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  Table of Contents  
ORIGINAL ARTICLE
Year : 2016  |  Volume : 53  |  Issue : 3  |  Page : 382-386
 

Prognostic factors effective on survival of patients with glioblastoma: Anadolu Medical Center experience


Department of Radiation Oncology, Anadolu Medical Center, Gebze 41400 Kocaeli, Turkey

Date of Web Publication24-Feb-2017

Correspondence Address:
HB Ayata
Department of Radiation Oncology, Anadolu Medical Center, Gebze 41400 Kocaeli
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.200664

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 » Abstract 

AIM: The aim of this study is to offer survival following radiation therapy using intensity-modulated radiotherapy or volumetric arc therapy with temozolomide in patients with glioblastoma. MATERIALS AND METHODS: Ninety-two previously treated patients with high-grade glioma (World Health Organization [WHO] grade IV) were studied in Anadolu Medical Center, Department of Radiation Oncology, between January 2006 and July 2015. The diagnosis was established by pathology in all cases. The median age was 59 years (range, 19–86 years). The median tumor diameter was 45 mm, and the rate of the multicentric tumors was 16.3%. The location of the tumor was temporal in 33.7%, parietal in 14.1%, frontal in 23.9%, occipital in 9.8%, and others in 18.5%. The gross total and subtotal resection were performed in 60.9% of the patients, partial resection in 26.1%, and only stereotactic biopsy in 13.0% of the patients. RESULTS: The median overall survival (OS) was 33.01 ± 4.76 months (95% confidence interval 25.64–40.38 months). 1, 2, and 5 years OS was 74.3%, 44.3%, and 31.8%, respectively. The median progression-free survival (PFS) was 27.36 ± 3.87 months (95% confidence interval 19.82–34.89 months). 1, 2, and 5 years PFS was 62.7%, 32.6%, and 27.2%, respectively. On univariate analysis, gender, extent of surgery, tumor size, Karnofsky performance status, and tumor suppressor gene (P53) were significant predictors of OS and PFS. On multivariate analysis, gender (PFS: P = 0.006, OS: P = 0.003), extent of surgery (PFS: P = 0.004, OS: P = 0.012), P53 (PFS: P = 0.003, OS: P = 0.021), and size of tumor (PFS: P = 0.005, OS: 0.012) remained significantly associated with PFS and OS. There is no statistically significant in OS and PFS between female and male (OS: log-rank: 0.79 P = 0.375, PFS: log-rank: 0.54 P = 0.465). PSF and OS were not significantly significant with total/near total resection compared with partial resection (PSF: P = 0.46 log-rank = 0.54, OS: P = 0.340 log-rank = 0.91). Patients with P53 <50% value and patients with P53 >50% value were compared and results were not found statistically significant (PSF: P = 0.917 log-rank = 0.01, OS: P = 0.892 log-rank = 0.02). For patients with tumor size <0 mm, small tumor size did not improve the PSF and OS (PSF: P = 0.291 log-rank = 1.11, OS: P = 0.288 log-rank = 1.13). CONCLUSION: Ninety-two previously treated patients with high-grade glioma (WHO Grade IV) were evaluated with multivariate analysis. Gender, extent of surgery, P53, and tumor size were found as prognostic factors affecting on survival.


Keywords: Glioblastoma, survival, temozolomide


How to cite this article:
Guden M, Ayata H, Ceylan C, Kilic A, Engin K. Prognostic factors effective on survival of patients with glioblastoma: Anadolu Medical Center experience. Indian J Cancer 2016;53:382-6

How to cite this URL:
Guden M, Ayata H, Ceylan C, Kilic A, Engin K. Prognostic factors effective on survival of patients with glioblastoma: Anadolu Medical Center experience. Indian J Cancer [serial online] 2016 [cited 2017 Apr 24];53:382-6. Available from: http://www.indianjcancer.com/text.asp?2016/53/3/382/200664



