|Year : 2013 | Volume
| Issue : 3 | Page : 381-386
Postoperative treatment of glioblastoma multiforme with radiation therapy plus concomitant and adjuvant temozolomide : A mono-institutional experience of 215 patients
Pramod Kumar Julka, Daya Nand Sharma, Supriya Mallick, Ajeet Kumar Gandhi, Nikhil Joshi, Goura Kisor Rath
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
|Date of Web Publication||8-Oct-2013|
Daya Nand Sharma
Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
Objective: To study the clinical results and prognostic factors of patients with glioblastoma multiforme (GBM) treated by postoperative radiation therapy (PORT) and concomitant temozolomide followed by adjuvant temozolomide.
Methods: From 2005 to 2008, 215 patients (median age 48 years) with GBM were treated with PORT plus temozolomide chemotherapy. Radiation therapy (RT) was employed with a dose of 60 Gy in 30 fractions over 6 weeks by conventional fractionation with concomitant temozolomide (75 mg/m 2 /day). Adjuvant therapy consisted of 6 cycles of temozolomide (150 mg/m 2 for 5 days, 28 days cycle). The primary end point of the study was overall survival (OS), and the secondary end points were progression free survival (PFS) and toxicity. OS was determined with respect to different variables to study the prognostic significance.
Results: Median follow up was 11 months (range 2-50 months). Median OS and PFS were 13 months and 11 months respectively. The 1-year and 2-year OS was 44% and 18% respectively. There was no statistical significant impact of age, sex, KP score, anatomical location and extent of surgery. Presentation without seizures (on univariate analysis) and 6 cycles of adjuvant temozolomide therapy (on univariate as well as multivariate analysis) were found significant prognostic factors. Sixteen patients developed grade III-IV neutropenia/thrombocytopenia during the course of RT.
Conclusion: Our results authenticate the role of concomitant and adjuvant temozolomide chemotherapy in combination with PORT for the management of GBM patients. We strongly recommend complete 6 cycle of adjuvant temozolomide since it significantly improved the survival in our study.
Keywords: Glioblastoma, radiotherapy, temozolomide
|How to cite this article:|
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 Can Res Ther 2013;9:381-6
|How to cite this URL:|
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 Can Res Ther [serial online] 2013 [cited 2019 Nov 12];9:381-6. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/381/119310
| > Introduction|| |
Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and accounts for approximately 45-50% of all gliomas.  It is one of the most aggressive tumors in the human body with a median survival of approximately one year. , Management of GBM, over the years, has progressively changed but the prognosis continues to be dismal. Earlier management protocols included surgery and adjuvant RT. , Initial treatment with surgery in the form of maximal safe resection has been an important treatment for a long time. The addition of RT to surgery improves the survival from 4-5 months to 9-12 months. ,,, More recently, management of GBM has progressed to incorporate surgery with postoperative radiotherapy (PORT) and concurrent chemotherapy. , The randomized trial by Stupp et al.  demonstrated that PORT with concomitant temozolomide, an oral alkylating agent, followed by adjuvant temozolomide significantly improved median survival from 12 months to 14 months. Since the publication of this trial.  in year 2005, RT plus concomitant and adjuvant temozolomide treatment has become the standard therapy for newly diagnosed GBM. Encouraged by this study,  our institution too has adopted the same protocol from year 2005 onwards. The aim of our present study is to analyze and report the clinical results and prognostic factors of GBM patients treated by PORT and concomitant temozolomide followed by adjuvant temozolomide.
| > Materials and Methods|| |
From 2005 to 2008, 215 patients with GBM were treated with PORT plus concomitant temozolomide followed by adjuvant temozolomide. Following eligibility criteria were considered before enrolling the patients: 1) histopathological proof of GBM, 2) age more than 18 years, 3) surgical treatment within last 4 weeks, 4) Karnofsky performance status of not less than 60, 5) no previous treatment with systemic chemotherapy or RT, 6) no co-morbid illness, 7) adequate hematological, hepatic and renal function status, and 8) written consent.
Various clinical characteristics of the 215 patients are given in [Table 1]. Age ranged from 18 to 77 years with a median of 48 years. There were 155 males and 60 females. Fronto-parietal region was the commonest tumor location. A total of 207 patients underwent surgical resection (complete resection 81, partial resection 126) and remaining 8 patients could undergo biopsy alone due to difficult anatomical location. Pathology slides were reviewed of the patients who were operated outside our institute.
