Brain metastases: changing visions Roberto Spiegelmann, MD Baiona, 2014 Head, Stereotactic Radiosurgery Unit Dept of Neurosurgery, Chaim Sheba Medical Center Tel Hashomer, Israel
The best current estimate is that brain metastases occur in at least 6% of all cancer patients. The proportion ranges from less than 1% in thyroid, liver, stomach, prostate, uterine or ovarian cancers, to 20% in lung cancer. Based on this estimate, metastatic brain tumors are thought to outnumber primary malignant brain tumors by at least three to one. Davis FG, Dolecek TA, McCarthy BJ, et al. Neuro-Oncology 2012;14(9):1171-77.
Other sources estimate that 24-45% of all cancer patients have brain metastases. Nussbaum ES, Djalilian HR, Cho KH, Hall WA. Cancer. 1996;78(8):1781-8 Most common intracranial tumor Annual incidence 8.3/100.000 Up to 50%will die as a direct result of them
Lung (50% of all metastases) Breast (most frequent source in women) Melanoma (40-60% of melanoma patients develop brain mets) Colon Kidney
Median Survival 1 month with no therapy 2 months with steroids 11 months with all we have
Surgery Radiosurgery Whole Brain RT
Surgery Immediate relief of site-related deficit fast resolution of edema
surgery large lesion with brain shift unknown diagnosis/accessible lesion obstruction of CSF pathways severe edema with neuro deficit
Surgery Technically straightforward: Clear delimitation from normal brain tissue Accessibility Stereotaxis/Neuronavigation minimize access trauma
Surgical limitations > 50% of patients are not candidates for surgery: tumor inaccessibility Tumor multiplicity extensive systemic disease
tissue manipulation scarring functional deterioration neural muscular-skeletal
Surgery Infection Bleeding Seeding
radiosurgery
Israel, 1993
Radiosurgery Troublesome definition of tumor control
Recurrence vs Radiation injury Confusion between both continues to compromise result assessment
Clinical Neurosurgery Volume 57, 2010
Recidive or radiation injury?
Delayed Contrast Extravasation MRI Treatment Response Assessment Maps (TRAMs) Method a) 2 series of T1-MRI: 2 & 75 min post contrast injection b) rigid/elastic co-registration and intensity-variation corrections c) early (2 min) images subtracted from late (75 min) images 75 min Gd 2 min Gd TRAM Blue = tumor tissue, efficient Gd clearance at 75 min Red = non tumor tissue, Gd accumulation at 75 min 2 0
Delayed Contrast Extravasation MRI: The Rationale A B C Blue/tumor: Morphologically, the vessel lumens are undamaged resulting in efficient contrast clearance D E F G H I Red/non-tumoral: Morphologically, vessels present significantly damaged lumens resulting in Gd accumulation 2 1
Delayed Contrast Extravasation MRI: Histological Validation Red = non-tumoral tissues: Blue = morphologically active tumor: validated by 44 histological samples 2
Surgery or radiosurgery?
radiosurgery deficit reversed by steroids asymptomatic mets
WBRT The classic approach to patients with multiple foci
Whole Brain Radiation Hair loss Acute mental effects Delayed diffuse brain cell injury Marginal effect upon frequent tumors: melanoma Renal Cells Carcinoma
Dose/efficacy Clinical situation Cure radiosensitive tumors (germinoma, lymphoma) Required dose 24 to 36 Gy 90% chance of controlling microscopic cancer 45 to 55 Gy 90% chance of curing a 1-cm squamous cancer 66 Gy A 1-cm lesion requires 66 Gy for local control.
In a series of lung cancer patients with brain mets surviving more than 1 year, 36 of 37 treated with WBRT had leukoencephalopathy compared with Only 1 of 31 who had radiosurgery alone Monaco EA, Faraji AH, Berkowitz O, et al, Cancer. 2013:226-232.
Hippocampal sparing
WBRT Not curative MMSE deterioration in long term less incidence of new brain disease in the short term New disease generates MMSE deterioration
WBRT can only affect contemporary overt or occult disease
Mix and Match Surgery + Radiosurgery Surgery + WBRT Radiosurgery + WBRT
Strange bed partners Radiosurgery in tumor bed after Surgery Is it worth?
Radiosurgery after Surgery Where is the residual tumor in the tumor bed?
