Merkezi Sinir Sistemi Tümörleri/Yüksek Dereceli Glioma

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Glioblastoma ve Yüksek Dereceli Gliomalar


Patoloji[değiştir]

  • University of Calgary, 2007 PMID 17696644 -- "The p75 Neurotrophin Receptor Is a Central Regulator of Glioma Invasion" (Johnston AL, PLoS Biol 5(8): e212, 2007)
    • Glioma fare modeli. Glioma invazyonu için p75 nörotrofin reseptörü (p75NTR)kritik düzenleyici olarak tanımlanmış. Bu invazyon nörotrofine bağlı ve hücre iskeletinde değişiklikler ile sonuçlanıyor.

Prognoz[değiştir]


  • EORTC 26981 / NCIC
    • Çalışma detayları için adjuvant therapy sayfasına gidebilirsiniz
    • RTOG RPA Validasyonu; 2006 PMID 16735709 -- Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. (Mirimanoff RO, J Clin Oncol. 2006 Jun 1;24(16):2563-9.)
      • Çalışmada RPA'nın prediktif gücü değerlendirilmiş. RPA şu şekilde adapte edilmiş
      • Sonuç: RPA prognostik önemini koruyor
Malign gliomalar için adapte edilmiş RPA Evreleri (Temozolomide ile sağkalım)
Evre Özellikler Medyan OS 2-yıllık OS p-değeri vs. kontrol
III Yaş <50, PS 0 21 vs. 15 ay %43 vs. %20 p<0.0001
IV Yaş <50, PS 1-2
Yaş >=50, Cerrahi, MMSE >=27
16 vs. 13 ay %28 vs. %11 p<0.01
V Yaş >=50, Yalnızca bx veya MMSE <27 10 vs. 9 ay %17 vs. %6 p=0.05
    • Nomogram; 2008 PMID 18082451 -- "Nomograms for predicting survival of patients with newly diagnosed glioblastoma: prognostic factor analysis of EORTC and NCIC trial 26981-22981/CE.3." (Gorlia T, Lancet Oncol. 2008 Jan;9(1):29-38. Epub 2007 Dec 21.)
      • Subanaliz. 573 hasta. RT + TMZ grubu (n=287), ve RT + TMZ grubu (MGMT durumu + olanlar)(n=103)
      • Nomograms: Medyan ve 2-yıllık sağkalımı öngörmek için geliştirilmişler. EORTC GBM Calculator sayfasından ulaşılabilir
      • Sonuç: MGMT promoter metilasyon durumu, yaş, performans durumu, rezeksiyon genişliği, ve MMSE gelecekteki çalışmalarda kullanılabilecek seçim ve stratifikasyon faktörleri olarak önerilmiş.
      • Yorum (editör): RTOG RPA sınıflamasından daha doğru. MGMT durumu belli olan hastalar için yaş multivaryant analizlerde etkili çıkmamış. Yalnızca MGMT durumu, Performans Skoru ve MMSE.
  • RTOG RPA; 1993 (1974-1989) - PMID 8478956 -- "Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials." Curran WJ et al. J Natl Cancer Inst. 1993 May 5;85(9):704-10.
    • RTOG / ECOG 1374, RTOG 79-18, ve RTOG 83-02 analizi. 74-01'de 1578 hasta vardı.
    • Yaş <50 veyar >=50 sağkalım için en önemli belirleyici.
GBM WHO Grade IV için RPA Evreleri (TMZ'siz)
Evre Özellikler Medyan Sağkalım (ay) 1-yıllık OS 2-yıllık OS
III Yaş <50, KPS 90-100 18 %70 %35
IV Yaş <50, KPS <90 veya
Yaş >=50, cerrahi rezeksiyon, iyi nörolojik fonksiyon
11 %45 %15
V Yaş >=50, KPS >=70, cerrahi rezeksiyon, çalışamaz veya
Yaş >= 50, KPS >= 70, yalnızca bx ve 54.4 Gy üzerinde RT veya
Yaş >=50, KPS <70 ve normal MS
9 %30 %6
VI Yaş >=50, KPS >=70, yalnızca bx ve 54.4 Gy üzerinde RT veya
Yaş >=50, KPS <70, anormal MS
5 %20 %4
  • Bu çalışmanın yeniden gözden geçirilmesinde (Abstract olarak yayınlanmış) 5 ve 6 grupları tek bir risk grubunda değerlendirmek daha doğru
  • RTOG Validasyonu; 1998 PMID 9422557 -- "Validation and predictive power of Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis classes for malignant glioma patients: a report using RTOG 90-06." (Scott CB, Int J Radiat Oncol Biol Phys. 1998 Jan 1;40(1):51-5.)
    • Yeni veri setini (RTOG 90-06) kullanarak RPA sınıflamasının validasyonu
    • Bulgular: Medyan OS ve 2-yıllık OS %95 güvenlik aralığında; '. sınıf haricinde tüm sınıflarda fark istatistiki olarak bariz (p<0.0001)
    • Sonuç: RPA sınıflarının validasyonu, gelecekteki Faz II çalışmalar için faydalı tarihi kontrol grubu.

Prognoz için biyolojik belirteçler[değiştir]

  • Duke; 2005 PMID 16282174 -- "Glioblastoma multiforme and the epidermal growth factor receptor." (Friedman HS, N Engl J Med. 2005 Nov 10;353(19):1997-9.)
    • EGFR gen amplifikasyonu
    • EGFR gen mutasyonu (en sık olanı EGFRvIII'dir)
    • Tümör süpresör olan PTEN kaybı
    • PDGFR α fazla ekspresyonu
  • Mutasyona uğramış p53
  • 1p ve 19q kromozomlar için heterozigosite kaybı, ilk olarak anaplastik oligodendrogliomalarda tanımlanmıştır.
  • MGMT onarım geni


MGMT[değiştir]

  • O6-methylguanine-DNA methyltransferase (MGMT) DNA onarım enzimidir. TMZ tedavisiyle bu enzim azaltılır.
  • MGMT geni 10q26 kromozumunda bulunur. Gen ürünü guaninin O6 pozisyonundan alkil grup ayırır. Bu bölge DNA alkilleyici ajanları için önemli bir DNA metilasyon bölgesidir.
  • Tümördeki yüksek MGMT seviyeleri bu çeşit kemoterapilere direnç yaratır.
  • Tümördeki düşük MGMT seviyeleri Nitroüre-tabanlı kemoterapi uygulanan GBM hastalarında daha uzun sağkalım ile ilişkilidir.
  • Promoterinin metilasyonu ile oluşan MGMT gen sessizliği daha iyi sağkalım iyi ilişkilidir.
  • EORTC / NCI Canada; 2005 - PMID 15758010 — "MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma." Hegi ME et al. NEJM 352:997-1003, 2005.
    • MGMT metilasyonu EORTC / NCI Canada çalışmasındaki hastalarda analiz edilmiş. 206 hasta analiz edilmiş. Hastaların %44'ünde PCR ile tespit edilebilen MGMT promoter metilasyonu mevcutmuş. Metile grupta çlümde %55 azalma varmış(HR=0.45). Medyan sağkalım 18.2 ay vs 12.2 ay. Metile grup için RT + TMZ grubunda tekbaşına RT grubuna göre bir fayda varmış (HR=0.21). Metilasyon olmayan rupta bu fark daha az olarak bulunmuş. 2-yıllık OS metile grupta %46 (RT+TMZ), %23 (tekbaşına RT); metile olmayan grupta %13.8 ve %2. Metile grupta medyan sağkalım 21.7 ay (RT + TMZ) metile olmayan grupta ise 12.7 ay (RT + TMZ) vs 11.8 ay (RT).
    • Metile grup için (RT+TMZ) 2-yıl OS %46 , %23 (tekbaşına RT)
    • Sonuç: TMZ'den fayda metile MGMT promoterli hastalarda daha fazla.

Kanser biyolojisi[değiştir]

Radyobiyoloji:

  • Birmingham, 2007 (UK) PMID 17324531 -- "Estimation of radiobiologic parameters and equivalent radiation dose of cytotoxic chemotherapy in malignant glioma." (Jones B, Int J Radiat Oncol Biol Phys. 2007 Jun 1;68(2):441-8.)
    • Medyan tümör α/β 9.3; medyan hücresel ikilenme zamanı 39.5 gün
    • Temozolomide: medyan eşdeğer BED 11Gy (2 Gy/fx'te 9.1 Gy)


Radyodirenç:

  • Duke, 2006 - PMID 17051156 — "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response." Bao S et al. Nature. 2006 Dec 7;444(7120):756-60.

