Updated Oncology 2015: State of the Art News & Challenging Topics CURRENT STATUS OF STEREOTACTIC RADIOSURGERY IN BRAIN METASTASES Mehmet Ufuk ABACIOĞLU Neolife Medical Center, İstanbul, Turkey Bucharest, 16 June 2015
Conflict of Interest Disclosure Receipt of honoraria: Varian, Brainlab
Stereotactic Radiosurgery (SRS) Stereotactic Ablative Radiotherapy (SABR) = High dose, precisely targeted radiation treatment given in single or few fractions
BRAIN METASTASES Increasing due to better diagnosis, longer survival Each year 400.000 new patients with BM in US Incidence and mortality more than any specific cancer!!! DS- GPA study*, 4259 pts, 11 Institutes 1 met= 40% 2-3 mets= 33% >3 mets= 27%
Steroids +/- WBRT n=48 Prednisone Prednisone + WBRT 40 Gy Clinical Remission 63% 61% Remission Duration 5 weeks 11 weeks Median Survival 10 weeks 14 weeks Horton J, Am J Roentgenol Radium Ther Nucl Med. 1971
QUARTZ trial BSC vs BSC+WBRT in NSCLC brain mets n=538 (not suitable for resection or SRS) KPS<70: 38% OS BSC: 57 days BSC+WBRT: 65 days Mulvenna PM, ASCO 2015
Diameter 20 mm 21-30 mm 31-40 mm MTD 24 Gy 18 Gy 15 Gy
WBRT +/- RS boost RTOG 9508, 1-3 mets, RPA I- II, 333 patients WBRT 3750 cgy/15 fx +/- RS Cause of death NS(>2/3 systemic) Single met OS 4.9 m 6.5 m, 2-3 mets NS Local control 71% vs 82% (p=0.01) Stable or increased KPS @ 6 months %27 vs %43 (p=0.03) Decrease in the steroid use Andrews, Lancet 2004
WBRT +/- RS boost 2-4 mets Pittsburg, 27 patients, early stopped due to interim analysis (60% of planned accrual) Local recurrence @1year 100% 8% Better brain control with WBRT+SRS Overall Survival 7.5 m vs 11 m (NS) Kondziolka, IJROBP 1999
RS Alone More common in routine practice Local control is high, morbidity low Overall survival is not different w/out addition of WBRT WBRT decreases the incidence of primary and new brain recurrences
RS +/- WBRT JROSG 99-1, 1-4 mets, <3 cm, 132 patients %85 RPA II, %50 active EC disease Intracranial relapse@1y 76% 47% (p<.001) Salvage tx n=29 n=10 (p<.001) OS similar(8 m vs 7.5 m) Neurological death 19% vs 23% (p=.64) Aoyama, JAMA 2006
n=160 n=199
Sx or RS +/- WBRT Obs WBRT PS 2 mos 10 m 9.5 m mos 10.9 m 10.7 m Kocher, JCO 2011
Sx or RS +/- WBRT Intracranial Control @ 2y Sx (%) Sx+WBRT (%) SRS (%) SRS+WBRT (%) Initial sites 59 27 31 19 New sites 42 23 48 33 Kocher, JCO 2011
EORTC 22952- QOL QLQ C30 + Brain Cancer Module Overall, patients in the observation only arm reported better HRQOL scores than did patients who received WBRT. The differences were statistically significant and clinically relevant mostly during the early follow- up period (for global health status at 9 months, physical functioning at 8 weeks, cognitive functioning at 12 months, and fatigue at 8 weeks). Soffietti, JCO 2013
MDACC, n=58, 1-3 met, RPA 1-2 Neurocognitive function with HVLT
Aoyama et al (JROSG) 2006: 132 pts Chang et al (MDACC) 2009: 58 pts Kocher et al (EORTC) 2011: 199 pts Overall 389 pts / 364 eligible for metaanalysis Sahgal, IJROBP2015
Median SRS SRS+WBRT Time to local recurrence Time to distant failure 6.6m 7.4m 4.7m 6.5m Overall survival 10m 8.2m
