Multimodal Treatment of Glioblastoma Multiforme: Results of 86 Consecutive Patients Diagnosed in Period 2003–2009

Czech version

Authors: R. Lakomý ^1,2; P. Fadrus ^2,3; P. Šlampa ^1,2; T. Svoboda ^2,3; L. Křen ^2,3; E. Lžičařová ^1,2; R. Belanová ^1,2; I. Šiková ^1,2; A. Poprach ^1,2; M. Schneiderová ^1,2; M. Procházková ^1,2; J. Šána ^1,2; O. Slabý ^1,2; M. Smrčka ^2,3; R. Vyzula ^1,2; M. Svoboda ^1,2
Authors‘ workplace: Masarykův onkologický ústav, Brno ¹; Lékařská fakulta Masarykovy Univerzity, Brno ²; Fakultní nemocnice, Brno ³
Published in: Klin Onkol 2011; 24(2): 112-120
Category: Original Articles

Overview

Backgrounds:
Glioblastoma multiforme is the most common malignant primary tumor of the brain in adults. Standard therapy consists in maximal surgical resection and adjuvant concurrent chemoradiotherapy and adjuvant therapy with temozolomid. This approach improves survival in comparison with postsurgical radiotherapy alone.

Patients and Methods:
Consecutive patients with histologically confirmed glioblastoma multiforme in the period from January 2003 to December 2009 underwent postoperative radiotherapy (1.8–2.0 Gy/d, total of 60 Gy) plus concurrent daily chemotherapy (temozolomide 75 mg/m²/d), followed by 6 cycles of temozolomide (150 to 200 mg/m² for 5 days, every 28 days) and were analyzed retrospectively. The primary end point was to describe the correlation between known clinical factors, treatment and progression free survival (PFS) and overall survival (OS). We assessed the toxicity and safety of the chemoradiotherapy.

Results:
Eighty-six patients (median age, 56 years; 60% male) were included. Most of them (> 80%) were of performance status (PS) 0-1 at the beginning of chemoradiotherapy. Total macroscopic resection was performed in 20% of the patients, subtotal in 65%, partial in 9%, and just biopsy in 6%. Median PFS was 7.0 months (2.0–35.5), median OS was 13.0 months (2.5–70). Postoperative performance status (PS), the extent of resection, and administration of planned treatment without reduction had statistically significant influences on PFS and OS. Median PFS and OS were 22.0, 7.0 and 6.0 months for PFS (p = 0.0018) in patients with PS 0, 1 and 2 respectively and 32.0, 13.0 and 9.0 months for OS (p = 0.0023). Patients with total removal of tumor had longer PFS (14.0 vs 6.0 months, HR = 0.5688; p = 0.0301) and OS (23.0 vs 12.0 months, HR 0.4977; p = 0.0093), as did patients without dose reduction of radiotherapy and/or chemotherapy. Patients with radiotherapy dose of over 54 Gy had PFS 8.0 vs 3.0 months (HR = 0.3313; p = 0.0001) and OS 15.0 vs 5.0 months (HR = 0.1730; p < 0.0001). Similarly, treatment with concurrent chemotherapy for more than 40 days was also important: PFS 8.0 vs 5.0 months (HR = 0.5300; p = 0.0023) and OS 17.0 vs 9.5 months (HR = 0.5943; p = 0.0175). Age, gender and position of tumor had no significant influence. Treatment-related hematology toxicity grades 3 and 4 occurred relatively often: thrombocytopenia (9%), leukopenia (6%), neutropenia (6%) and lymphopenia (25%). Thrombo-embolic events were dominant in non-hematology toxicity. Serious toxicity occurred mainly in the subgroup of patients with PS 2. Treatment of progression was useful in selected patients. Second surgery was of the most benefit (OS 24.0 vs 12.5 months, HR = 0.5325; p = 0.0111).

Conclusion:
Postoperative performance status, extent of resection, successful administration of the majority of planned concurrent chemoradiotherapy and possibility of surgical treatment at the time of recurrence correlate with better prognosis for our patients with glioblastoma. Our experience indicates that performance status should be the main factor in decisions about treatment intensity. Treatment of malignant glioma requires a multidisciplinary team.

Key words:
glioblastoma multiforme – chemotherapy – radiotherapy – survival – toxicity

Sources

1. Laws ER, Parney IF, Huang W et al. Glioma Outcomes Investigators. Survival following surgery and prognostic factors for recently diagnosed malignant glioma: data from the Glioma Outcomes Project. J Neurosurg 2003; 99(3): 467–473.