 » Introduction Top


Glioblastoma (GBM) is the most common malignant primary central nervous system tumors in adults and among the most aggressive of all tumors and classified by the World Health Organization (WHO) as a grade IV glioma. One of the most challenging problems in the therapy of GBM is its extremely complex and heterogeneous molecular biology. In spite of technical advances in surgery and radiotherapy (RT), median survival time is reported as less than a year after diagnosis. Management of gliomas requires a coordinated team by many disciplines, including neurosurgery, neuropathology, neurology, radiation oncology, and medical oncology. Standard treatment includes extensive surgery followed by RT with concurrent temozolomide (TMZ) (75 mg/m 2 daily), followed by the minimum of 6 months of adjuvant TMZ (150–200 mg/m 2 for 5 days every 28 days). Postoperative RT has been reported to significantly prolong patient survival.[1],[2] Three-dimensional conformal RT, intensity-modulated radiotherapy (IMRT), and volumetric arc therapy (VMAT) are precise RT techniques with modern imaging techniques and computer technology. These techniques are aimed at improving the radiation dose to the tumor area while reducing the radiation dose to normal tissues.[3] The significant increase in overall survival (OS) can be considered a major progress and, thus, the current standard for patients with GBM is considered RT together with the concomitant and adjuvant application of TMZ. There have been documented cases of GBM patients surviving longer than 3 years, termed long-term survival, representing approximately 3%–5% of GBM patients.[4] Survival of GBM patients longer than 5 years, however, is exceptional, representing as few as 0.5% of patients.[5] Survival data for up to 5 years are now available.[6] Of the 254 patients who received the standard combined protocol, 16% were alive after 3 years, and 9.8% were still alive after 5 years. The most recent follow-up report also included a survival analysis with respect to various prognostic variables. Five-year survival of patients under the age of 50 was 17%, compared to 6.4% for those over the age of 50.

The aim of this retrospective study is to offer survival following RT using IMRT or VMAT with TMZ in patients with GBM.


 » Materials and Methods Top


Ninety-two previously treated patients with high-grade glioma (WHO grade IV) were studied in Anadolu Medical Center, Department of Radiation Oncology, between January 2006 and July 2015. The diagnosis was established by pathology in all cases. The median age was 59 years (range, 19–86 years). The median tumor diameter was 45 mm, and the rate of the multicentric tumors was 16.3%. The location of the tumor was temporal in 33.7%, parietal in 14.1%, frontal in 23.9%, occipital in 9.8%, and others in 18.5%. The gross total and subtotal resection were performed in 60.9% of the patients, partial resection in 26.1%, and only stereotactic biopsy in 13.0% of the patients. Using the patients' charts and electronic medical records system (hospital ınformation system), last follow-up, and death, the following data were obtained: Gender, age, tumor pathology, location and size, extent of surgery, RT dose, Karnofsky performance status (KPS), time between surgery and RT, use of TMZ, use of chemotherapy or other treatments, and survival time. Patients' characteristics were evaluated as described in [Table 1].
Table 1: Patient characteristics

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Target volume definition and treatment planning

For simulation, all patients were immobilized using a commercially available thermoplastic mask in supine position. Computed tomography (CT) image data were reconstructed in 2.5 mm slice thickness and registered with preoperative magnetic resonance imaging (MRI). Treatment planning was performed using a noncontrast planning CT scan fused with contrast-enhanced T1 and T2 fluid-attenuated inversion recovery sequences from the postoperative diagnostic MRI scan [Figure 1]. The gross tumor volume (GTV) was defined by the radiation oncologist according to the International Commission on Radiation Units and Measurements Report No: 62.[7] The clinical target volume (CTV) included the GTV, and planning target volume was delineated as the CTV plus 3–5 mm expansion. All patients were treated with IMRT or VMAT planning techniques. All patients underwent inverse planning on the Eclipse™ treatment planning system (Varian Medical Systems, Palo Alto, CA, USA) between 50 and 60 Gy to the CTV with 25–30 fractions.
Figure 1: (a) Preoperative contrast-enhanced T1 magnetic resonance imaging. (b) Postoperative contrast-enhanced T1 magnetic resonance imaging. (c) T2 fluid-attenuated inversion recovery magnetic resonance imaging sequences. (d) Planning computed tomography and red wash = planning target volume

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All patients were evaluated by a medical oncologist and received daily TMZ (75 mg/m 2/day) for 6 to 7 weeks beginning at the start of RT.

