Multiple Craniotomies in the Management of Multifocal and Multicentric Glioblastoma Raymond Sawaya, M.D.

Multiple GBM Lesions are not Rare Glioblastoma Multiple Synchronous Gliomas ~ 0.5 – 20%

Pathogenesis Not Clearly Understood Zülch, 1957 Willis, 1967 Metastasis ? Willis, 1967 multi-focal growth Kyritsis et al.,1994  p53 gene mutation (? Genetic Background)

Management ? Biopsy Radiation Resection

Literature Questions more than answers Case Reports and 3 Series

Literature Case Reports Ampil et al., 2007

50 patients with MF GBM (1995-2005) The Policy: Int. J. Radiation Oncology Biol. Phys., Vol. 69, No. 3, pp. 820–824, 2007 50 patients with MF GBM (1995-2005) The Policy: Remove one tumor focus WBRT or 3D Conformal RT Concurrent Chemotherapy 42% Median Survival 8.1 months

40 patients with Multiple CNS Tumors (1988-1993) 10 Multicentric 30 Multifocal The Policy: Removal of all tumor(s) [no description] Radiotherapy 30 patients received Chemotherapy

Salvati et al., 1997 Cont.

51 patients with MF Gliomas (1988-1992) European Journal of Radiology, 16 (1993) 163-170 51 patients with MF Gliomas (1988-1992) Describes the Radiological Characteristics with No Comments on the Management The Median Survival Time was 6 months

Illustrative Case 47 y/o M; Anesthesiologist H/A, Focal seizure in the Lt Leg Neurological Exam: Normal

Multiple craniotomies in the management of multifocal and multicentric glioblastoma Wael Hassaneen, MD, Nicholas B. Levine, MD, Dima Suki, PhD, Abbhijit Salaskar, MBBS, Alessandra de Moura Lima, Ian McCutcheon, MD, Sujit Prabhu, MD, Frederick F. Lang, MD, Franco DeMonte, MD, Ganesh Rao, MD, Jeffrey S. Weinberg, MD, David Wildrick PhD, Ken Aldape, MD, and Raymond Sawaya, MD Under review

Objectives Complications Survival Do multiple craniotomies increase the risks to the patients? Survival Is the overall survival with multiple lesions who undergo extensive resections, similar to that of patients with a single lesion?

Multicentric vs. Multifocal T1 + C Flair Multicentric Multifocal

Study Design Cases MC MF Controls Solitary 9 patients 11 patients Study period: 1993-2008

Matching Factors (1:1 Ratio) 6000 surgically treated GBM 20 controls Preop KPS score Extent of resection Age at surgery Year of surgery Tumor Functional Grade

Clinical Characteristics Cases MF/MC Controls Solitary Age, Median, range 52, (32-78) 52, (31-75) Median KPS; Range 80; 50-100 Gender (%) M 14(70) 7(35) F 60 (30) 13(65)

Clinical Characteristics Tumor NO. Cases MF/MC Controls Solitary 1 20 2 18 (90) 3 2 (10)

Clinical Characteristics Location Cases MF/MC Controls Solitary All Right 9 (45) All Left 6 (30) 11 (55) Right and Left 5 (25)

Clinical Characteristics Tumor Worst Functional Grade TFG Cases MF/MC Controls Solitary Non or Near Eloquent Brain 12 (60) Eloquent Brain 8 (40)

Clinical Characteristics Tumor Status The Study included New and Recurrent Lesions Cases MF/MC Controls Solitary All New 11 (55) 9 (45) New and Recurrent All Recurrent 10 (50) All Residual 1 (5)

Clinical Characteristics Symptoms Cases MF/MC Controls Solitary Motor deficit 7 (35) 11 (55) Speech Deficit 6 (30) Memory Deficit 3 (15) Visual Deficit 4 (20) HA 8 (40) Altered Mental Status Unstable Gait 2 (10) Sensory Deficit 1 (5) Cranial Nerve Deficit Seizures Patient may have > 1 symptom

Clinical Characteristics Management Cases MF/MC Controls Solitary No. of Craniotomies 1 20 (100) 2 Circumferential Resection 10 (50) 12 (60) Median % EOR, Range 100; 75-100 100; 80-100

Clinical Characteristics Management Cont. Cases MF/MC Controls Solitary p Value Radiotherapy* 100% 0.75 Chemotherapy 45% 90% 0.13 * Except for 3 patients who lost to follow up in each group

Multiple Craniotomies Postop. Complications Category Multiple Craniotomies (Cases) Single Craniotomy (Controls) p Value Overall Complications 6 (30) 7 (35) 1.0 Overall Major 2 (10) 0.13 Neurological 5 (25) Major Neurological 0.24 Regional 0.49 Major Regional N/A Systemic 1 (5) Major Systemic Mortality

Overall Survival 2 Patients still alive in each Group Cases Controls MF/MC Controls Solitary Median Survival 9.7 mos 10.5 mos (P= 0.34)

Overall Survival (Group) KPS > 80 Solitary MF/MC

Overall Survival Multicentric 12.9 mos Multifocal 9.6 mos

Overall Survival for New Lesions Multicentric N = 5 Multifocal N = 6 Solitary N = 9 12.9 mos 9.6 mos 14.6 mos (P= 0. 014)

Overall Survival (New Lesions) En Bloc Resection Solitary MF MC

F/U at 1 year

F/U at 16 mos

Limitations of the Study Retrospective Case Series Small sample size Highly selected cases Patients treated by other modalities (biopsy, resection of one lesion….) were not included in the study.

Conclusions Morbidity: Multiple Craniotomies appear similar to Single Craniotomies Survival: MF and MC GBM may benefit from complete resection of all the lesions Future Studies: Prospective Assessment of the role of Multiple Craniotomies in the management of MF MC glioblastomas