Tedavi[değiştir]

  • Cerrahi primer tedavi modalitesidir. Cerrahiye uygun olmayanlar ve yalnızca Bx uygulanan hastaların sonuçları kötüdür.
  • Post-op EBRT standart tedavidir.
    • 30 fraksiyonda 60 Gy (doz eskalasyonu ya da farklı fraksiyonasyon şemalarının faydası yok)
    • >60 yaş üzeri hastalarda 40Gy/15fr 60Gy/30fr ile benzer sonuçlar veriyor.
    • >70 yaş üzeri ve KPS >=70 hastalarda, RT 50/28 GY destek tedavi ile kaşılaştırıldığında QoL veya konitif fonksiyonlarda düşmeye yol açmadan ( orta düzeyde sağkalım faydası (medyan 29 hafta vs. 17 hafta) sağlıyor.
    • >70 yaş üzeri ve kötü KPS, tekbaşına destek tedavi uygun bir seçenek.
  • Post-op RT'ye temozolomid eklenmesi halen etkili bir standart tedavi şekli.

Cerrahi[değiştir]

Derleme

  • Singapore, 2007 PMID 17549284 -- "The Role of Surgery in High-grade Glioma - Is Surgical Resection Justified? A Review of the Current Knowledge." (Pang BC, Ann Acad Med Singapore. 2007 May;36(5):358-6.)

Radyoterapi[değiştir]

RT vs. Destek Tedavi[değiştir]

  • BTCG 69-01 ve 1981 SGSG çalışmaları RT'nin destek tedaviden çok daha iyi sağkalım sonuclarına (iki kat) ve RT tedavinin standart bileşenidir.
  • 2002 Derleme PMID 12242114 -- "Radiotherapy for newly diagnosed malignant glioma in adults: a systematic review." (Laperriere N, Radiother Oncol. 2002 Sep;64(3):259-73.)
    • 6 randomize çalışmanın verilerinin toplanması ve değerlendirilmesi sonucunda: destek tedavi ile karşılaştırıldığında RT lehine bariz sağkalım faydası gösterilmiştir (1 yıllık mortalite için RR 0.81)
  • SGSG, 1981 -- "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: a prospective multicenter trial of the Scandinavian Glioblastoma Study Group." (Kristiansen K, Cancer. 1981 Feb 15;47(4):649-52.)
    • Randomize. 118 hasta. Grade III/IV. Kol 1) 45 Gy WBRT + bleomycin, kol 2) 45 Gy WBRT, kol 3) destek tedavi
    • Medyan OS: 10.8 ay vs. 10.8 ay vs. 5.2 ay (SS)
    • Sonuç: RT dramatik olarak destek tedaviden daha iyi. Bleomycin'in ekstra katkısı yok.
  • BTSG 69-01 -- BCNU vs RT vs RT + BCNU vs İzlem
    • Randomize, 4 kol. 303 hasta, anaplastik glioma, cerrahi ve steroid sonrası. Kol 1) Tekbaşına BCNU, kol 2) Tekbaşına RT, kol 3) RT + BCNU, kol 4) destek tedavi. BCNU 1-3 günlerde her 6-8 hafta bir uygulanmış. RT 50-60 Gy tüm beyine uygulanmış.
    • 1978 PMID 355604 -- "Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial." (Walker MD, J Neurosurg. 1978 Sep;49(3):333-43.)
      • Sonuç: medyan OS OBS 3.2 ay vs. BCNU 4.2 ay vs. RT 8.1 ay vs. RT + BCNU 8.0 ay (SS)
      • Toksisite: Kabul edilebilir trombositopeni ve lökopeni
    • Not: Bu çalışma RT'nin destek tedaviden daha iyi olduğunu söyleyen ilk çalışmadır.

Yaşlıda:

  • France (Association of French-Speaking Neuro-Oncologists), 2007 (2001-2005) - PMID 17632898 -- "Radiotherapy for Glioblastoma in the Elderly." Keime-Guibert F et al. New Engl J Med. 2007 Apr 12;356(15):1527-1535.
    • Randomize. Cerrahi sonrası RT veya destek tedaviye randomize edilmişler.
    • 85 hasta. >70 yaş, GBM veya AA, KPS >=70. Cerrahi %50 hastada yalnızca Bx. Destek tedavi steroid ve antiepileptikleri içeriyor. RT CTV'ye(kontrastlanan tümör + 2 cm) 180cGy/fx da toplam 50 Gy uyguanmış. Ön sonuç analizinden sonra çalışma durdurulmuş.
      • Medyan takip 21 hafta. 21'inci haftada hastaların %90'ı ölmüş. RT grubunda hastaların ölümünde %53 azalma rapor edilmiş. madyan sağkalım 12 hafta fayda etmiş (29.1 vs 16.9 hafta). PFS 14.9 hafta vs 5.4 hafta. QoL ve nöropsikiyatrik ölçümlerde iki grup arasında fark yok, her iki parametrede zamanla azalmakta.
    • Sonuç: Yaşlı hastalarda RT QoL'ı olumsuz etkilemeden sağkalımda orta düzeyde bir iyileşmeye neden olmaktadır.

WBRT vs. Lokal RT[değiştir]

  • Halen kullanılan tedavi alanları (RTOG tanımlaması):
    • Önce preop BT/MRG'de kontrast tutan lezyon ve çevreleyen ödem ile birlikte + 2 cm marj ile oluşan tedavi volümüne 46 Gy/23 fx. Eğer ödem yoksa marj 2.5 cm olmalıdır.
    • Daha sonra 14 Gy/7 fx boost eklenmeli: tedavi volümü yalnızca kontrast tutan lezyon + 2.5 cm marj ile çizilir.
  • WBRT ile karşılaştırılabilen sonuçlar
  • %80-90 recurrence is lokaldir (BT'de kontrastlanan lezyonun + 2 cm içinde)
  • WBRT ile ilişkili nörotoksisiteden kaçınılmaktadır
  • WBRT multifokal hastalıkta önerilebilir, fakat bu durumda nadirdir.
  • MD Anderson, 1991 - PMID 1851573 -- Outcome and patterns of failure following limited-volume irradiation for malignant astrocytomas. (Garden AS, Radiother Oncol. 1991 Feb;20(2):99-110.)
    • Retrospektif. GBM'li 39 AA'lı 21 olmak üzere toplam 60 hasta 1982-1986 yılları arasında tedavi edilmşlerdir.
    • RT: 53'ü lokal alandan tedavi edilmiş, 7 si WBRT ile tedavi edilmiştir.
  • BTCG 80-01, 1989 - PMID 2661738 -- Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001. (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
    • Randomize. 571 hasta 3 kemoterapi rejimine randomize edilmiş.
    • RT hastaları 1982-1983: WBRT 60.2 Gy
    • RT hastaları 1982-1983: WBRT 60.2 Gy veya WBRT 43 Gy + 17.2 Gy boost tedavisine randomize edilmişlerdir.
    • Sonuç: Sağkalımda fark yoktur. WBRT + boost WBRT kadar etkilidir

Marjlar

  • Tubingen (Germany), 1994 - PMID 8184112 -- Malignant glioma: patterns of failure following individually tailored limited volume irradiation. (Hess CF, Radiother Oncol. 1994 Feb;30(2):146-9.)
    • Retrospektif. 66 hasta. RT: 60 Gy, CTV = GTV + 2cm
    • %86 yineleme tedavi volümü içinde ortaya çıkmıştır.
    • Sonuç: Sınırlı alanlar uygundur.
  • Duke, 1989 - PMID 2557310 -- Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post-mortem topographic anatomy with CT correlations. (Halperin EC, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1347-50.)
    • GBM'li 15 hasta, BT görüntüleri rehberliğinde Bx ve tedavi alanlarıyla karşılaştırılmış.
    • 9/11 olguda, kontrast tutan lezyon + 1 cm marj tümörü kaçırmış.
    • 5/11 olguda, kontrast tutan lezyon + ödem + 1cm marj tümörü kaçırmış
    • kontrast tutan lezyon + ödem + 3cm marj tümörü kapsamak için gerekli (11 hastanın sonuçlarına göre)
    • Tümör sinr yolakları boyunca ilerliyor ve sıklıkla corpus callosum'u geçiyor.
  • MSKCC, 1989 - PMID 2542195 -- Patterns of failure following treatment for glioblastoma multiforme and anaplastic astrocytoma. (Wallner KE, Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1405-9.)
    • Retrospektif. 34 BT görüntüleri değerlendirildi (GBM 25, AA 9); 1983-1987 yıllarında tedavi edildi.
    • Yineleme: %78 cerrahi tümör sınırı + 2 cm içinde tekraklamış. Yalnızca 1 olguda karşı hemisferde tekrarlamış
    • Sonuç: Parsiyel beyin ışınlaması uygun
  • PMID 3033172 -- Imaging-based stereotaxic serial biopsies in untreated intracranial glial neoplasms. (Kelly PJ, J Neurosurg. 1987 Jun;66(6):865-74.)
    • Tedavi edilmemiş glial neoplazmı olan 40 hastaya, BT ve MRI ile seri bx (195 biyopsi örneği) yapılmış.
    • Kontrast tutulumu tümör dokusuyla çok büyük oranda ilişkili kontrast tutulumu olmayan dokuda tümör yok.
    • Parankimdeki hipodansite izole tümör hücreleri ya da düşük dereceli gliomalar.
    • İzole tümör hücre infiltrasyonu MRG'deki T2 görüntülerine uzanıyor.
  • PMID 6252514 -- Assumptions in the radiotherapy of glioblastoma. (Hochberg FH, Neurology. 1980 Sep;30(9):907-11.)
    • 35 BT görüntüsü değerlendirilmiş ve otopsilerle karşılaştırılmış.
    • Gross ve mikroskopik tümör uzanımı (2 cm içinde) hastaların 29/35'inde gösterilmiş. Subependimal yayılıma bağlı olarak 4 olguda kaçırılmış.
    • Multisentrisite tedavi edilmeyen hastaların %4'ünde ve tedavi edilenlerin %6'sında görülmüş. tüm lezyonlar BT'de saptanmış.
    • 2 cm marj içinde yineleyen hastalık oranı %90. Daha ötede tekrarlayan hastlıklar BT'de gösterilmiş.