Statistical analysis

Progression-free survival (PFS) and OS rates were calculated using Kaplan–Meier method and compared between groups using log-rank statistics. Cox regression model was used for univariate and multivariate analyses. Statistical analyses were performed with SPSS version 17.0.1 (SPSS Inc., Chicago, IL, USA). Statistical significance was defined as P < 0.05.


 » Results Top


Between January 2006 and July 2015, 92 patients with GBM were treated with IMRT or VMAT techniques. The median age at the start of RT was 55 years (range, 19–86). Tumor size was median 45 mm (range, 25–85) as shown in [Table 1]. Seventy-seven patients had primary GBM and 15 patients had secondary GBM on the basis of the pathologic assessment. Patients (60.9%) underwent subtotal and near subtotal resection, (26.1%) partial, and (13%) biopsy alone. All patients received concurrent TMZ during their radiation therapy, and also all of the patients received maintenance TMZ after the completion of radiation therapy.

The median OS was 33.01 ± 4.76 months (95% confidence interval 25.64–40.38 months). 1, 2, and 5 years OS was 74.3%, 44.3%, and 31.8%, respectively. The median PFS was 27.36 ± 3.87 months (95% confidence interval 19.82–34.89 months). 1, 2, and 5 years PFS was 62.7%, 32.6%, and 27.2%, respectively [Figure 2]. On univariate analysis, gender, extent of surgery, tumor size, KPS, and tumor suppressor (P53; tumor protein) were significant predictors of OS and PFS [Table 2]. Multivariate analysis for OS and PFS was built using all factors found to be significant on univariate analyses.
Figure 2: Kaplan–Meier estimates of progression-free (a) and overall survival (b)

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Table 2: Univariate analysis of factors associated with progression free survival and overall survival

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On multivariate analysis, gender (PFS: P =0.006, OS: P =0.003), extent of surgery (PFS: P =0.004, OS: P =0.012), P53 (PFS: P =0.003, OS: P =0.021), and size of tumor (PFS: P =0.005, OS: 0.012) remained significantly associated with PFS and OS [Table 3].
Table 3: Multivariate analysis of factors associated with progression free survival and overall survival

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No significant differences in outcomes were observed between the patient's gender [Figure 3]. Five-year female OS and PSF were 41.4% and 35.1%, respectively, and 5-year male OS and PSF were 27.1% and 22.9%, respectively. The median female OS and PFS were 37.78 ± 6.62 (24.79–50.77) and 31.93 ± 6.91 (18.38–45.48). The median male OS and PFS were 23.69 ± 2.41 (18.96–28.41) and 19.58 ± 2.49 (14.69–24.46). There is no statistically significant difference in OS and PFS between female and male (OS: log-rank: 0.79 P = 0.375, PFS: log-rank: 0.54 P = 0.465).
Figure 3: Comparison of Kaplan–Meier estimates of clinical outcomes between female (female, solid line) and male genders (male, dashed line). (a) Progression-free survival (b) overall survival

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In patients who underwent resection, we investigated the effect of extent of surgery on PSF and OS. PSF and OS were not significantly significant with total/near total resection compared with partial resection (PSF: P =0.46 log–rank = 0.54, OS: P =0.340 log-rank = 0.91). Five-year PSF and OS rates of 30.6% and 36.4% with total/near total resection versus 19.7% and 26.1 with partial resection. The median PFS and OS were 29.39 ± 4.95 months (19.69–39.09 months) and 30.76 ± 4.05 (22.82–38.70 months) for total/near resection, respectively, whereas median PFS and OS were 29.88 ± 4.47 (12.28–25.11) and 24.72 ± 3.74 (17.39–32.05) for partial resection [Figure 4]. Similarly, we analyzed the effect of tumor size on PSF and OS. For patients with tumor size <30 mm, small tumor size did not improve the PSF and OS (PSF: P =0.291 Log–rank = 1.11, OS: P =0.288 log-rank = 1.13).
Figure 4: Comparison of Kaplan–Meier estimates of clinical outcomes between the patients who had gross total or near total resection (total or near total, solid line) and partial resection (partial resection, dashed line). (a) Progression-free survival (b) overall survival

