Treating Brain Metastases in the Changing World of Oncology: Matthew Ewend, MD Kay and Van Weatherspoon Professor Chair, Department of Neurosurgery

Treating Brain Metastases in the Changing World of Oncology: Matthew Ewend, MD Kay and Van Weatherspoon Professor Chair, Department of Neurosurgery

Disclosures Consultant: None Stock Holdings: None Paid Speaking Arrangements: None Research Support: Eisai Gliadel for Brain Metastases Off Label Gliadel BCNU wafers Would everyone check to see they have their attorney? I seem to have ended up with two

CNS Metastasis by Primary Site Ryken T et al. Textbook of Neurooncology, 2005 Total CNS mets per year ~98,000 170,000.

With rare excepfons, treatment of brain metastases is palliafve Survival QOL CogniFve funcfon

Prognosis: Survival by RTOG RPA Class Class Class I <65, KPS >70 Controlled 1 No extracranial dz Class II Everyone else Class III KPS < 70 Survival 7.1m 4.2m 2.3m RPA=recursive parffoning analysis Gaspar L et al, Int J Radiat Oncol Biol Phys, 2000

Factors AffecFng Survival in Women with Brain Metastases from Breast Cancer SUBTYPE AGE RACE *OS = Time from Original Breast Cancer Diagnosis to Death Carey Anders, ASCO 2010 Abstract #1027

Survival remains poor in patients with triple negative breast cancer and brain metastases. Study Time Period # Pts. Median survival Dawood 2009 1980-2006 42 2.9 months Lin 2008 2000-2006 53 4.9 months Eichler 2008 2001-2005 21 4.0 months Nam 2008 2001-2006 47 3.4 months Carey 2010 (abstr #1027) Niwinska 2010 (abstr #1029) 1988-2008 30 2.9 months 2003-2009 106 4 months Survival dominated by extracranial progression

Survival may be improving in patients with HER-2+ breast cancer and brain metastases. Study Time Period # Pts Median survival Tham 2006 1970-1999 21 ~3 months Bendell 2003 1998-2000 42 13 months Gori 2007 1999-2005 43 23 months Stemmler 2006 2000-2004 42 13 months Eichler 2008 2001-2005 30 17 months Melisko 2008 1997-2007 35 23 months ~50% of paients (in some series) die of CNS progression

As cancer therapy improves, our treatments will change: What if the field changes? If breast cancer survival doubles, does that change need for whole brain radiafon? Yes brain is sanctuary site need more aggressive brain therapy No if pafents live longer, side effects will be more evident

How do we treat brain metastases?

Strategies for Brain Metastases Followed By Surgery Radiosurgery Whole Brain Radia5on ObservaFon 1 2 3 Surgery X X X Radiosurgery 4 X 5 Whole Brain RadiaFon 6 7 X Systemic Therapy 8 9 10

Disease Extent Dictates Choices Solitary met Oligometastasis Mul5ple metastases

When to Operate? Significant mass effect Tumor, edema, blood Unknown diagnosis At presentafon Following radiafon therapy Recurrence Posterior fossa?

Improved Survival Following Surgery and RadiaFon or RadiaFon Alone for Single Brain Metastases Median Survival (wks.) P<0.01 Patchell, NEJM, 1990

Does Whole Brain RadiaFon Work?

PostoperaFve Radiotherapy for the Treatment of Single Brain Metastases: Results 1 100 P <.001 WBRT No WBRT Patients, % 80 60 40 20 18 70 P <.001 10 46 P =.003 P <.01 44 40 14 14 0 Overall Recurrence Recurrence at Original Site Recurrence at Other Sites Death From Neurologic Causes 1. Patchell RA, et al. JAMA. 1998;.280:1485-1489. 16

Post surgical Radiotherapy for Brain Metastasis: ProspecFve Trial Survival (not significant) radiafon 48 weeks observafon 43 weeks FuncFonal Independence (not significant) radiafon 37 weeks observafon 35 weeks Patchell, JAMA 280:1527, 1998

What is cognifve effect of WBRT?

