Effect of Concomitant and Adjuvant Temozolomide on Prognosis and Survival in Glioblastoma Multiforme

Öz

Objective: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The most common problem in the follow-up after GBM treatment is the lack of local control. This study aims to evaluate the efficacy and safety of Temozolomide (TMZ) in cases who received post-surgical radiotherapy and TMZ treatment in GBM compared to cases who received only radiotherapy treatment after surgery. Materials and Methods: The cases diagnosed with GBM were divided into two groups. The first group was divided into cases that received only radiotherapy after surgery, and the second group (combined treatment group) was divided into cases that received post-surgical radiotherapy and TMZ treatment. 28 cases who received radiotherapy and TMZ treatment after surgery and 26 cases who received only radiotherapy after surgery were included in the study. Local fractionated radiotherapy (60 Gy total dose: 2 Gyx5 days/week for 6 weeks) was applied to all cases. Only in the second group, 75 mg/m2/day 7 days/week orally, 200 mg/m2/day 5 days as monotherapy for 6 weeks, and six cycles of TMZ every 28 days were administered concomitantly. In addition to the effect of TMZ on prognosis and survival, the effects of age, gender, and resection size on progression-free survival (PSS) and overall survival (GSS) were evaluated in both groups. Results: There was no statistically significant benefit in terms of both PFS and OS in both groups for age and gender, a statistically significant benefit was found for resection size (total-subtotal). At the end of the study, PFS was 14 months in the combined treatment group and 6 months in the radiotherapy alone group (P<0.0001). OS was 16 months in the combined treatment group and 12.5 months in the radiotherapy alone group (P=0.0354). Conclusion: Combined (RT + TMZ) treatment after total surgical treatment was found to be more effective on prognosis and survival than radiotherapy alone.

Anahtar Kelimeler

• Glioblastoma Multiforme
• Temozolomide
• Surgery

Glioblastoma Multiforme’de Konkomitant ve Adjuvant Temozolomid’in Prognoz ve Sağkalıma Etkisi

Öz

Amaç: Glioblastoma multiforme (GBM) erişkinde en sık görülen malign primer beyin tümörüdür. GBM tedavi sonrası izlemde en sık karşılaşılan problem lokal kontrolün sağlanamamasıdır. Bu çalışmada amaç, GBM'de cerrahi sonrası radyoterapi ve Temozolomid (TMZ) tedavisi alan olguların, cerrahi sonrası sadece radyoterapi tedavisi alan olgunlara göre TMZ 'in etkinlik ve güvenilirliğini değerlendirmektir. Gereç ve yöntemler: GBM teşhisi almış olgular iki gruba ayrıldı. Birinci grup cerrahi sonrası sadece radyoterapi tedavisi gören olgular, ikinci grup ise (kombine tedavi grubu) cerrahi sonrası radyoterapi ve TMZ tedavisi gören olgular olarak ayırıldı. Cerrahi sonrası radyoterapi ve TMZ tedavisi alan 28 olgu ve cerrahi sonrası sadece radyoterapi verdiğimiz 26 olgu çalışmaya alınmıştır. Tüm olgulara lokal fraksiyone radyoterapi (60 Gy toplam doz: 2 Gyx5 gün/hafta, 6 hafta boyunca) uygulandı. Sadece ikinci gruba konkomitan olarak oral yoldan 75 mg/m2/gün 7gün/hafta, 6 hafta boyunca monoterapi olarak 200 mg/m2/gün 5gün, altı siklus her 28 günde bir TMZ uygulandı. TMZ prognoz ve sağkalım üzerine etkisine ilave olarak yaş, cinsiyet ve rezeksiyon boyutunun her iki grupta progresyonsuz sağkalım süresi (PSS) ve genel sağkalım süresi (GSS) üzerine etkisi değerlendirildi. Bulgular: Her iki gruptada önemli prognostik faktörlerden, yaş ve cinsiyet için hem PSS, hem de GSS bakımından istatistiksel olarak anlamlı olmayan yarar saptanırken, rezeksiyon boyutu (total-subtotal) için istatistiksel olarak anlamlı yarar saptandı. Çalışma sonucunda PSS, kombine tedavi grubunda 14 ay, tek başına radyoterapi grubunda ise 6 ay idi (P<0.0001). GSS, kombine tedavi grubunda 16 ay, tek başına radyoterapi gurubunda ise 12.5 ay idi (P=0,0354). Sonuç: Total cerrahi tedavi sonrası kombine (RT + TMZ) tedavi, tek başına radyoterapiye göre prognoz ve sağkalım üzerinde daha etkili olduğu saptanmıştır.