<50 yo patients <50 yo patients had a similar local and distant failure with SRS alone mos in pts 50: 13.6m vs 8.2m mos in pts >50: 10.1m vs 8.6m
Comment n of <50yo patients is only 68 Post hoc analysis Lung cancer is more frequent in the SRS+WBRT group, while RCC is more in the SRS group Better OS with SRS compared to SRS+WBRT may be overvalued We need to conduct disease specific prospective studies
Brown P, ASCO 2015
Brown P, ASCO 2015
Brown P, ASCO 2015
Brown P, ASCO 2015
Largest tumour <10 cc and <3 cm in longest diameter Total cumulative volume 15 cc KPS 70 1194 pts, 23 centers in Japan Yamamoto, Lancet Oncol 2014
Any adverse event 7% vs 9% vs 9% Yamamoto, Lancet Oncol 2014
SRS for multiple mets Karlsson, Neurosurgery 2009 4 centers 1921 patients Chang, J Neurosurg 2010 323 patients 1-5 6-10 11-15 >15
NAGKC 12-01 SRS for 5 Brain Mets A Randomized Controlled Study Of Neurocognitive Outcomes In Patients With Five Or More Brain Metastases Treated With SRS or WBRT 10 cc largest tumor volume 15 cc total tumor volume Planned accrual n: 120 Primary endpoint: NCF at 6 months
Local control according to diameter/dose Goodman, IJROBP 2001
Large mets Surgical resection is the standard treatment Prompt response with decompression Increased QOL, better neurological outcome Definite pathologic dx Not feasible for all patients Fractionated SRS may be a viable option Increase the local control Deecrease the toxicity of single fx SRS
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2006-2012, 135 pts with 1-3 mets (w/o previous WBRT) < 2cm: 3x12 Gy (44%) 2cm: 3x9 Gy (56%) 1-3 mm PTV margin mgtv 10.1 cc (1.6-48.4) mptv 16.4 cc (3.4-62.7 cc)
mos: 14.8m LC 1y: 88% LC 2y: 72% Radionecrosis 12/171 mets (7%) 9% at 1y, 17% @2y Poor prognosis for LC on MVA: Melanoma histology
1990-2009, 11 studies reporting LC rates, fixed dose & size of mets
SRS series Local Control 6m 12m 21Gy >80% >80% 18Gy >80% >60% 15Gy >80% <50%
fsrt series Local Control 6m 12m fsrt >90% >70%
180 patients n % Age Neolife Medical Center, 2011-2014 TrueBeam STx with Novalis using ExacTrac and Brainlab 6- D couch median 59 (29-87) Gender (F/M) 68/112 38% / 62% Number of mets median 2 1 78 43% 2-3 59 33% 4-10 29 16% >10 14 8% Median Range Largest diameter 20 mm (4-60 mm) Vol of largest met 3.2 cc (0.02-59.4 cc) Total volume 4.4 cc (0.02-59.4 cc) ESTRO Forum 2015 PO- 0802
Patient characteristics n % Primary tumor Lung 118 65% Breast 29 16% GIS 12 7% Renal, Melanoma 12 7% Others 9 5% Primary controlled 114 63% Distant metastasis present 108 60% Newly diagnosed/recurrent 117/63 65%/35% Previous WBRT 63 35%
Diameter and Fractionation >30 mm 33 21-30 mm 11-20 mm 5 28 50 37 SRS FSRT </=10 mm 23 4 0 18 35 53 70 Fractions Doses % 1 fx (n=56) median 18 Gy (14-20 Gy) 31 3 fx (n=51) median 24 Gy (18-27 Gy) 28 4 fx (n=2) (20-24 Gy) 1 5 fx (n=71) median 30 Gy (22.5-40 Gy) 40
OS and diameter mos= 12 m (New 13m, Rec 8m) 20mm= 17m 21-30mm= 12m 30 mm= 7m
Local Control and diameter Local control in >3 cm mets New Rec 6m (%) 1y (%) 10 mm 100 100 11-20 mm 89 74 21-30 mm 94 70 30 mm 97 69
54yo, NSCLC, Metastasectomy 7 m ago 60 mm, 59 cc, 5x6 Gy Before 3 months 9 months
SRS to Surgical Cavity Patients with mass effect may need resection for decompression
