of 24.6 months for extended therapy compared to 16.5 months for current standard. In multivariate analysis, more than six cycles of adjuvant TMZ were an independent prognostic factor for both PFS and overall survival. These data suggest extended adjuvant TMZ should be considered in patients with newly diagnosed GBM.
In our study, the 2-year overall survival was not significantly different for patients with time to postoperative RT ≤30 days and >30 days. In a single-institutional retrospective review of 161 GBM patients by Randolph et al., overall survival and PFS were not different between time to RT >28 days compared to <28 days. Loureiro et al. also reported similar results showing no impact on overall survival due to delay in RT following surgical resection.,
The median survival, 1-year overall survival, and 2-year overall survival for the entire cohort were 8 months, 20%, and 3.27%, respectively. Factors significantly affecting survival were age, concurrent, and adjuvant TMZ whereas KPS, extent of resection could not significantly affect survival.
| » Conclusions|| |
Factors such as age, KPS, extent of surgical resection, concurrent chemotherapy, and adjuvant chemotherapy have a significant impact on the outcome of results, as seen in our study, a proven by other studies. Compared to our study, Stupp et al. had a better outcome as patients enrolled in clinical trial have strict selection criteria. Therefore, the level of benefit found in clinical trial may not translate into the unselected general population. Various other constraints leading to lower outcomes are financial constraints, access to or delivery of standard treatment.
As it has been proven that concurrent and adjuvant temozolomide has definite survival benefit. The standard of care should be maximum safe resection with concurrent and adjuvant chemotherapy in all affording patients with good performance status.
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Conflicts of interest
There are no conflicts of interest.
| » References|| |
Ries LA, Eisner MP, Kosary CL, Hankey BF, Millar BA, Clegg L, et al
, editors. SEER Cancer Statistics,1973-1998. Bethesda, MD: National Cancer Institute; 2001.
Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al.
CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol 2013;15 Suppl 2:ii1-56.
Żukiel R, Piestrzeniewicz R, Nowak S, Jankowski R, Wieloch M. History of surgical treatment of brain tumors. Neuroskop 2004;6:9-19.
Ohgaki H, Kleihues P. Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 2005;64:479-89.
Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, et al.
Genetic pathways to glioblastoma: A population-based study. Cancer Res 2004;64:6892-9.
Kleihues P, Ohgaki H. Primary and secondary glioblastomas: From concept to clinical diagnosis. Neuro Oncol 1999;1:44-51.
Padmalatha C, Harruff RC, Ganick D, Hafez GB. Glioblastoma multiforme with tuberous sclerosis. Report of a case. Arch Pathol Lab Med 1980;104:649-50.
Grips E, Wentzensen N, Sutter C, Sedlaczek O, Gebert J, Weigel R, et al.
Glioblastoma multiforme as a manifestation of Turcot syndrome. Nervenarzt 2002;73:177-82.
Sánchez-Ortiga R, Boix Carreño E, Moreno-Pérez O, Picó Alfonso A. Glioblastoma multiforme and multiple endocrine neoplasic type 2 A. Med Clin (Barc) 2009;133:196-7.
Broekman ML, Risselada R, Engelen-Lee J, Spliet WG, Verweij BH. Glioblastoma multiforme in the posterior cranial fossa in a patient with neurofibromatosis type I. Case Rep Med 2009;2009:757898.
Young RM, Jamshidi A, Davis G, Sherman JH. Current trends in the surgical management and treatment of adult glioblastoma. Ann Transl Med 2015;3:121.
Schiff D, Lee EQ, Nayak L, Norden AD, Reardon DA, Wen PY. Medical management of brain tumors and the sequelae of treatment. Neuro Oncol 2015;17:488-504.
Osborn AG, Salzman KL, Katzman G, Provenzale J, Castillo M, Hedlund G, et al
. Diagnostic Imaging: Brain. 1st ed. Amirsys, Salt Lake City; 2004.
Bourekas EC, Varakis K, Bruns D, Christoforidis GA, Baujan M, Slone HW, et al.
Lesions of the corpus callosum: MR imaging and differential considerations in adults and children. AJR Am J Roentgenol 2002;179:251-7.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N
Engl J Med 2005;352:987-96.
Julka PK, Sharma DN, Mallick S, Gandhi AK, Joshi N, Rath GK. Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide: A mono-institutional experience of 215 patients. J Cancer Res Ther 2013;9:381-6.
Munshi A, Jalali R. Therapy for glioma: Indian perspective. Indian J Cancer 2009;46:127-31.
] [Full text]
Curran WJ Jr., Scott CB, Horton J, Nelson JS, Weinstein AS, Fischbach AJ, et al.
Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials. J Natl Cancer Inst 1993;85:704-10.
Stenning SP, Freedman LS, Bleehen NM. Prognostic factors for high-grade malignant glioma: Development of a prognostic index. A report of the medical research council brain tumour working party. J Neurooncol 1990;9:47-55.
Kumar N, Kumar P, Angurana SL, Khosla D, Mukherjee KK, Aggarwal R, et al.
Evaluation of outcome and prognostic factors in patients of glioblastoma multiforme: A single institution experience. J Neurosci Rural Pract 2013;4 Suppl 1:S46-55.
Lutterbach J, Sauerbrei W, Guttenberger R. Multivariate analysis of prognostic factors in patients with glioblastoma. Strahlenther Onkol 2003;179:8-15.
Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al.
Amultivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. J Neurosurg 2001;95:190-8.
Jalali R, Basu A, Gupta T, Munshi A, Menon H, Sarin R, et al.
Encouraging experience of concomitant temozolomide with radiotherapy followed by adjuvant temozolomide in newly diagnosed glioblastoma multiforme: Single institution experience. Br J Neurosurg 2007;21:583-7.
Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 2011;115:3-8.
Slotman BJ, Eppinga WS, Reijneveld JC, Noske DP, Buter J, Braam LM, et al
. Impact of extent of resection of glioblastoma multiforme (GBM) in the era of chemoradiation. J Clin Oncol 2009;15S: e13029.
Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al.
Association of the extent of resection with survival in glioblastoma: A Systematic review and meta-analysis. JAMA Oncol 2016;2:1460-9.
Cheo ST, Lim GH, Lim KH. Glioblastoma multiforme outcomes of 107 patients treated in two Singapore institutions. Singapore Med J 2017;58:41-45.
Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al.
Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.
Roldán Urgoiti GB, Singh AD, Easaw JC. Extended adjuvant temozolomide for treatment of newly diagnosed glioblastoma multiforme. J Neurooncol 2012;108:173-7.
Randolph DM 2nd
, McTyre ER, Paulsson AK, Holmes JA, Hinson WH, Lesser GJ, et al.
Impact of timing of radiotherapy in patients with newly diagnosed glioblastoma. Clin Neurol Neurosurg 2016;151:73-8.
Loureiro LV, Pontes Lde B, Callegaro-Filho D, Koch Lde O, Weltman E, Victor Eda S, et al.
Waiting time to radiotherapy as a prognostic factor for glioblastoma patients in a scenario of medical disparities. Arq Neuropsiquiatr 2015;73:104-10.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]
[Table 1], [Table 2], [Table 3], [Table 4]