BT/MRG füzyonu

  • Michigan, 1992 - PMID 1429103 -- The clinical utility of magnetic resonance imaging in 3-dimensional treatment planning of brain neoplasms. (Thornton AF, Int J Radiat Oncol Biol Phys. 1992;24(4):767-75.)
    • MRG T1 BT tümör volümü ile ve MRG T2 BT ödem alanı ile korole bulunmuş.
    • Her iki modaliteyi de kullanmak gerekiyor: Her iki çalışmada da %43 füzyon yapılmış volüm görülmüşken, yalnıca MRG'de %37 tümör volümü ve yalnızca BT'de %20 tümör volümü görülebilmiş.

Doz Tanımlamaları[değiştir]

  • Bugün önerilen doz 30 fraksiyonda 60 Gy'dir
  • >60 hastalar için 15 fraksiyonda 40 Gy (ABD'de15 fraksiyonda 45 Gy daha yaygın olarak kullanılmaktadır)


  • Cross Cancer Inst (Canada), 2004 - PMID 15051755 -- Abbreviated course of radiation therapy in older patients with glioblastoma multiforme: a prospective randomized clinical trial. (Roa W, J Clin Oncol. 2004 May 1;22(9):1583-8.)
    • Randomize. >60 yaş 100 hasta 1) RT 60Gy/30fx, ve 2) 40Gy/15fx. Standart RTOG alanları
    • Medyan OS: 5.1 ay vs. 5.6 ay (NS). 40Gy/15fx gruba daha az kortikosteroid ihtiyacı olmuş.
    • Sonuç: yaşlı hastalar için uygun tedavi seçeneği
  • RTOG 98-03, 1998-2003 ASTRO Abstract -- Phase I/II Conformal Three-Dimensional Radiation Therapy Dose Escalation Study in Patients with Supratentorial Glioblastoma Multiforme: Report of the Radiation Therapy Oncology Group 98-03 Protocol. (Werner-Wasik, ASTRO 2004, Abstract 2769)
    • Faz I/II. 209 hasta 3B-konformal RT ile 66 Gy, 72 Gy, 78 Gy ve 84 Gy ile doz artışı yapılmış. Tümör hacmine göre stratifikasyon yapılmış. Aynı zamanda ödem volümünü tedavi alanına dahil etmemenin etkisi araştırılmış.
    • RT PTV1: 2 Gy/fx 46 Gy GTV + 15mm + 3mm
    • RT PTV2: 2 Gy/fx 66 Gy, 72 Gy, 78 Gy ve 84 Gy GTV + 3mm boost
    • Sonuç: Doz artışı uygun.
  • Michigan 2002 - PMID 11896114 -- Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy. (Chan JL, J Clin Oncol. 2002 Mar 15;20(6):1635-42.)
    • Retrospektif. 34 hasta 3-B konformal tedavi ile 90 Gy tedavi edilmişler. Medyan takip 11.7 ay
    • Yineleme: %78 santral, %13 alan içinde, %9 sınırda, %0 distal. Medyan OS 11.7 ay, 1-yıllık OS %47, 2-yıllık OS %13
    • Sonuç: Lokal başarısızlık yine devam ediyor
  • MRC BR2,1991 - PMID 1654987 -- A Medical Research Council trial of two radiotherapy doses in the treatment of grades 3 and 4 astrocytoma. The Medical Research Council Brain Tumour Working Party. (Bleehen NM, Br J Cancer. 1991 Oct;64(4):769-74.)
    • Randomize. 474 hasta post-op 20 fraksiyonda 45 Gy vs. 30 fraksiyonda 60 Gy 1:2 randomizasyon kullanılmış
    • RT Kol 1: 45 Gy/20 fx tüm bilinen ve potansiyel tümör alanlarına
    • RT Kol 2: 60 Gy/20 fx
    • Medyan OS: 9 ay vs. 12 ay (SS); Ek bir akut RT toksisitesi yok.
  • RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, -- "Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group." (Nelson DF et al. NCI Monogr. 1988;(6):279-84.)
    • Randomize. Yüksek dereceli glioma. 1) 60 Gy WBRT vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60 Gy + CCNU + Dacarbazine
    • Medyan OS: 60 Gy WBRT 9.3 ay vs. 60 Gy WBRT + 10 Gy boost 8.2 ay (NS)
  • BTSG PMID 231022 -- An analysis of dose-effect relationship in the radiotherapy of malignant gliomas. (Walker MD, Int J Radiat Oncol Biol Phys. 1979 Oct;5(10):1725-31.)
    • Medyan OS: RT'siz 18 hafta vs. 50 Gy 28 hafta vs. 55 Gy 36 hafta vs. 60 Gy 42 hafta
  • MRC Meta-analysis, 2002: PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8.
    • Meta-analiz, 12 çalışma, 3004 hasta. Primer olarak kemoterapi etkisine bakan bir çalışma, fakat RT analizi de yapılmış
    • Çalışmalar RT 60 Gy vs. RT <60 Gy: HR 0.88 vs. HR 0.77 (p=0.1). fark yok.

Hiperfraksiyonasyon[değiştir]

  • RTOG 94-11, 1994-1995 - PMID 11121633 -- Phase II, two-arm RTOG trial (94-11) of bischloroethyl-nitrosourea plus accelerated hyperfractionated radiotherapy (64.0 or 70.4 Gy) based on tumor volume (> 20 or < or = 20 cm(2), respectively) in the treatment of newly-diagnosed radiosurgery-ineligible glioblastoma multiforme patients. (Coughlin C, Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1351-8.)
    • Faz II. 26 enstitüden 108 hasta. Hastalar tümör hacmine göre RT'ye randomize edilmiş ve sonrasında heriki kola da BCNU eklenmiş
    • RT: Arm A (>20 cm3): 64 Gy given 1.6 Gy/fx BID (BED comparable to 60/20) vs. Arm B (<20 cm3): 70.4 Gy given 1.6 Gy/fx BID
    • Toplam sağkalım: 9.1 ay ve 11.0. Önceki RTOG verileriyle karşılaştırılabilir sonuçlar. Toksisiteler tolere edilebilir düzeyde.
    • Sonuç: Daha kısa RT sonuçları karşılaştırılabilir
  • RTOG 90-06, 1996 - No PMID, No survival benefit of hyperfractionated radiotherapy (RT) to 72 Gy and carmustine versus standard RT and carmustine for malignant glioma patients: Preliminary results of RTOG 90-06 (Curran WJ, Proc Am Soc Clin Oncol. 1996. 15:154 Abstract)
    • 1.2 Gy/fx BID + carmustine 72 Gy vs. standard RT + carmustine randomize edilmişlerdir
    • Fark yok
    • <50 yaş hastalarda sağkalım HF RT ile azalmış; nedeninin de artmış tedavi toksisitesi ile daha uzun süre yaşadıklarından olabileceği yorumu yapılmış
  • RTOG 83-02 (1983-89)
    • Faz I/II. AA + GBM. BCNU ile birlikte hiperfraksiyone RT veya akselere HF RT ile doz artışı.
    • 786 hasta. HF (1.2 Gy BID 64.8, 72, 76.8, veya 81.6 Gy) veya AHF (1.6 Gy BID 48 veya 54.4 Gy). Hepsi BCNU almış.
    • PMID 8608540, 1996 -- "Final report of a phase I/II trial of hyperfractionated and accelerated hyperfractionated radiation therapy with carmustine for adults with supratentorial malignant gliomas. Radiation Therapy Oncology Group Study 83-02." Werner-Wasik M et al. Cancer. 1996 Apr 15;77(8):1535-43.
      • Ortalama toplam sağkalım GBM için 9.6 - 11 ay. Doza bağlı olarak sağkalımda fark yok.
      • AA hastaları için, düşük HF dozlarıyla (64.8 - 72) daha iyi sağkalım mevcut. GBM için yüksek HF dozlarıyla daha iyi sağkalım var(78.6 - 81.6).
    • PMID 1451073, 1992 — "A randomized trial of accelerated hyperfractionated radiation therapy and bis-chloroethyl nitrosourea for malignant glioma. A preliminary report of Radiation Therapy Oncology Group 83-02." Curran WJ Jr et al. Cancer. 1992 Dec 15;70(12):2909-17.
    • PMID 8380567, 1993 — "Hyperfractionated radiation therapy and bis-chlorethyl nitrosourea in the treatment of malignant glioma--possible advantage observed at 72.0 Gy in 1.2 Gy B.I.D. fractions: report of the Radiation Therapy Oncology Group Protocol 8302." Nelson DF et al. Int J Radiat Oncol Biol Phys. 1993 Jan 15;25(2):193-207.
  • BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1389-96.
    • 603 hasta. Tüm hastalara cerrahi rezeksiyon yapılmiş. RT WBRT (kol 3 haricinde 30-35 fr 60 Gy) olarak uygulanmış. Kol 1: RT+BCNU IV x 3 gün, 8 haftada bir tekrar. Kol 2: RT+strep IV her hafta x 6 hafta sonra 2 hafta dinlenme, her 8 haftada bir tekrar. Kol 3: HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Kol 4: RT+miso sonra BCNU. Miso haftada 2 RT öncesi 4-6 saat. RT sonrası, her 8 haftada bir BCNU.
    • Sonuç: Gruplar arasında fark yok. (60/30 vs. 66/60 1.2 Gy BID)