Addition of Sx to WBRT Patchell #1, Kentucky, 1990, n=48 OS: 15w vs 40 w, LR: 52% vs 20% Noordijk, Leiden, 1994, n=63 OS 6m vs 10 m Mintz, Canada, 1996, n=84 (lower KPS pts) OS 6m vs 6m
Addition of WBRT to Sx Patchell #2, 1998, n=95 LR 46% vs 10% (p<0.001) Distant brain progression 37% vs 14% (p<0.01) Neurological death 44% vs 14% (p=0.003) Overall survival (43w vs 48w) and functional independence NS
After surgery, at 2 years, WBRT reduced the probability of relapse at initial sites from 59% to 27% (p<0.001)
SRS as an alternative to WBRT after surgery in order to improve local control eliminate/delay the toxicity of WBRT
Preop Postop SRS Plan 3 months
>1000 pts LC=70-100% Amsbaugh MJ, Austin J Med Oncol. 2014
SRS for Surgical Cavity Small cavity = Single fraction Large cavity = Fractionated
Fractionation in larger cavities n=101, >3cm cavities 3x9 Gy, 2 mm margin Local control 93%@1y 84%@2y Similar in radiosensitive and resistant histologies Radionecrosis 9% (symptomatic 5%) Minniti, IJROBP 2013
Timing of SRS Usually 2-4 weeks after Sx The greatest volume change occurs immediately after surgery (postop days 0-3) There is no need to wait for cavity shrinkage after 1 or 2 weeks Atalar, Neurosurgery 2013
Effect of additional margin on LC Difficulty of delineation of resection bed after Sx Study Local Control (%) 0 vs 2 mm Toxicity (%) 0 vs 2 mm Nataf, France, 2008, n=93 72 vs 69 (NS) 7 vs 20 (p=0.02) Choi, Stanford, 2012, n=120 84 vs 97 (p=0.042) 8 vs 3 (NS)
Neoadjuvant SRS Clearer delineation of the target Theoretically reduces the risk of intraoperative spread Possible additional mass effect which may complicate the resection n=47, median 14 Gy (11.6-18 Gy) Median 1 day (0-17d) between SRS and Sx LC@1y 86% Asher, IJROBP 2014
Prognostic factors for LC Superficial with dural involvement and >3 cm higher local recurrence Brennan, IJROBP 2014
Prognostic factors for LC Breast cancer = leptomeningeal spread 24 vs 9% compared to non- breast histologies (p=0.004) Atalar, IJROBP 2013
Complications of Postop SRS Any clinical toxicity 0-26% Surgical Radionecrosis 3% Neurocognitive function is reported to be better compared to WBRT, though prospective comparison is awaited
Can we replace RT with supra total resection? Yoo, J Neurosurg 2009
Ongoing Phase III Trials Arm 1 Arm 2 Primary endpoint MDACC Observation Cavity SRS NCCTG- NCI- NRG 1270 WBRT Cavity SRS Poland WBRT Cavity SRS Local Control Overall Survival Neurocognitive Function Failure- free Survival Neurocognitive Function
Conclusion- I SRS alone is an effective treatment for brain metastases (not limited with number) For tumors <2 cm, single fraction achieves high local control with low toxicity For larger mets hypofractionation may increase the local control rate with lower toxicity Histopathology, number and cumulative volume of mets may further guide for the choice of treatment
Conclusion- II Surgery alone has a high rate of local recurrence which requires salvage treatments Both local recurrence and the salvage treatments may impair the QOL of the patients. SRS to the cavity is an effective local RT method which increases the local control with lesser toxicity compared to WBRT