Radiation Therapy Treatment
PORT was started within 4-6 weeks of surgery. Treatment was delivered on either Linear Accelerator using 6 MV X-rays or Co-60 teletherapy unit. Computerized tomography (CT) simulation was done in all patients for RT planning. A total dose of 60 Gy in 30 fractions over 6 weeks was planned in 2 phases employing conventional fractionation regime (2 Gy per fraction, five days per week, from Monday to Friday). In the first phase, radiation dose of 50 Gy was delivered to initial RT field covering gross tumor volume plus surrounding edema on pre-surgical CT/MRI images with a margin of 2.0-2.5 cm. This was followed by second phase treatment to deliver boost dose of 10 Gy to encompass the contrast enhancing tumor plus 2 cm margin.
Chemotherapy with temozolomide was given to all patients at a dose of 75 mg/m 2 /day, 7 days per week, during the course of radiotherapy. It was administered orally (empty stomach), from the first to the last day of RT. Patients were reviewed every week during the course of RT by physical examination and blood chemistry. Temozolomide therapy was discontinued if patient developed Grade III hematological toxicity. At one month after completion of RT, patients were given at least six cycles of adjuvant temozolomide (dose 150 mg/m 2 /day) according to the standard 5-day schedule every 28 days. Antiemetic prophylaxis with ondensetron was given before the initial doses of concomitant temozolomide and then during the adjuvant 5-day courses of temozolomide. MRI scan was done after 3 cycles to assess the disease status. If MRI revealed signs of disease progression, the temozolomide was stopped.
Follow up and clinical assessment
After the completion of adjuvant temozolomide therapy, first follow up was done after one month and then every 3 months thereafter. Physical examination was done at each visit and MRI scan was performed every 3 months till one year and then 3-6 months or if there was a suspicion of disease progression. Assessment of toxicity was done according to the Common Terminology Criteria for Adverse Events; version 3.0. Tumor progression was defined according to the criteria of MacDonald et al.
The primary end point of the study was overall survival (OS), and the secondary end points were progression free survival (PFS) and toxicity. OS was defined as the period from the date of histopathological diagnosis to the date of death or last follow up; and PFS was defined as the period from the date of histopathological diagnosis to the date of disease progression. Statistical analysis was performed using SPSS 11.5 version. OS and PFS were determined by the Kaplan-Meier method.  The survival curves were compared by the log rank test. OS and PFS were determined with respect to different variables like age (<50 versus >50 years), sex, anatomical location, presentation with and without seizures, extent of surgery, number of cycles of adjuvant temozolomide (6 versus <6 cycles) etc. The impact of these variables on OS and PFS was assessed by using univariate and multivariate analysis (Cox-regression model). Log rank test was used to find out the P value and a value of <0.05 was considered significant.
| > Results|| |
Median follow up period was 11 months (2-50 months). Treatment details are shown in [Table 2]. Of 215 patients, 198 completed the planned RT dose of 60 Gy. Remaining 17 patients received RT dose ranging from 8-58 Gy. Ten patients could not complete 50 Gy. Of 205 patients who completed more than 50 Gy, 12 had interruptions for a period ranging from 3-14 days during the course of RT. In none of the patients, the duration of RT exceeded 8 weeks. No patient died during the course of RT.
| > Toxicity|| |
During concomitant RT and temozolomide, 16 patients developed grade III-IV neutropenia/thrombocytopenia. Ten patients developed signs of raised intracranial pressure requiring hospitalization. Four had pneumonitis and recovered with antibiotics. When explained about the risks of continuing the temozolomide further, 14 of them opted not to take it further. Another 8 patients withdrew from the temozolomide therapy for unknown reasons. Thus, temozolomide was discontinued in 22 patients and could not complete 75% of the planned dose. During adjuvant temozolomide therapy, 11 patients developed grade III-IV neutropenia/thrombocytopenia and temozolomide had to discontinued in them. Thirty eight patients could not complete 6 cycles of adjuvant temozolomide therapy and could complete 0-5 cycles. Thus, of 193 patients who were eligible for adjuvant temozolomide, only 155 could complete 6 cycles.
Median OS and PFS were 13 months and 11 months respectively. The 1-year and 2-year OS was 44% and 18% respectively [Figure 1]. The 1-year and 2-year PFS was 34% and 12% respectively [Figure 2]. We studied the correlation of various prognostic variables and the OS rate. There was no statistical significant impact of age, sex, KP score, anatomical location and extent of surgery [Table 3]. As shown in [Figure 3], female patients had better 1-year OS than males (58% vs 39%, P value 0.2). Presentation without seizures and complete adjuvant temozolomide therapy were found to be significant prognostic factors on univariate analysis. Patients who presented with history of seizures had significantly poorer 1-year OS than without the seizures (26% vs 49%, P value 0.02) [Figure 4], however, this difference was found to be insignificant on multivariate analysis (P value 0.9). The 1-year OS in patients who underwent complete resection and partial resection was 47% and 41% respectively (P value 0.18) [Figure 5]. As depicted in [Figure 6], patients who completed 6 cycles of temozolomide therapy had improved 1-year OS than who completed <6 cycles (67% vs 22%) and this difference was highly significant on univariate analysis (P value 0.000) as well as multivariate analysis (P value 0.001).