Short course palliative RT[değiştir]

May be considered as palliation for poor prognosis patients

45 Gy in 15 fractions Şablon:Fact

3 Gy x 17 = 51 Gy

  • Johns Hopkins (1975-93) - PMID 9212001, 1997 — "Short course radiotherapy is an appropriate option for most malignant glioma patients." (Kleinberg L, Int J Radiat Oncol Biol Phys. 1997 Apr 1;38(1):31-6.)
    • Retrospective. 219 pts with GBM or AA treated: 3 Gy x 10 initially to large field (often whole brain), 2 week break, followed by 3 Gy x 7 conedown boost, total of 51 Gy over 5.5 weeks. Chemotherapy in 29% (nitrosourea).
    • Median survival by RTOG RPA class: I - 68 m, II - 57 m, III - 22 m, IV - 13 m, V - 8 m, VI - 5 m. For each RPA group, similar survival as in pts treated aggressively on prior RTOG studies.
    • Conclusion: The short regimen is an appropriate treatment option for most malignant glioma patients. Do not recommend this treatment for favorable prognosis pts (RPA class 1-3) because only few pts from those groups included (21%).

3 Gy x 10 = 30 Gy

  • Canada - PMID 8040031, 1994 — "A prospective study of short-course radiotherapy in poor prognosis glioblastoma multiforme." (Bauman GS, Int J Radiat Oncol Biol Phys. 1994 Jul 1;29(4):835-9.)
    • 29 pts, GBM, with age >= 65 or KPS <= 50
    • Tumor stable or improved in 60% of pts at 1 month evaluation. Median survival 6 months. (Historical results for similar patients treated with full dose RT: 10 months; supportive care only: 1 month). Survival advantage for full dose RT for pts with KPS > 50.
    • Conclusion: Elderly pts with a low pretreatment KPS <= 50 may be treated adequately with short, palliative RT

Radiosurgery[değiştir]

  • RTOG 93-05
    • 203 pts. GBM. All pts had surgery. Randomized to postoperative 1) SRS followed by EBRT 60 Gy + BCNU (q8w x 6), or 2) EBRT + BCNU, no SRS. SRS dose 16-24 Gy, based on size.
    • 2004, PMID 15465203 — "Randomized comparison of stereotactic radiosurgery followed by conventional radiotherapy with carmustine to conventional radiotherapy with carmustine for patients with glioblastoma multiforme: report of Radiation Therapy Oncology Group 93-05 protocol." Souhami L et al. Int J Radiat Oncol Biol Phys. 2004 Nov 1;60(3):853-60.
      • Median f/u 5 yrs. MS 13.5 m (SRS) vs 13.6 m
    • Conclusion: no difference in survival

Reviews:

  • ASTRO review, 2005 - PMID 16111571 — "The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma." Tsao MN et al. Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):47-55.
    • Conclusion: "For patients with malignant glioma, there is Level I-III (I=randomized trial, II=controlled trial, III=opinion) evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU. The use of radiosurgery boost is associated with increased toxicity. For patients with malignant glioma, there is insufficient evidence regarding the benefits/harms of using radiosurgery at the time of progression or recurrence. There is also insufficient evidence regarding the benefits/harms in the use of stereotactic fractionated radiation therapy for patients with newly diagnosed or progressive/recurrent malignant glioma."

Proton Therapy[değiştir]

  • Harvard
    • 1999 PMID 10433313 -- "Accelerated fractionated proton/photon irradiation to 90 cobalt gray equivalent for glioblastoma multiforme: results of a phase II prospective trial." (Fitzek MM, J Neurosurg. 1999 Aug;91(2):251-60.)
      • Phase II. 23 patients, GBM, residual <60 ml, KPS >=70. Dose escalation with mixed photon/proton beam to 90 CGE
      • Outcome: 2-year OS 34%, median OS 20 months which was 5-11 months higher than historical RTOG/MRC control. Tumor regrowth in areas of 60-70 Gy; only 1 recurrence in 90 Gy volume
      • Conclusion: Dose of 90 CGE prevented central recurrence in almost all cases
    • 1992 PMID 1310962 -- "Comparative treatment planning: proton vs. x-ray beams against glioblastoma multiforme." (Tatsuzaki H, Int J Radiat Oncol Biol Phys. 1992;22(2):265-73.)
      • Treatment planning. 90 CGE dose. 3D-CRT vs proton comparison
      • Outcome: Protons less non-target brain than photon, especially in deep-seated structures. V70 was 175 ml for photon vs 94 ml for proton plans
      • Conclusion: For subpopulation of patients, 90 CGE could be delivered
    • 1990 (1973-1987) PMID 2165739 -- "Fractionated proton radiation therapy of cranial and intracranial tumors." (Austin-Seymour M, Am J Clin Oncol. 1990 Aug;13(4):327-30.)
      • Retrospective. 144 patients (chordoma/chondrosarcoma 110, meningioma 13, craniopharyngioma 12, glioma 9). Glioma were intermediate/high grade. Median dose >71 CGE (62.8-79.4)
      • Outcome: No patient with high grade glioma survived
      • Conclusion: Moderate dose proton therapy doesn't make a meaningful contribution to management of high grade glioma

Carbon Ion Therapy[değiştir]

  • Chiba; 2007 (1994-2002) PMID 17459607 -- "Phase I/II clinical trial of carbon ion radiotherapy for malignant gliomas: combined X-ray radiotherapy, chemotherapy, and carbon ion radiotherapy." (Mizoe JE, Int J Radiat Oncol Biol Phys. 2007 Oct 1;69(2):390-6. Epub 2007 Apr 24.)
    • Phase I/II. 48 patients, malignant glioma (AA 16, GBM 32). Photons 50/25 + carbon ion dose escalation 16.8/8 -> 18.4/8 -> 20/8 -> 22.4/8 -> 24.8/8 GyE. Chemotherapy ACNU
    • Outcome: median OS GBM: low dose 7 months vs. intermediate dose 19 months vs. high dose 26 months. Median OS AA: 15 months vs. 35 months vs. 56 months
    • Toxicity: No Grade 3+, Grade 2 clinical 8%, Grade 2 radiographic 8%
    • Conclusion: Combined therapy shows potential efficacy; improved survival with higher carbon dose

Treatment toxicity[değiştir]

Please see the Brain Treatment Toxicity section

Chemotherapy[değiştir]

  • RT/Temozolomide: 2-year OS benefit 26.5% vs 10.4%, median surival +2 months
  • RT/other chemo: 2-year OS benefit: 20% vs. 15%, median survival +2 months (12-trial meta-analysis)


  • MRC Meta-analysis, 2002: PMID 11937180 — "Chemotherapy in adult high-grade glioma: a systematic review and meta-analysis of individual patient data from 12 randomised trials." Stewart LA. Lancet. 2002 Mar 23;359(9311):1011-8.
    • Meta-analysis, 12 trials, 3004 pts.
    • 15% decrease in risk of death. 1-year survival increase of 6% and 2 month increase in median survival.
See further discussion in Dose determination section
  • 1993: PMID 8453582 — "Meta-analysis of radiation therapy with and without adjuvant chemotherapy for malignant gliomas in adults." Fine HA et al. Cancer. 1993 Apr 15;71(8):2585-97.
    • Meta-analysis, 16 trials, 3000 pts. Compared radiation alone vs radiation + chemo for high-grade astrocytomas and GBM.
    • Increase in survival of 10% at 1 year, 8.6% at 2 yrs. Survival benefit is earlier for AA than for GBM.