2. Hentschel SJ, Sawaya R. Optimizing outcomes with maximal surgical resection of malignant gliomas. Cancer Control 2003; 10(2): 190–114.

3. Walker MD, Green SB, Byar DP et al. Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery. N Engl J Med 1980; 303(23): 1323–1329.

4. Kala M, Cwiertka K, Hajdúch M. Nové trendy v chemoterapii nádorů mozku – léčba dle histologických diagnóz. Klin Onkol 2000; 13(4): 107–111.

5. Fine HA, Dear KB, Loeffler JS et al. Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults. Cancer 1993; 71(8): 2585–2597.

6. Stewart LA. Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials. Lancet 2002; 359(9311): 1011–1018.

7. Stupp R, Mason WP, van den Bent MJ et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005; 352(10): 987–996.

8. Stupp R, Hegi ME, Mason WP et al. European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. 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(5): 459–466.

9. Hegi ME, Diserens AC, Gorlia T et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005; 352(10): 997–1003.

10. Esteller M, Garcia-Foncillas J, Andion E et al. Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000; 343(19): 1350–1354.

11. Hegi ME, Diserens AC, Godard S et al. Clinical trial substantiates the predictive value of O-6-methylguanine-DNA methyltransferase promoter methylation in glioblastoma patients treated with temozolomide. Clin Cancer Res 2004; 10(6): 1871–1874.

12. Paz MF, Yaya-Tur R, Rojas-Marcos I et al. CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 2004; 10(15): 4933–4938.

13. Perry JR, Bélanger K, Mason WP et al. Phase II trial of continuous dose-intense temozolomide in recurrent malignant glioma: RESCUE study. J Clin Oncol 2010; 28(12): 2051–2057.

14. Wick A, Pascher C, Wick W et al. Rechallenge with temozolomide in patients with recurrent gliomas. J Neurol 2009; 256(5): 734–741.

15. Nečesalová E, Kuglík P, Cejpek P et al. Studium polyzomie chromozomu 7, monozomie chromozomu 10, amplifikace genu EGFR a delece genu p53 u multiformního glioblastomu pomocí metody fluorescenční in situ hybridizace (FISH). Klin Onkol 2006; 19(1): 9–14.

16. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971; 285(21): 1182–1186.

17. Fine HA, Figg WD, Jaeckle K et al. Phase II trial of the antiangiogenic agent thalidomide in patients with recurrent high-grade gliomas. J Clin Oncol 1999; 18(4): 708–715.

18. Neyns B, Sadones J, Joosens E et al. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol 2009; 20(9): 1596–1603.

19. Rich JN, Reardon DA, Peery T et al. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol 2004; 22(1): 133–142.

20. Peereboom DM, Shepard DR, Ahluwalia MS et al. Phase II trial of erlotinib with temozolomide and radiation in patients with newly diagnosed glioblastoma multiforme. J Neurooncol 2010; 98(1): 93–99.

21. Galanis E, Buckner JC, Maurer MJ et al. Phase II trial of temsirolimus (CCI-779) in recurrent glioblastoma multiforme: a North Central Cancer Treatment Group Study. J Clin Oncol 2005; 23(23): 5294–5304.

22. Reardon DA, Fink KL, Mikkelsen T et al. Randomized phase II study of cilengitide, an integrin-targeting arginine-glycine-aspartic acid peptide, in recurrent glioblastoma multiforme. J Clin Oncol 2008; 26(34): 5610–5617.

23. Vredenburgh JJ, Desjardins A, Herndon JE 2nd et al. Bevacizumab plus irinotecan in recurrent glioblastoma multiforme. J Clin Oncol 2007; 25(30): 4722–4729.

24. Friedman HS, Prados MD, Wen PY et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009; 27(28): 4733–4740.

25. Radiation Therapy Oncology Group 0825, American College of Radiology. Phase III double-blind placebo-controlled trial of conventional concurrent chemoradiation and adjuvant temozolomide plus bevacizumab versus conventional concurrent chemoradiation and adjuvant temozolomide in patients with newly diagnosed glioblastoma [online]. September 29, 2009. Cited 2010-01-20. Available from: http://www.rtog.org/members/protocols/0825/0825.pdf.

26. Batchelor TT, Duda DG, di Tomaso E et al. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 2010; 28(17): 2817–2823.

27. Batchelor T, Mulholland P, Neyns B et al. A phase III randomized study comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, with lomustine alone in recurrent glioblastoma patients. Ann Oncol 2010; 21 (Suppl 8): viii4.