|Table 3: Kaplan Meier survival and prognostic variables (univariate analysis)|
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|Figure 4: The overall survival of patients with and without seizures at presentation|
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|Figure 5: The overall survival of patients with complete versus partial surgical resection|
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|Figure 6: The overall survival of patients who completed 6 cycles vs<6 cycles of adjuvant temozolomide.|
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| > Discussion|| |
PORT was the standard adjuvant treatment of GBM until 2005.  Addition of chemotherapy to PORT failed to show any significant survival advantage in many trials , but Stupp et al. published a randomized trial in 2005 demonstrating a clear benefit with temozolomide chemotherapy. Thereafter, the standard adjuvant treatment of GBM has changed to PORT plus concomitant temozolomide chemotherapy followed by further 6 cycles of temozolomide chemotherapy. We adopted this standard treatment in year 2005 and treated 215 patients till 2008. The clinical outcome of these 215 patients constitutes the basis of this present report. Our broad aim was to study whether the duplication of Stupp's regime has provided comparable results in our group of patients. Additionally, we wanted to find out whether any subgroup of patients, depending upon various prognostic factors, had a higher benefit.
At a glance, [Table 4] shows the comparison of our results with the temozolomide arm of study by Stupp et al. The median survival of 13 months, 1-year OS and 2-year OS rates of 44% and 18% respectively in our study reveal comparable results. Our results further authenticated the role of temozolomide chemotherapy in the management of GBM. Even though the nature and design of trial by Stupp et al. is different from ours and a strict comparison of the results may not be worthwhile; our results seem to be comparable. The study by Stupp et al. is a randomized multi-institutional trial while ours is a single arm but mono-institutional trial. The median age of our patients is less than those in the study by Stupp et al. (48 vs 56 years). In our study, 22 patients (10%) could not complete 75% of the planned dose of concomitant temozolomide and 38 patients (19.6%) could not complete 6 cycles of adjuvant temozolomide therapy. Thus, a total of 155 patients (72%) in our study could complete 6 cycles of adjuvant temozolomide therapy as compared to 47% in the trial by Stupp et al. The better compliance rate for adjuvant temozolomide therapy in our series may be due to the fact that we, unlike Stupp et al.,  did not escalate the dose of temozolomide from 150 mg/m 2 to 200 mg/m 2 from second cycle onwards. Athanassiou et al. too used a dose intensified schedule and reported that 61.4% patients could complete the planned 6 cycles of adjuvant temozolomide therapy. Though the 1-year and 2-year OS rates are higher in Stupp's study,  the 1-year and 2-year PFS rates are slightly higher in our study [Table 4]. The median OS in the two studies is almost same.
Stupp et al. have recently published the 5-year survival data of their earlier study.  Benefits of adjuvant temozolomide with RT lasted throughout 5 years of follow-up. The 5-year OS in temozolomide plus RT and RT alone arm was 9.8% and 1.9% respectively (P value 0.0001). However, they could not find any prognostic factor and thus concluded that combined chemo-radiotherapy benefits all subgroups of patients with GBM.
van Genugten et al.,  in 2010, reported the results of 125 patients treated with RT alone (58 patients) versus chemo-radiotherapy (67 patients). They observed 1-year and 2-year OS of 46.8% and 18% respectively in temozolomide arm. These Figures are very much similar to our study. Their 1-year and 2-year PFS rates of 26.6% and 9.5% are also not very different from our study (34% and 12%).
Hematological toxicity is the main toxicity associated with temozolomide. The frequency of severe hematological toxicity reported in most trials ,,, is less than 10%. Such toxicity was 7% during the concomitant therapy in our study. Incidence of other complications like pneumonitis, skin rash in our study is also within acceptable limits.
Subgroup analysis revealed absence of seizures and 6 cycles of adjuvant temozolomide therapy as the significant prognostic factors in our study. Other factors like age, sex, anatomical location, KP score, extent of surgery etc failed to show any significant impact on survival. On multivariate analysis, adjuvant temozolomide therapy with 6 cycles was found to be significant prognostic factor but the absence of seizures did not affect the prognosis. Erpolat et al. also found that patients completing 6 cycles of adjuvant temozolomide therapy had significantly better outcome. They observed a median survival of 22.7 months for patients completing 6 cycles of adjuvant temozolomide as compared to 12 months for patients not completing 6 cycles of therapy and this difference was statistically significant (P value 0.011).