Radiosurgery after Surgery When residual is obvious
Cystic metastasis A cystic metastasis in eloquent brain is a major challenge for total (oncological) removal
Cystic metastases are tricky collapse once opened thin layer of tumor cells difficult to remove without poking the surrounding tissue When in eloquent area, this may result in functional damage/residual tumor islands left behind
Radiosurgery for cystic mets irradiating water large area of irradiation: high comp risk
combine Drain the cyst Irradiate residual tumor
At presentation 62 y old. NSCCa lung Left hemiparesis Focal seizures Post Ommaya aspiration 18 months post radiosurgery
05/01/2009 21/01/2009 23/05/2009
05/01/2009 23/05/2009
Radiosurgery and whole brain radiation
Local Control with SRS Boost Study WBRT + SRS P value When RTOG 71% 82%.01 1yr Tufts 87% 91% NS? Pittsburgh 8% 100%.0005 1 yr
Relapse After Radiosurgery Recurrence RS without RT (67) RS + RT (65) Relative Risk P-value Local bed 30% 14% 1.2 <.0001 Distant brain 52% 18% 1.7 <.0001 Note: Local failure at 1 year, distant brain failure at 6 months Withholding WBRT significantly increases relapse in the brain and locally. Aoyama, JAMA 2006
troublesome definitions Local tumor progression was defined as a radiographic increase of 25% or more in the size of a metastatic lesion If an MRI result showed central or heterogeneous low intensity and if the lesion size decreased on serial studies, brain necrosis was scored
ends meet Death was attributed to neurologic causes in 22.8% in the WBRT/SRS group and in 19.3% in the SRS-alone group The median survival time was 7.5 months with WBRT/SRS and 8.0 months with SRS alone.
take home Although surgery and SRS are both focal treatments, SRS is less invasive and may be repeated more often than surgical intervention early detection of a brain recurrence and early salvage brain treatment may prevent neurologic deterioration and neurologic death, even when WBRT is not included in the initial treatment.
SRS alone without upfront WBRT was associated with increased brain tumor recurrence; however, it did not result in worsened neurologic function or increased risk of neurologic death. Therefore, SRS alone could be a treatment option, provided that frequent monitoring of brain tumor status is conducted
The main reason we still do it is that RS for multiple simultaneous foci is cumbersome, lengthy, and costly
Masaaki Yamamoto, et al, Lancet Oncol 2014; 15: 387 95 We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. Standard stereotactic radiosurgery procedures were used in all patients; tumor volumes smaller than 4 ml were irradiated with 22 Gy at the lesion periphery and those that were 4 10 ml with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with fi ve to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1 30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of2014. We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13 9 months [95% CI 12 0 15 6] in the 455 patients with one tumor, 10 8 months [9 4 12 4] in the 531 patients with two to four tumors, and 10 8 months [9 1 12 7] in the 208 patients with five to ten tumors. Overall survival did not differ between the patients with two to four tumors and those with five to ten (HR 0 97, 95% CI 0 81 1 18 [less than non-inferiority margin], p=0 78; pnon-inferiority<0 0001). Stereotactic radiosurgeryinduced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumor had one or more grade 3 4 event compared with 13 (2%) patients with two to four tumors and six (3%) patients with five to ten tumors.
The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumors (50 [9%] patients with two to four tumors vs 18 [9%] with five to ten; p=0 89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumor and one each in the other two groups). Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases.
Baschnagel AM, Meyer KD, Chen PY, et al. J Neurosurg. 2013:1139-1144 250 patients with 1 to 14 brain metastases initially managed with radiosurgery alone. The 1-year local control rate was 92%, and the median time to distant brain failure was 8 months. Total tumor volume was a better predictor of overall survival than number of brain metastases and a better predictor of distant brain failure and even local brain tumor control..
Instead of WBRT Follow up closely Increase imaging diagnostic power Salvage radiosurgery for new mets
need Better tools for multiple metastases radiosurgery
Multiple Mets Treament Module
Brainlab multiple mets module Image-based non stereotactic (CT with mask, no stereo localizer)
8 mets Planning time: 20 Total treatment time: 20 Total beam-on time: 6
So far 5 patients 8 mets 5 mets 4 mets (2) 3 mets No acute toxicity
ra mbmm
ra mbmm
Relative Volume (%) 4 Mets 22 Gy Brain Metastases vs. RapidArc 100 Brain RA Rt occipital RA Fronto Polar RA 80 Lt Parietal RA Lt Cerebellar RA Brain 60 Rt Occipital Fronto Polar Lt Parietal 40 Lt Cerebellar 20 0 0 5 10 15 20 25 Dose (Gy)
A requiem for whole brain radiotherapy?
Radiosurgery for multiple brain mets Logistical and technical barriers are down Strong rationale Cost efficient Effective