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Five-year PSF and OS rates of 25% and 26.8% with tumor size <30 mm versus 25.4% and 32.8 with tumor size ≥30 mm. The median PFS and OS were 28.12 ± 7.54 months (13.34–42.90 months) and 33.91 ± 6.85 (20.47–47.34 months) for tumor size <30 mm, respectively, whereas median PFS and OS were 20.57 ± 2.75 (15.18–25.96) and 27.51 ± 23.42 (20.8–34.20) for tumor size ≥30 mm, respectively [Figure 5].
Figure 5: Comparison of Kaplan–Meier estimates of clinical outcomes between the patients with small tumors than 30 mm (<30 mm, solid line) and the patients with large tumors than 30 mm (>30 mm, dashed line). (a) Progression-free survival (b) overall survival

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We also investigated the effect of P53 tumor protein value on PSF and OS. Patients with P53 <50% value and patients with P53 >50% value were compared and results were not found statistically significant (PSF: P =0.917 log-rank = 0.01, OS: P =0.892 log-rank = 0.02). Five-year PSF and OS rates of 32% and 36.6% for P53 <50% value versus 42.4% and 21.4% for P53 >50% value, respectively. The median PFS and OS were 28.65 ± 7.12 months (14.52–52.28 months) and 37.05 ± 9.07 (19.26–54.83 months) for P53 <50 value, respectively, whereas median PFS and OS were 31.98 ± 6.04 (17.03–47.90) and 35.46 ± 8.11 (19.56–51.38) for P53 >50%, respectively.


 » Discussion Top


Between January 2006 and July 2015, 92 patients with GBM were evaluated with IMRT or VMAT techniques in this study as a retrospective. The median age at the start of RT was 55 years. Tumor size was median 45 mm. Seventy-seven patients had primary GBM and 15 patients had secondary GBM on the basis of the pathologic assessment. Standard treatment involves a multimodal approach, combining maximum surgical resection, irradiation, and chemotherapy. In our study, patients underwent subtotal and near subtotal resection, partial, and biopsy alone. Despite the use of many effective treatments that include maximum safe surgical resection and RT, the prognosis of patients with GBM remains poor. In our study, we found that the median OS was 33.01 ± 4.76 months. 1, 2, and 5 years OS was 74.3%, 44.3%, and 31.8%, respectively. The median PFS was 27.36 ± 3.87 months. Ballmann et al. reported that the median survivals were 10.2 months (95% CI, 9.7–10.7 months) for patients with newly diagnosed GBM and 5.0 months (95% CI, 4.6–5.4 months) for patients with recurrent GBM. The median PFS times were 5.3 months (95% CI, 5.0–5.6 months) for patients with newly diagnosed GBM and 1.8 months (1.7–2.0 months) for patients with recurrent disease.[8] In the other study, deSouza et al. reported that 1- and 3-year survival rates were 20.7% and 4.4%, respectively, for patients in 1999–2000, improving to 40% and 10.3% for patients in 2009–2010 groups. The median OS was 0.36 and 0.74 in 1999–2000 and 2009–2010 groups, respectively.[9] Our results were consistent with the latest literature on survival for the GBM patients. Chang et al. reported that the 18-month survival rates for age older than 60 were found as 40%, 20%, and 8%, respectively. Similarly, in our study, both univariate and multivariate analyses showed that the patients' age is adverse prognostic factors on survival [Table 2] and [Table 3]. On multivariate analysis, gender, extent of surgery, P53, and size of tumor remained significantly associated with PFS and OS. In patients who underwent resection, we investigated the effect of extent of surgery on PSF and OS. PSF and OS were not significantly significant with total/near total resection compared with partial resection. Some studies reported that the extent of resection was on effective prognostic factors on survival.[10] RTOG studies reported that survival rate was decreased in patients who underwent only biopsy.[10] The median survival was 11.3 months in patient who underwent nearly total resection, whereas median survival was 6.6 months in patients who underwent only biopsy. Allahdini et al. showed that maximal resection of tumor volume is an independent variable associated with longer survival times in patient with GBM.[11] For patients with tumor size <30 mm, small tumor size did not improve the PSF and OS. Patients with P53 <50% value and patients with P53 >50% value were compared and results were not found statistically significant. Many studies indicated that lower KPS value has an adverse effect on survival compared to higher KPS value. Chang et al. reported that the 18-month survival rates for KPS ≥70, KPS <70 were 34% and 13%, respectively. Similarly, in our study, both univariate and multivariate analyses showed that KPS value is adverse prognostic factors on survival.