Temozolomide[değiştir]

  • An oral alkylating agent.
  • Standard of care as concurrent chemotherapy with conventional RT
  • Neoadjuvant TMZ does not appear to be beneficial
  • Largest benefit for TMZ is in patients with low MGMT expression, but since there is nothing else to give patients with high MGMT expression, they are also treated with TMZ
  • Marseille, 2007 PMID 17442989 -- "Correlation between O6-methylguanine-DNA methyltransferase and survival in inoperable newly diagnosed glioblastoma patients treated with neoadjuvant temozolomide." (Chinot OL, J Clin Oncol. 2007 Apr 20;25(12):1470-5.)
    • Phase II. 29 patients. Induction dose-dense TMZ (7-days on/7-days off) x4 cycles, then conventional RT.
    • Outcome: Median PFS 4 months, median OS 6.1 months.
    • Stratified by MGMT: PFS low expression 5.5 months vs. high expression 1.9 months (SS); OS 16 months vs. 5 months (SS)
    • Toxicity (Grade 3-4): thrombocytopenia 20%, neutropenia 17%
    • Conclusion: Induction dose-dense TMZ inferior to standard concomitant RT + TMZ
  • Greece (2000-2002) -- RT vs. RT + TMZ
    • Randomized, Phase II. 130 patients with GBM, KPS >=60. Surgery. Arm 1) RT 60/30 vs. Arm 3) Same RT + concurrent TMZ 75 mg/m2 1 hour prior to RT, then adjuvant TMZ 150 mg/m2 x6 cycles. RT CTV1=T2 + 2 cm margin to 46/23, CTV2=T1 + 2.5 cm margin to 60/30
    • 2005 PMID 15800329 -- "Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme." (Athanassiou H, J Clin Oncol. 2005 Apr 1;23(10):2372-7.)
      • Outcome: Median TTP RT 5.2 months vs. RT + TMZ 10.8 months (SS); 1-year PFS 37% vs. 8% (SS). Median OS 8 months vs. 13 months (SS); 1-year OS 16% vs. 56% (SS)
      • Toxicity: Grade 3+4 leukopenia 3%, thrombocytopenia 5%. One death from sepsis
      • Conclusion: TMZ combined with RT more effective than RT alone
  • EORTC / NCIC 26981-22981/CE.3 (2000-2002) -- RT vs. RT + TMZ
    • Randomized. 573 patients with GBM, s/p biopsy or surgery (GTR 40%). Arm 1) RT alone vs Arm 2) RT with concurrent daily temozolomide (T) 7 days/wk followed by six cycles of adjuvant T given 5 days monthly. RT given 60/30, CTV = GTV + 2-3 cm margin. Temozolomide dose was 75 mg/m2 concurrent and 150-200 mg/m2 adjuvant.
    • 2-years; 2005 PMID 15758009 — "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma." (Stupp R, New Engl J Med 352(10):987-996, 2005.) Median F/U 2.3 years
      • Outcome: median OS RT 12.1 months vs. RT + T 14.6 months (SS); 2-year OS 10% vs. 26% (SS). On subgroup analysis, no benefit if biopsy only or if PS = 2.
      • Toxicity: Grade 3-4 toxicity 7%
      • Conclusion: Addition of temozolomide resulted in clinically meaningful and statistically significant survival benefit, with minimal toxicity
    • 5-years; 2009 PMID 19269895; "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." (Stupp R, Lancet Oncol. 2009 May;10(5):459-66.) >5yr med fu
      • Outcome: Median OS RT 12.1 mo vs RT + TMZ 12.1 mo (SS). 2-year OS 11% vs. 27%; 5-year OS 2% vs. 10%. Benefit in all subgroups, including 60-70 year old (10.9 months vs. 11.8 months). Benefit it RPA III 14.8 mo vs. 18.7 mo
      • MGMT: Methylation strongest predictor of outcome: methylated 23.4 mo vs. unmethylated 12.6 mo (SS)
      • Salvage: Second surgery 24%, repeat RT 5%, salvage chemo 54%, supportive care only 39%
      • Conclusion: Benefits of adjuvant TMZ lasted through 5 years, though few patients survive that long
Overall Survival
Follow up XRT & Temodar XRT
Median OS 14.6 mo 12.1 mo
2 years 27.2% 10.9%
3 years 16.0% 4.4%
4 years 12.1% 3.0%
5 years 9.8% 1.9%
    • Please see the overview section for discussion of MGMT promoter status and other prognostic variables from this trial

BCNU (Carmustine)[değiştir]

  • CNS Cancer Consortium (1988-1991) -- Concurrent Mitomycin C
    • Randomized. 2x2 design. 377 patients (69% GBM). Arm 1) RT alone vs. Arm 2) RT + mitomycin C. Then randomized Arm 1) BCNU vs. Arm 2) BCNU + 6-MP. RT 61.2 Gy
    • 1996 PMID 8598355 -- "A phase III randomized prospective trial of external beam radiotherapy, mitomycin C, carmustine, and 6-mercaptopurine for the treatment of adults with anaplastic glioma of the brain. CNS Cancer Consortium." (Halperin EC, Int J Radiat Oncol Biol Phys. 1996 Mar 1;34(4):793-802.)
      • Outcome: median OS initial randomization both arms 10.8 months (NS). Median OS second randomization BCNU 11.4 months vs. BCNU/6-MP 9.3 months (NS). Significantly fewer patients terminanted RT in RT only group compared with concurrent mitomycin C
      • Conclusion: No benefit for mitomycin C, more patients terminated therapy. No benefit for adding 6-MP to BCNU
  • BTCG 80-01 - PMID 2661738 -- "Randomized trial of three chemotherapy regimens and two radiotherapy regimens and two radiotherapy regimens in postoperative treatment of malignant glioma. Brain Tumor Cooperative Group Trial 8001." (Shapiro WR, J Neurosurg. 1989 Jul;71(1):1-9.)
    • Randomized. 571 patients to 3 chemo regiments (BCNU, BCNU/procarbazine, BCNU/hydroxyurea/procarbazine/VM-26).
    • RT patients accrued 1982-1983: WBRT 60.2 Gy
    • RT patients accrued 1982-1983: randomized to WBRT 60.2 Gy or WBRT 43 Gy + 17.2 Gy cone-down boost
    • Conclusion: no difference in survival. WBRT + boost as effective as WBRT
  • BTCG 77-02, 1989 (1978-80) - PMID 2542193 — "Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma." Deutsch M et al. Int J Radiat Oncol Biol Phys. 1989 Jun;16(6):1389-96.
    • 603 pts. All pts had surgery. RT was whole brain (60 Gy in 30-35 fx except arm 3). Arm 1: RT+BCNU IV x 3 days, repeat q8wk. Arm 2: RT+strep IV q week x 6 weeks then 2 week rest, repeat q8w. Arm 3: HF-RT+BCNU. 1.1 Gy BID x 60 fx = 66 Gy. Arm 4: RT+miso then BCNU. Miso 2x/week 4-6 hr before RT. After RT, BCNU q8weeks.
    • No difference in survival among groups.
  • BTCG 75-01, 1983 -- PMID 6337710 -- "Comparisons of carmustine, procarbazine, and high-dose methylprednisolone as additions to surgery and radiotherapy for the treatment of malignant glioma." (Green SB, Cancer Treat Rep. 1983 Feb;67(2):121-32.)
    • Randomized. 690 patients post-op to 60 Gy RT and 1) BCNU, 2) Medrol, 3) Procarbazine, 4) BCNU + Medrol
    • Medrol alone not good. BCNU + Medrol not good in poor prognosis. Other groups comparable.
  • RTOG 74-01 / ECOG 1374, 1988 - PMID 3281031, — "Combined modality approach to treatment of malignant gliomas--re-evaluation of RTOG 7401/ECOG 1374 with long-term follow-up: a joint study of the Radiation Therapy Oncology Group and the Eastern Cooperative Oncology Group." Nelson DF et al. NCI Monogr. 1988;(6):279-84.
    • Randomized. High grade glioma. 1) 60 Gy whole brain vs 2)60 Gy + 10 Gy boost vs 3)60 Gy + BCNU vs 4)60 Gy + CCNU + DTIC
    • No difference in survival. For pts age > 60, no benefit for chemo. For age 40-60, benefit for BCNU
  • BTCG 72-01 - PMID 7001230, 1980 — "Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery." (Walker MD et al. N Engl J Med. 1980 Dec 4;303(23):1323-9.)
    • 467 pts. HGG. After surgery, randomized to MeCCNU (semustine), RT, BCNU (carmustine) + RT, or MeCCNU + RT.
    • RT +/- BCNU/MeCCNU significantly better than MeCCNU alone. RT alone comparable to RT+BCNU or RT+MeCCNU.
  • NCCTG 93-72-52 / SWOG 9503 (1994-99) - PMID 16921039, 2006 — "Phase III trial of carmustine and cisplatin compared with carmustine alone and standard radiation therapy or accelerated radiation therapy in patients with glioblastoma multiforme: North Central Cancer Treatment Group 93-72-52 and Southwest Oncology Group 9503 Trials." Buckner JC et al. J Clin Oncol. 2006 Aug 20;24(24):3871-9.
    • 401 pts. 4 arm (2x2): BCNU vs BCNU + cisplatin, accelerated RT (ART) vs standard RT (SRT).
    • Chemotherapy weekly, concurrent with RT x 8 weeks. RT 64.8 Gy / 1.8 / 48 d (SRT) or 48 Gy / 1.2 Gy BID / 15 d (ART).
      • Worse toxicity with BCNU + cisplatin. No SS difference in survival at 2 yrs.
    • Conclusion: no improvement in survival