Anahtar Kelimeler

• Glioblastoma multiforme
• temozolomid
• radyoterapi
• cerrahi

Kaynakça

1. 1.Grochans S, Cybulska AM, Simińska D, et al. Epidemiology of Glioblastoma Multiforme–Literature Review. Cancers. 2022; 14(10): 2412-32. https://doi.org/10.3390/cancers14102412
2. 2.Perry A, Wesseling P. Histologic classification of gliomas. Handb Clin Neurol. 2016; 134: 71-95. https://doi.org/10.1016/B978-0-12-802997-8.00005-0.
3. 3.Batash R, Asna N, Schaffer P, et al. Glioblastoma multiforme, diagnosis and treatment; recent literature review. Current medicinal chemistry. 2017; 24(27): 3002-09. https://doi.org/10.2174/0929867324666170516123206
4. 4.Makowska M, Smolarz B, Romanowicz H. microRNAs (miRNAs) in Glioblastoma Multiforme (GBM)—Recent Literature Review. International Journal of Molecular Sciences. 2023; 24(4): 3521. https://doi.org/10.3390/ijms24043521
5. 5.Ozawa T, Faddegon AB, Hu JL. Response of ıntracerebral human glioblastoma xenografts to multifraction radiation exposures. Int J Radiat Oncol Biol Phys. 2006;66:263-70. https://doi.org/10.1016/j.ijrobp.2006.05.010
6. 6.Iturrioz-Rodríguez N, Sampron N, Matheu A. Current advances in temozolomide encapsulation for the enhancement of glioblastoma treatment. Theranostics. 2023; 13(9): 2734-56. https://doi.org/10.7150/thno.82005
7. 7.Janjua TI, Cao Y, Ahmed-Cox A, et al. Efficient delivery of Temozolomide using ultrasmall large-pore silica nanoparticles for glioblastoma. J Control Release. 2023; 357: 161-74. https://doi.org/10.1016/j.jconrel.2023.03.040
8. 8.Mason WP, Cairncross JG. Drug Insight: temozolomide as a treatment for malignant gliomaimpact of a recent trial. Nat Clin Pract Neurol. 2005; 1: 88-95. https://doi.org/10.1038/ncpneuro0045

9. 9.Major N, Patel NA, Bennett J, et al. The Current State of Radiotherapy for Pediatric Brain Tumors: An Overview of Post-Radiotherapy Neurocognitive Decline and Outcomes. Journal of Personalized Medicine. 2022; 12(7): 1050. https://doi.org/10.3390/jpm12071050
10. 10.Stupp R, Mason WP, Van Den Bent MJ. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-96. https://doi.org/10.1056/NEJMoa043330
11. 11.Woo PYM, Law THP, Lee KKY, et al. Repeat resection for recurrent glioblastoma in the temozolomide era: a real-world multi-centre study. Br J Neurosurg. 2023; 18: 1-9. https://doi.org/10.1080/02688697.2023.2167931
12. 12.Di L, Shah AH, Mahavadi A, et al. Radical supramaximal resection for newly diagnosed left-sided eloquent glioblastoma: safety and improved survival over gross-total resection. J Neurosurg. 2022; 138(1): 62-9. https://doi.org/10.3171/2022.3.JNS212399
13. 13.Rykkje AM, Larsen VA, Skjøth-Rasmussen J, et al. Timing of Early Postoperative MRI following Primary Glioblastoma Surgery-A Retrospective Study of Contrast Enhancements in 311 Patients. Diagnostics (Basel). 2023; 13(4): 795. https://doi.org/10.3390/diagnostics13040795
14. 14.Stupp R, Dietrich PY, Ostermann Kraljevic S, et al. Promising survival for patients with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus temozolomide followed by adjuvant temozolomide. J Clin Oncol. 2002; 20(5): 1375-82. https://doi.org/10.1200/JCO.2002.20.5.1375
15. 15.Reardon DA, Egorin MJ, Quinn JA, et al. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol. 2005; 36: 9359-68. https://doi.org/10.1200/JCO.2005.03.2185
16. 16.Athanassiou H, Synodinou M, Maragoudakis E, et al. Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme. J Clin Oncol. 2005; 10:2372-7. https://doi.org/10.1200/JCO.2005.00.331
17. 17.Huang B, Yu Z, Liang R. Effect of long-term adjuvant temozolomide chemotherapy on primary glioblastoma patient survival. BMC Neurol. 2021; 21(1): 424. https://doi.org/10.1186/s12883-021-02461-9
18. 18.Revilla-Pacheco F, Rodríguez-Salgado P, Barrera-Ramírez M, et al. Extent of resection and survival in patients with glioblastoma multiforme: Systematic review and meta-analysis. Medicine (Baltimore). 2021; 100(25): e26432. https://doi.org/10.1097/MD.0000000000026432
19. 19.Fariña Nuñez MT, Franco P, Cipriani D, et al. Resection of recurrent glioblastoma multiforme in elderly patients: a pseudo-randomized analysis revealed clinical benefit. Journal of Neuro-Oncology. 2020; 146: 381-7. https://doi.org/10.1007/s11060-020-03393-z
20. 20.Leal-Noval SR, Casado M, Palomares C, et al. Prospective assessment of platelet function in patients undergoing elective resection of glioblastoma multiforme. Platelets. 2023; 34(1): 2216802. https://doi.org/10.1080/09537104.2023.2216802