Limitation of our analysis does not include MGMT promoter methylation status because MGMT promoter methylation was the strongest predictor for outcome and benefit from TMZ in the EORTC-NCIC study.[4]


 » Conclusion Top


Ninety-two previously treated patients with high-grade glioma (WHO Grade IV) were evaluated with multivariate analysis. Gender, extent of surgery, P53, and tumor size were found as prognostic factors affecting on survival. Future studies should include analysis of patients with MGMT promoter methylation because MGMT promoter methylation was the strongest predictor for outcome. Evaluation of the effect on survival of RT techniques is in progress in our series.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
Ohashi T, Takeda A, Shigematsu N, Fukada J, Sanuki N, Amemiya A, et al. Does dis¬tribution analysis of axillary lymph nodes for three dimensional radiotherapy with a field-in-field tech¬nique for breast cancer. Int J Radiat Oncol Biol Phys 2009;73:80-7   Back to cited text no. 1
    
2.
Nakamatsu K, Suzuki M, Nishimura Y, Kanamori S, Koike R, Shibata T, et al. Treatment outcome and dose-voulme histogram analysis of si¬maltaneous integrated boost method for malignant gliomas using intensity-modulated radiotherapy. Int J Clin Oncol 2008;13:48-53.   Back to cited text no. 2
    
3.
MacDonald SM, Ahmad S, Kachris S, Vogds BJ, DeRouen M, Gittleman AE, et al. Intensity modulated radiation therapy versus three-dimension¬al conformal radiation therapy for the treatment of high grade glioma: A dosimetric comparison. J Appl Clin Med Phys 2007;8:47-60.   Back to cited text no. 3
    
4.
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 randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10:459-66.  Back to cited text no. 4
    
5.
Wong ET, Hess KR, Gleason MJ, et al. Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. J Clin Oncol 1999;17:2572-8.  Back to cited text no. 5
    
6.
Barker FG, Chang SM, Gutin PH, et al. Survival and functional status after resection of recurrent glioblastoma multiforme. Neurosurgery1998;42:709-20.  Back to cited text no. 6
    
7.
International Commission On Radiation Units and Measurements. Prescribing, Recording and Reporting Photon Beam Therapy, (Supplement to ICRU Report50). ICRU Report 62. Bethesda, MD: ICRU; 1999.  Back to cited text no. 7
    
8.
Ballman Karla, Buckner J.C, Brown P, et al. The relationship between six month progression free survival and 12-months overall survival end points for phase II trials in patients with glioblastoma multiforme. Neuro Oncology 2006:29-38.  Back to cited text no. 8
    
9.
Desouza R M, Shaweis H, Han C, Sivasubramiam V, et al. Has the survival of patients with glioblastoma changed over the years? British Journal of cancer 2015;1-5.  Back to cited text no. 9
    
10.
Chang CH, Horton J, Schoenfeld D, et al. Comparison of post-operative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. Cancer 1983;52:997-1007.  Back to cited text no. 10
    
11.
Allahdini F, Amirjamshidi A, Reza-Zarei M, et al. Evaluating the prognostic factors effective on the outcome of patients with glioblastoma multiformis: does maximal resection of the tumor lengthen the median survival?. World Neurosurgery 2009;73:128-34.  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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