BCNU wafers (Gliadel)[değiştir]

  • Meta-Analysis; 2007 (UK) PMID 17999840 -- "The effectiveness and cost-effectiveness of carmustine implants and temozolomide for the treatment of newly diagnosed high-grade glioma: a systematic review and economic evaluation." (Garside R, Health Technol Assess. 2007 Nov;11(45):iii-iv, ix-221.)
    • Meta-analysis, Markov modeling for effectiveness and cost-effectiveness. BCNU: 2 RCT and 2 observations studies
    • Outcome: No difference in OS, but unpublished long-term follow-up suggests significant survival benefit based on very few patients at risk. No difference in PFS. Subgroup analysis for WHO Grade IV no significant OS benefit.
    • Cost estimate: Surgery + RT is ~£17,000. BCNU additional £6,600, for 0.122 QALYs. Incremental cost-effectiveness ratio (ICER) £54,500/QALY. Assuming pay threshold £30,000, BCNU wafer not cost effective in 89% simulations; in 15% simulations BCNU wafer did more harm than good
    • Conclusion: BCNU wafers survival benefit not proven in Grade III, and not present in Grade IV. The intervention will likely not be considered cost-effective by NHS


  • Multinational (1997-99) -- placebo vs. BCNU wafer
    • Randomized. 14 countries. 240 patients, malignant gliomas (86% GBM). At primary surgical resection, Arm 1) placebo vs. Arm 2) BCNU wafers. All patients received RT 55-60 Gy.
    • 2003 PMID 12672279 — "A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma." (Westphal M, Neuro-oncol. 2003 Apr;5(2):79-88.)
      • Outcome: median OS placebo 11.6 vs. BCNU wafer 13.9 months (SS); 29% reduction in risk of death. BCNU also improved time to KPS decline and neuroperformance measures decline.
      • Toxicity: comparable, except CSF leak 1% vs. 5%, intracranial HTN 2% vs. 9%
      • Conclusion: Local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma
    • Comment (PMID 17999840 above): Published analysis was stratified by country. Per-protocol unstratified analysis of data (submitted to FDA) reveals no OS advantage (p=0.08). Further updated data (submitted to FDA) reveals OS advantage (p=0.02) but this is driven by few patients, mostly Grade III, with long survival. There is no difference in 1 or 2 year OS.
  • Turku University (Finland)(1992-1993) -- placebo vs. BCNU wafer
    • Randomized. 32/100 planned patients with high grade (Grade III-IV) glioma. Closed prematurely as carmustine became unobtainable. Arm 1) Surgery + placebo vs. Arm 2) Surgery + carmustine polymer
    • 1997 PMID 9218294 -- "Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study." (Valtonen S, Neurosurgery. 1997 Jul;41(1):44-8; discussion 48-9.)
      • Outcome: median OS placebo 9.2 months vs. 13.4 months (SS); for GBM 9.2 months vs. 12.3 months (SS). At end of study, 6% vs. 31% alive
      • Conclusion: Locally applied carmustine polymer at time of primary surgery has benefit on survival

Phase II Protocols[değiştir]

  • Thessaloniki, 2006 (Greece) PMID 17214326 -- "Post-operative combined radiation and chemotherapy with temozolomide and irinotecan in patients with high-grade astrocytic tumors. A phase II study with biomarker evaluation." (Fountzilas G, Anticancer Res. 2006 Nov-Dec;26(6C):4675-86.)
    • Phase II. 45 patients (38 GBM, 7 AA) treated with RT 60 Gy + TMZ + irinotecan. 22 patients completed 6 cycles. Medium F/U 50 months
    • Toxicity: Neutropenia 37%, N/V 66%, diarrhea 31%, infection 44%. 5/45 fatal vaso-occlusive disease
    • Survival: overall 12.8 months, progression-free 7.7 months
    • Conclusion: too toxic
  • RTOG 94-17 (1995-97) - Tirapazamine
    • 124 pts. GBM. Phase II. RT 60 Gy + tirapazamine (3x/week x 12). Two dose levels.
    • 2000: PMID 10715295 — "Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme." (Del Rowe J, J Clin Oncol. 2000 Mar;18(6):1254-9.)
    • For summary, see results presented in chart below (Summary - ASCO Abstract 2002, Seiferheld)
    • Conclusion: "Survival in the population treated with radiation and tirapazamine was equivalent to the control population."
  • RTOG 86-12 - IUdR
    • "Survival improvement in anaplastic astrocytoma, combining external radiation with halogenated pyrimidines: final report of RTOG 86-12, Phase I-II study."
    • PMID 8407393 (1993), PMID 8985039 (1996)
  • Summary ASCO Abstract -- Five years of glioblastoma multiforme(GBM) phase II trials at the Radiation Therapy Oncology Group (RTOG). (Seiferheld W, ASCO Abstracts, 2002)
    • Conclusion: "None of the experimental agents from these studies demonstrated statistically significant improvement in survival from the historical control after adjusting for RPA class. On the other hand, it is important to realize that several of the studies exhibited survival similar to the historical control, and with fewer life-threatening toxicities. These results question the standard practice of concurrent BCNU for GBM patients."
RTOG Phase 2 Trials
Trial Agent N MOS (Observed) MOS (Expected) p-value
94-17 Tirapazamine (159mg/m2) 53 10.8 10.8 NS
94-17 Tirapazamine (260mg/m2) 68 9.5 9.7 NS
95-13 Topotecan 79 9.3 10.1 NS
96-02 Paclitaxel 61 9.7 9.6 NS
97-10 ß-Interferon 60 13.2 10.2 NS
98-06 Thalidomide 89 10.0 9.5 NS

Trials that failed[değiştir]

  • Dose escalation > 60 Gy - Michigan, RTOG 74-01
  • Accel. hyperfract - RTOG
  • Radiosurgery - RTOG 93-05
  • Brachytherapy - NCI-Canada, BTSG
  • Proton boost - MGH
  • BCNU
  • Hyperfract (72 Gy) - RTOG 83-02, 90-06, BTCG 77-02
  • Neoadj. chemo - ECOG
  • Boron neutron capture (BNC)


Trials to add[değiştir]

RTOG trials to add:

  • 7611 - neutron boost
  • 7918 - WBRT + (BCNU vs misonidazole and BCNU)
  • 8007 - neutron boost
  • 8409 - WBRT + AZQ (aziridinylbenzoquinone)


Review[değiştir]

  • Multi-institutional; 2008 PMID 18712283 -- "Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults." (Buatti J, J Neurooncol. 2008 Sep;89(3):313-37. Epub 2008 Aug 20.)

Radiation Oncology:TOC


High Grade Glioma: Recurrences


Epidemiology[değiştir]

  • Rotterdam, 2007 (2000-2005) ASCO Abstract -- "The incidence of pseudo-progression in a cohort of malignant glioma patients treated with chemo-radiation with temozolomide." (Taal W, Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S (June 20 Supplement), 2007: 2009)
    • Retrospective. 65 patients with malignant glioma, treated with RT/TMZ followed by TMZ x6 cycles
    • Outcome: 35% (23) patients had MRI signs of progression after end of RT, with clinical deterioration in 18% (12). In 12/23 stabilization/improvement of symptoms on continued TMZ. No impact of dexamethasone dose
    • Conclusion: Up to 50% of patients may suffer from pseudo-progression; should continue TMZ


Salvage RT[değiştir]

  • Review; 2007 PMID 17760992 -- "Radiotherapeutic alternatives for previously irradiated recurrent gliomas." (Combs SE, BMC Cancer. 2007 Aug 30;7(1):167)
  • Michigan, 2002 (1996-99) - PMID 11896114 — "Survival and failure patterns of high-grade gliomas after three-dimensional conformal radiotherapy." Chan JL et al. J Clin Oncol. 2002 Mar 15;20(6):1635-42.
    • Retrospective. 34 pts. Pts with HGG treated to 90 Gy using IMRT. Defined recurrences as central (>95% of volume in high dose region), in-field(80% to 95%), marginal (20% to 80%), and distant (<20%). For planning, used GTV=enhancing tumor (no edema). PTV1=0.5 cm margin, PTV2=1.5 cm, PTV3=2.5 cm. 90 Gy prescribed to PTV1, 70 Gy to PTV2, 60 Gy to PTV3.
    • 67% had recurrence. 78% were central, 13% in-field, 9%, 0% distant.
    • Conclusion: predominant treatment failure is local/central. This suggests that close margins in conformal treatment do not increase the risk of marginal or distant recurrences.