Chang abstract

Randomized 58 PaFents 28 SRS + WBRT 30 SRS alone CogniFve funcfon Chang Lancet Oncology 10:1037 2009

Probability of NeurocogniFve Decline at 4 months aner SRS or SRS/WBRT SRS alone had longer survival (15 m vs. 6 m), more recurrences(27% vs. 73%), worse local control (67% vs. 100%) SRS + WBRT associated with greater risk of learning and memory decline at 4 months then SRS alone. Recommended SRS and close observafon Chang Lancet Oncology 10:1037 2009

RTOG 0214 A Sun et al: JCO 29:279, 2011

PCI for NSCLC: CogniFve FuncFon A Sun et al: JCO 29:279, 2011

PCI for NSCLC: Randomized Trial No differences in Overall survival Disease free survival QOL, ADL Differences in Memory/recall at 1 year (HVLT, immediate and delayed) MMSE, HVLT (immediate and delayed) at 3 months Developing Brain Metastasis ( 8% PCI vs. 18% observafon) A Sun et al: JCO 29:279, 2011

What do we know about using WBRT It prevents recurrence It doesn t yet prolong survival There are (potenfal) cognifve implicafons Could augmented local therapy be an alternafve in appropriate cases?

Use of Local BCNU Wafers in PaFents with Brain Metastases

Ewend et. al., Neurosurgery, 1998

Phase I II Trial of Surgery, BCNU Polymer Wafers, and XRT for Treatment of Brain Mets Single arm, 6 insftufons 25 pafents Brain metastasis pafent appropriate for surgery of single lesion Endpoints Recurrence paserns, survival, toxicity, QOL

6 centers; 25 pafents; 52% lung primary

Recurrence Rates following Surgery/ BCNU Wafers/WBRT Site Number Histology Surgical Bed 0/25 (0%) none In brain, distant to surgery 4/25 (16%) Lung (2) Breast (2) Cauda equina 1/25 (4%) Melanoma MulFple spinal lesions, intradural 1/25 (4%) Yolk sac tumor

CombinaFon of surgery, local BCNU and WBRT has very low local recurrence rate. What are the outcomes with surgery and local BCNU alone, especially cognifvely?

Effects of Surgery with BCNU Wafer Placement on NeurocogniFve FuncFon in PaFents with One to Three Brain Metastases Ewend MG, Meyers CA, Silva E, Booth Jones M, Jain S, and Brem S Presented at ASCO, May 2011

PaFent Demographics 59 pafents received BCNU wafers placed 5 excluded for pathology, protocol violafons Pathology 39% NSCLC, 28% melanoma, 13% breast cancer 55.6% had addifonal metastases in other organs Single brain lesion 87%, 2 3 lesions 13% RPA Class 1 36%, RPA Class 2 64%

NeurocogniFve TesFng Performed

Hopkins Verbal Learning Test: Immediate and Delayed Recall, RecogniFon

Controlled Oral Word AssociaFon (COWA) and Trail making test B

Local recurrence 14/50 pts.

Study Conclusions NeurocogniFve funcfon improved following surgery + BCNU wafer placement Well tolerated Local Recurrence rate (14/50) midway between Surgery + XRT 10% Surgery alone 46%* Compared with Patchell, JAMA, 1998

Treatment of Brain Metastases: Conclusions Brain Mets not one disease Histology and subtypes maser Each treatment has a role Whole brain radiafon is effecfve but not a free shot Individualizing therapy is the next challenge Surgical therapy with local therapy can improve cognifve outcomes at one year

Treatment of Brain Metastases: Personalizing therapy Conclusions WBRT for those at high risk for early disseminated recurrence Local therapy only for those with localized disease and good long term prognosis How do we figure out at the beginning who is who?

QuesFons