Absence of seizures as a favorable prognostic factor is the surprise finding of our study, though only on univariate analysis. Generally, patients presenting with seizures have better or equal prognosis but our patients with seizures had significantly inferior survival [Figure 4]. However, we will analyze this factor in detail in near future and probably report it, if worth. Since these patients are routinely prescribed anti-epileptics for minimum of 2 years, interaction of temozolomide and antiepileptics cannot be ruled out. We could come across only limited literature , pertaining specifically to prognostic significance of seizures in GBM patients. Ozbek et al. retrospectively analysed 76 patients of GBM to study the prognostic significance of seizures at initial presentation. Eleven patients (14%) presented with seizures as compared to 28% in our study. They observed significant superior survival in patients presenting with seizures on univariate (P value 0.026) as well as multivariate analysis (P value 0.043). Whittle et al. studied the seizures, though in patients with oligodendroglial tumors, and found that patients with seizures had a significantly lower age ( P<0.001) at diagnosis (median 36 years) than those without seizures (57 years). Based on the results, they suggested that younger age, but not the presence of seizures, is a significant independent prognostic variable. Curran et al. also showed that history of seizures did not play a significant role in the outcome of malignant glioma.
In conclusion, treatment of GBM with PORT plus concomitant and adjuvant temozolomide provides comparable results in terms of survival and toxicity in our group of patients. Our results further authenticate the role of temozolomide chemotherapy in the management of GBM. We strongly recommend complete 6 cycles of adjuvant temozolomide therapy based on better survival in this subgroups of patients in our study. The compliance with constant dose of adjuvant temozolomide (150 mg/m 2 ) throughout 6 cycles in our study was found better than escalated dose schedule (200 mg/m 2 ) used in the literature and therefore, we suggest the un-intensified dose schedule. The prognostic significance of seizures at presentation in GBM patients treated with PORT plus concomitant and adjuvant temozolomide and the effect of anticonvulsant drugs should be further studied.
| > References|| |
|1.||Siker ML, Donahue BR, Vogelbaum MA. Primary Intracranial Neoplasms. In: Halperin EC, Parez CA, Brady LW, editors. Perez and Brady's Principles and Practice of Radiation Oncology. 5 th ed. Philadelphia: Lippincott Williams and Wilkins; 2008. p. 718-50. |
|2.||DeAngelis LM. Brain tumors. N Engl J Med 2001;344:114-23. |
|3.||Kristiansen K, Hagen S, Kollevold T, Torvik A, Holme I, Nesbakken R, et al. Combined modality therapy of operated astrocytomas grade III and IV. Confirmation of the value of postoperative irradiation and lack of potentiation of bleomycin on survival time : a0 prospective multicenter trial of the Scandinavian Glioblastoma Study Group. Cancer 1981;47:649-52. |
|4.||Walker MD, Green SB, Byar DP, Alexander E Jr, Batzdorf U, Brooks WH, et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980;303:1323-9. |
|5.||Walker MD, Alexander E Jr, Hunt WE, MacCarty CS, Mahaley MS Jr, Mealey J Jr, et al. Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978;49:333-43. |
|6.||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. |
|7.||Fine HA, Dear KB, Loeffler JS, Black PM, Canellos GP. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993;71:2585-97. |
|8.||Athanassiou H, Synodinou M, Maragoudakis E, Paraskevaidis M, Verigos C, Misailidou D, et al. Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol 2005;23:2372-7. |
|9.||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. |
|10.||Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277-80. |
|11.||Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Assoc 1958;53:457-81. |
|12.||Stewart LA. Chemotherapy in adult high-grade glioma : a0 systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002;359:1011-8. |
|13.||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. |
|14.||van Genugten JA, Leffers P, Baumert BG, Tjon-A-Fat H, Twijnstra A. Effectiveness of temozolomide for primary glioblastoma multiforme in routine clinical practice. J Neurooncol 2010;96:249-57. |
|15.||Erpolat OP, Akmansu M, Goksel F, Bora H, Yaman E, Büyükberber S. Outcome of newly diagnosed glioblastoma patients treated by radiotherapy plus concomitant and adjuvant temozolomide : a0 long-term analysis. Tumori 2009;95:191-7. |
|16.||Ozbek N, Cakir S, Gursel B, Meydan D. Prognostic significance of seizure in patients with glioblastoma multiforme. Neurol India 2004;52:76-8. |
|17.||Whittle IR, Beaumont A. Seizures in patients with supratentorial oligodendroglial tumours. Clinicopathological features and management considerations. Acta Neurochir (Wien) 1995;135:19-24. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3], [Table 4]