Salvage chemotherapy[değiştir]

  • Duke, 2007 (2005-2006) PMID 17947719 -- "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme." (Vredenburgh JJ, J Clin Oncol. 2007 Oct 20;25(30):4722-9.)
    • Phase II. 35 patients. Initial regimen bevacizumab 10 mg/kg with irinotecan. Then bevacizumab 15 mg/kg and irinotecan
    • Outcome: 6-month PFS 46%, OS 77%. Response rate 95% and significant improvements in cognitive and functional status
    • Toxicity: 1 CNS hemorrhage, 4 thromboembolic events
    • Conclusion: Bevacizumab/irinotecan effective for recurrent disease, with moderate toxicity

Radiation Oncology:TOC


In process of being cross-linked from the Glioma chapter


Low grade gliomas (WHO I-II)[değiştir]

Adjuvant RT Dose[değiştir]

  • Intergroup NCCTG/RTOG/ECOG (1986-1994) -- 50.4 Gy vs. 64.8 Gy
    • Randomized. 203 patients. Age >18. Included low grade astrocytoma, oligodendroglioma, or mixed oligoastrocytoma; pilocytic astrocytomas were excluded. Randomized to 50.4 Gy vs 64.8 Gy. RT technique: 2 cm margin around preoperative tumor volume, 1 cm margin for boost after 50.4 Gy.
    • 5-years; 2002 PMID 11980997 — "Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study." (Shaw E et al. J Clin Oncol. 2002 May 1;20(9):2267-76.) Median F/U 6.4 years
      • 5-year outcome: OS low dose 72% vs. high dose 65% (NS); time-to-progression 58% vs. 52% (NS). Failure within field 92%
      • Toxicity: more often and more severely in high dose arm (2.5% vs 5%)
      • Poor prognosis: astrocytoma, age >40, tumor >=5 cm (5-year OS if <40 and oligodendroglioma 82% vs. >40 and astrocytoma 32%)
      • Conclusion: No benefit for higher RT dose
  • EORTC 22844 (1985-1991) -- 45 Gy vs. 59.4 Gy
    • Randomized. 343 patients. Age 16-65. Included astrocytoma, oligodendroglioma, mixed oligoastrocytoma. Excluded completely excised pilocytic astrocytoma. Surgery first. Randomized to low dose 45 Gy vs high dose 59.4 Gy at 1.8 Gy/fx. RT technique: 2 cm margin around enhancing tumor to 45 Gy, reduced field 1 cm margin to 54 Gy and minimal margin to 59.4 Gy.
    • 5-years; 1996 PMID 8948338, 1996 — "A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844." Karim AB et al. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):549-56. Median F/U 6.2 years
      • 5-year outcome: No difference in OS (58% vs 59%) or PFS (47% vs 50%)
      • Predictors: Age, size, neurologic status, amount of surgery
      • Conclusion: No dose response above 45 Gy

Adjuvant vs Salvage Radiotherapy[değiştir]

  • EORTC 22845 (1986-97) -- Adjuvant vs. salvage RT
    • Randomized. 314 patients. Age 16-65. Supratentorial low grade astrocytoma, low grade oligoastrocytoma, or low grade oligodendroglioma. Excluded small completely resected pilocytic astrocytomas, optic nerve gliomas, brainstem gliomas, third ventricle gliomas, and infratentorial gliomas. Surgery first. Randomized to early radiotherapy with 54 Gy (1.8 Gy/fx) vs delayed radiotherapy until the time of progression. CT with contrast every 4 months until progression. Technique: preop CT + 2 cm margins to 45 Gy, reduced field to 1 cm after 45 Gy.
    • 2005 PMID 16168780 — "Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial." (van den Bent MJ et al. The Lancet Volume 366, Issue 9490, 17 September 2005, Pages 985-990.) Median F/U 7.8 years
      • Outcome: Median PFS early RT 5.3 yrs vs delayed RT 3.4 yrs (SS). 5-year PFS 55% vs. 35% (SS). Median OS 7.4 vs 7.2 yrs (NS). 65% of pts in control group received RT at progression, 4% in early RT received salvage RT. At 1 yr, better control of seizures in early RT group (25% vs. 41%, SS).
      • After progression: survival early RT 1.0 years vs. delayed RT 3.4 years (SS). ~70% transformed to high grade tumors, regardless if they had RT or not. Most recurrences within field
      • Toxicity (compared at 1 year for patients still tumor free at 2 years): No difference in cognitive deficit, focal deficit, performance status, or headaches.
    • Conclusion: Early RT lengthens PFS and controls seizures, but doesn't impact OS
    • Comment: tumor planning off CT, central path showed 26% were high grade tumors but balanced between arms, no QoL analysis

Adjuvant RT +/- Chemotherapy[değiştir]

  • RTOG 98-02 / INT (1998-2002) -- RT +/- PCV
    • Randomized arm + observation arm. 362 patients, WHO Grade II supratentorial astrocytoma, oligoastrocytoma, or oligodendroglioma
      • High risk LGG (age >=40 or STR/bx; 251 patients): Arm 1) RT 54/30 alone vs. Arm 2) RT + PCV x6 cycles. RT given T2 + 2 cm block-edge margin
      • Low risk LGG (age <40 and GTR; 111 patients): Observation only
    • 6-years; 2008 ASCO Abstract 2006 -- "Final report of Radiation Therapy Oncology Group (RTOG) protocol 9802: Radiation therapy (RT) versus RT + procarbazine, CCNU, and vincristine (PCV) chemotherapy for adult low-grade glioma (LGG)." (Shaw EG, J Clin Oncol 26: 2008 (May 20 suppl; abstr 2006)) Median F/U 5.9 years
      • High risk outcome: 5-year OS RT 63% vs. RT + PCV 72% (NS); PFS 46% vs. 63% (p=0.06). In years 0-2 no difference, beyond 2 years significant benefit for RT+PCV. HR for death 0.52, for PFS 0.45
      • Conclusion: PFS but not OS were improved with addition of PCV. Beyond 2 years, OS advantage, and decreased risk of death by 48%

High Grade (WHO III) Gliomas[değiştir]

Adjuvant RT +/- Chemotherapy[değiştir]

  • EORTC 26951 (1996-2002) -- RT +/- adjuvant PCV
    • Randomized. 368 patients. AO and AOA (>25% oligodendroglial elements). Median age 49. Surgery followed by RT within 6 weeks 59.4/33, then Arm 1) observation vs. Arm 2) PCV (procarbazine 60, lomustine 110, vincristine 1.4) x6 cycles. Adjuvant PCV discontinued in 38%; 80% of RT arm received chemo at progression. RT PTV1 = T2 + 2.5cm to 45/25, then PTV2 = T1 + 1.5cm to 59.4/33. Primary endpoint OS
    • 5-years; 2006 PMID 16782911 — "Adjuvant procarbazine, lomustine, and vincristine improves progression-free survival but not overall survival in newly diagnosed anaplastic oligodendrogliomas and oligoastrocytomas: a randomized European Organisation for Research and Treatment of Cancer phase III trial." (Van den Bent MJ et al. J Clin Oncol. 2006 Jun 20;24(18):2715-22.). Median F/U 5 years
      • Outcome: median OS RT+PCV 3.4 years vs RT 2.6 years (NS); PFS: 1.9 years vs 1.1 years (SS)
      • 1p/19q Analysis: Combined deletion in 25%; 5-year OS 74%; 5-year OS RT+PCV 74% vs. RT 75% (NS); PFS 69% vs. 50% (NS). Comparison of 5-year OS 1p/19q deleted 74% vs. 1p/19qWT ~30%
      • Conclusion: Adjuvant PCV does not prolong OS, but improves PFS. Patients with 1p/19q deletion have significantly better outcome, though not impacted by addition of PCV
  • EORTC 26882 (1988-2000) -- RT +/- adjuvant BCNU/DBD
    • Randomized. Stopped early due to slow accrual. 193/212 patients, anaplastic astrocytoma. Two cohorts: 58 anaplastic astrocytoma patients from original EORTC 26882 cohort + 135 patients from extended accrual focusing on AA only. Arm 1) RT alone vs. Arm 2) RT + concurrent BCNU/DBD followed by adjuvant BCNU/DBD x1 year. RT 60/30. Primary endpoint OS.
    • 2008 PMID 18248979 -- "Adjuvant dibromodulcitol and BCNU chemotherapy in anaplastic astrocytoma: results of a randomised European Organisation for Research and Treatment of Cancer phase III study (EORTC study 26882)." (Hildebrand J, Eur J Cancer. 2008 Jun;44(9):1210-6. Epub 2008 Jan 14.)
      • Pathology: At central path review, 53% of AA cases couldn't be confirmed. AA 35%, AOA 8%, AO 2%, GBM 25%, low grade glioma 23%, other diagnosis 7%
      • Outcome: median OS RT 2.0 years vs. RT + BCNU/DBD 2.3 years (NS), no difference in PFS
      • Conclusion: No benefit in OS or PFS with addition of BCNU/DBD

Adjuvant RT vs. Adjuvant Chemotherapy[değiştir]

  • NOA-04 (Germany)(1999-2005) -- RT 54-60 Gy vs. PCV vs. temozolomide
    • Randomized. 318 patients, supratentorial WHO Grade III glioma. Arm 1) RT 54-60 Gy in 6 weeks vs. Arm 2) CCNU 110 mg/m2, vincristine 2 mg, procarbazine 60 mg/m2 x4 cycles vs. Arm 3) temozolomide 200 mg/m2 x8 cycles. Primary endpoint time-to-failure
    • 2008 ASCO Abstract -- "Randomized phase III study of sequential radiochemotherapy of oligoastrocytic tumors of WHO-grade III with PCV or temozolomide: NOA-04." (Wick Wolfgang W. J Clin Oncol 26: 2008 (May 20 suppl; abstr LBA2007))
      • Outcome: median TTF RT 3.6 years vs. PCV/Temodar 3.6 years (NS), median OS 5+ years vs. 5+ years (NS)
      • Predictors: oligo component (oligodendroglioma or oligoastrocytoma), LOH 1p/19q , MGMT+
      • Toxicity: Grade 3-4 hematologic significantly higher for PCV than temozolomide
      • Conclusion: No difference in TTF between RT and chemotherapy (PCV or temozolomide)

Sequential chemo->RT vs RT alone[değiştir]

  • RTOG 9402 / INT 0149 (1994-2002) -- Sequential PCV -> RT vs. RT alone
    • Randomized. 289 patients with supratentorial AO and AOA (>25% oligodendroglioma component), KPS >=60. Randomized to PCV x4 cycles prior to RT vs RT alone after maximal surgical resection. Arm 1) PCV (procarbazine, CCNU, vincristine) x4 cycles followed by RT vs. Arm 2) RT alone. RT given 59.4/33/ PTV1 = T2 + 2cm, PTV2 = T1 + 1cm
    • 2006 PMID 16782910 — "Phase III trial of chemotherapy plus radiotherapy compared with radiotherapy alone for pure and mixed anaplastic oligodendroglioma: Intergroup Radiation Therapy Oncology Group Trial 9402." (Cairncross G, J Clin Oncol. 2006 Jun 20;24(18):2707-14.) Median F/U 5.1 years
      • Outcome: Median OS PCV->RT 4.9 years vs. RT 4.7 years (NS). PFS 2.6 years vs. 1.7 years (SS).
      • Toxicity: Grade 3-4 induction PCV 65%, RT after PCV 8% vs. RT alone 5%
      • Chromosomes: LOH 1p/19q combined in 46%, AO 57% vs. AOA 14% (SS). Lower risk of tumor progression PFS 4.0 v 1.3 years(SS), and median OS not-reached vs. 2.8 years (SS). No effect of treatment on survival
      • Conclusion: No impact on survival. Improved PFS but at significant toxicity cost. Patients with 1p/19q deletion have significantly improved outcome

Glioblastoma Multiforme (WHO IV)[değiştir]

Temozolomide[değiştir]

  • Greece (2000-2002) -- RT vs. RT + TMZ
    • Randomized, Phase II. 130 patients with GBM, KPS >=60. Biopsoy or surgery. Arm 1) RT 60/30 vs. Arm 3) Same RT + concurrent TMZ 75 mg/m2 1 hour prior to RT, then adjuvant TMZ 150 mg/m2 x6 cycles. RT CTV1=T2 + 2 cm margin to 46/23, CTV2=T1 + 2.5 cm margin to 60/30
    • 2005 PMID 15800329 -- "Randomized phase II study of temozolomide and radiotherapy compared with radiotherapy alone in newly diagnosed glioblastoma multiforme." (Athanassiou H, J Clin Oncol. 2005 Apr 1;23(10):2372-7.)
      • Outcome: Median TTP RT 5.2 months vs. RT + TMZ 10.8 months (SS); 1-year PFS 37% vs. 8% (SS). Median OS 8 months vs. 13 months (SS); 1-year OS 16% vs. 56% (SS)
      • Toxicity: Grade 3+4 leukopenia 3%, thrombocytopenia 5%. One death from sepsis
      • Conclusion: TMZ combined with RT more effective than RT alone
  • EORTC / NCIC 26981-22981 (2000-2002) -- RT vs. RT + TMZ
    • Randomized. 573 patients with GBM, s/p biopsy or surgery (GTR 40%). Arm 1) RT alone vs Arm 2) RT with concurrent daily temozolomide (T) 7 days/wk followed by six cycles of adjuvant T given 5 days monthly. RT given 60/30, CTV = GTV + 2-3 cm margin. Temozolomide dose was 75 mg/m2 concurrent and 150-200 mg/m2 adjuvant.
    • 2005 PMID 15758009 — "Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma." (Stupp R, New Engl J Med 352(10):987-996, 2005.) Median F/U 2.3 years
      • Outcome: median OS RT 12.1 months vs. RT + T 14.6 months (SS); 2-year OS 10% vs. 26% (SS). On subgroup analysis, no benefit if biopsy only or if PS = 2.
      • Toxicity: Grade 3-4 toxicity 7%
      • Conclusion: Addition of temozolomide resulted in clinically meaningful and statistically significant survival benefit, with minimal toxicity
    • 2009 PMID 19269895; "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." (Stupp R, Lancet Oncol. 2009 May;10(5):459-66.) >5-year med. fu
      • Overall survival was 27·2% (95% CI 22·2—32·5) at 2 years, 16·0% (12·0—20·6) at 3 years, 12·1% (8·5—16·4) at 4 years, and 9·8% (6·4—14·0) at 5 years with temozolomide, versus 10·9% (7·6—14·8), 4·4% (2·4—7·2), 3·0% (1·4—5·7), and 1·9% (0·6—4·4) with radiotherapy alone (hazard ratio 0·6, 95% CI 0·5—0·7; p<0·0001).
      • A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60—70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy.

High Grade (WHO III-IV) Gliomas[değiştir]

BCNU wafers (Gliadel)[değiştir]

  • Multinational (1997-99) -- placebo vs. BCNU wafer
    • Randomized. 14 countries. 240 patients, malignant gliomas (86% GBM). At primary surgical resection, Arm 1) placebo vs. Arm 2) BCNU wafers. All patients received RT 55-60 Gy.
    • 2003 PMID 12672279 — "A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma." (Westphal M, Neuro-oncol. 2003 Apr;5(2):79-88.)
      • Outcome: median OS placebo 11.6 vs. BCNU wafer 13.9 months (SS); 29% reduction in risk of death. BCNU also improved time to KPS decline and neuroperformance measures decline.
      • Toxicity: comparable, except CSF leak 1% vs. 5%, intracranial HTN 2% vs. 9%
      • Conclusion: Local chemotherapy with BCNU wafers is well tolerated and offers a survival benefit to patients with newly diagnosed malignant glioma
  • Turku University (Finland)(1992-1993) -- placebo vs. BCNU wafer
    • Randomized. 32/100 planned patients with high grade (Grade III-IV) glioma. Closed prematurely as carmustine became unobtainable. Arm 1) Surgery + placebo vs. Arm 2) Surgery + carmustine polymer
    • 1997 PMID 9218294 -- "Interstitial chemotherapy with carmustine-loaded polymers for high-grade gliomas: a randomized double-blind study." (Valtonen S, Neurosurgery. 1997 Jul;41(1):44-8; discussion 48-9.)
      • Outcome: median OS placebo 9.2 months vs. 13.4 months (SS); for GBM 9.2 months vs. 12.3 months (SS). At end of study, 6% vs. 31% alive
      • Conclusion: Locally applied carmustine polymer at time of primary surgery has benefit on survival


WBRT vs. Observation[değiştir]

  • BTCG 69-01 -- BCNU vs RT vs RT + BCNU vs Observation
    • Randomized, 4 arms. 303 patients, anaplastic gliomas, treated with surgery and steroids. Arm 1) BCNU alone, Arm 2) RT alone, Arm 3) RT + BCNU, Arm 4) best supportive care. BCNU was given on days 1-3 q6-8 wks. RT was 50-60 Gy to whole brain.
    • 1978 PMID 355604 — "Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial." (Walker MD, J Neurosurg. 1978 Sep;49(3):333-43.)
      • Outcome: median OS OBS 3.2 months vs. BCNU 4.2 months vs. RT 8.1 months vs. RT + BCNU 8.0 months (SS)
      • Toxicity: Acceptable thrombocytopenia and leukopenia
    • Note: This trial established first evidence for post-op RT over supportive management