# Radiation Oncology/Palliation/Brain Metastases/SRS

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Brain Metastases: SRS

## Overview

* WBRT alone and SRS alone have same OS and LC, but published as abstract only.
* WBRT + SRS showed KPS benefit overall, and OS benefit in single met compared to WBRT alone
* WBRT alone comparable to WBRT + SRS, in active extracranial disease (or poor performance status). Unclear if WBRT needed in controlled extracranial disease or if SRS is sufficient; retrospective evidence suggests worse outcome without it
* No published randomized trial of surgery vs. SRS alone for single met. Retrospective study suggests improved LC with SRS over surgery
* 1 mm margin better than none
* AANS/CNS; 2010 PMID 19960227 -- "The role of stereotactic radiosurgery in the management of patients with newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline." (Linskey ME, J Neurooncol. 2010 Jan;96(1):45-68. Epub 2009 Dec 4.)
** Target population: Adults, with lesions amenable to SRS (<3 cm diameter, <1 cm midline shift) and KPS ≥ 70
** SRS + WBRT vs WBRT alone
*** (Level 1): SRS + WBRT improved survival in single brain met
*** (Level 2): SRS + WBRT improved local control and functional status in 1-4 brain mets
*** (Level 3): SRS + WBRT may improve survival for patients with 2-3 brain mets
*** (Level 4): SRS + WBRT may improve survival for patients with multiple mets and KPS <70
** SRS + WBRT vs SRS alone
*** (Level 2): SRS alone may provide equivalent survival; conflicting evidence of local and distal recurrence. Careful surveillance warranted
** Surgery + WBRT vs SRS +/- WBRT
*** (Level 2): Surgery + WBRT vs SRS + WBRT both effective treatement strategies
*** (Level 3): Surgery + WBRT vs SRS alone conflicting evidence
** SRS alone vs WBRT alone
*** (Level 3): SRS alone appears superior for survival advantage

## Radiosurgery vs surgery

* Cochrane Review, 2006 PMID 16437498 -- "Surgery versus radiosurgery for patients with a solitary brain metastasis from non-small cell lung cancer." (Fuentes R, Cochrane Database Syst Rev. 2006 Jan 25;(1):CD004840.)
** No randomized trials. 686 references found, but none of sufficiently good quality for this review
** Conclusion: No meaningful conclusions can be drawn
* Mayo Clinic, 2003 (1991-99) - PMID 12654423 — "A comparison of surgical resection and stereotactic radiosurgery in the treatment of solitary brain metastases." O'Neill BP et al. Int J Radiat Oncol Biol Phys. 2003 Apr 1;55(5):1169-76.
** Retrospective. 74 pts neurosurgery, 23 radiosurgery. Median f/u 20 mos. No difference in OS. 0% of RS pts had local recurrence vs 58% of NS group.
** Improved local control for radiosurgery compared to neurosurgery.

## WBRT or Radiosurgery

* Rhode Island Hospital / Brown University - ASTRO abstract #7 — "Randomized treatment of brain metastasis with gamma knife radiosurgery, whole brain radiotherapy or both." Chougule PB et al. Int J Radiat Oncol Biol Phys 2000; 48(3 Suppl 1): 114.
** 96 pts. 1-3 mets. No difference in median survival. Local brain control rate 87% (RS), 91% (RS+WBRT), vs 62% (WBRT). New brain lesions in 43% vs 19% vs 23%.
** 51 pts had surgical resection of large, symptomatic lesions prior to randomization
* University of Cologne; 2004 PMID 15127155 - "Linac radiosurgery versus whole brain radiotherapy for brain metastases. A survival comparison based on the RTOG recursive partitioning analysis." (Kocher M. Strahlenther Onkol. 2004 May;180(5):263-7.)
** Retrospective analysis with historical controls.
** Group 1. 117 pts (1991-1998) with 1-3 mets receiving SRS alone. 22% had salvage therapy.
** Group 2. 138 pts (1978-1991) with 1-3 mets receiving WBRT. 7% had salvage therapy (WBRT)
** OS stratified by RPA Class.
** RPA I - SRS: 25m vs. 4.7m (very few pts)
** RPA II - SRS: 5.9m vs. 4.1m (SS)
** RPA III - SRS: 4.2m vs. 2.5m (NS)
** Conclusion: "Radiosurgery in patients with one to three cerebral metastases results in a substantial survival benefit only in younger patients with a low systemic tumor burden when compared to WBRT alone. It cannot be excluded that this effect is partially caused by the available salvage options after radiosurgery."

## WBRT +/- Radiosurgery

* One randomized trial (RTOG 95-08), suggests KPS benefit to WBRT + SRS, and survival benefit for 1 met. Patients RPA 2 with controlled extracranial disease

### Randomized

* RTOG 95-08 (1996-2001) -- WBRT vs WBRT + SRS
** Randomized. 331 patients, 1-3 brain mets with maximum diameter 4 cm, RPA class 1 (26%) or class 2 (74%), lung 63%. Arm 1) WBRT 37.5/15 vs Arm 2) WBRT + radiosurgery (24-18-15 Gy based on size)
** 2004 PMID 15158627 Full text — "Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial." (Andrews DW, Lancet. 2004 May 22;363(9422):1665-72.)
*** Outcome: Mean OS WBRT 5.7 months vs WBRT+SRS 6.5 months (NS); single metastasis 4.9 months vs 6.5 months (SS) though (NS) on multivariate analysis. Higher 3-month response rate and control at 1 yr (71% vs 82%). No difference in overall time to progression (any intracranial failure) and no difference in neurologic death. Local recurrence 43% more likely with WBRT than WBRT+SRS. Improved KPS (4% vs 13%) and decreased steroid use at 6 months but no difference in mental status.
*** Toxicity: Acute G3+ WBRT 0% vs WBRT+SRS 3%; Late G3+ 3% vs 6%
*** Conclusion: WBRT+SRS improved KPS, no difference in OS. Benefit in OS for single metastasis
* Pittsburgh -- WBRT vs WBRT + SRS
** Randomized. Trial stopped early after significant interim benefit in local control for WBRT+SRS arm. 27 patients, 2-4 brain metastases <2.5 cm, KPS ≥ 70. Arm 1) WBRT 30/12 vs Arm 2) WBRT + SRS 16 Gy. Primary outcome brain control.
** 1999 PMID 10487566 — "Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases." Kondziolka D et al. Int J Radiat Oncol Biol Phys. 1999 Sep 1;45(2):427-34.
*** Outcome: 1-year local failure WBRT 100% vs WBRT+SRS 8% (SS); time-to-failure 6 months vs 36 months (SS). Median OS WBRT 7.5 months vs WBRT+SRS 11 months (NS). However, patients in WBRT arm who received salvage SRS median OS 11 months (NS to WBRT+SRS), while patients who received only WBRT median OS 7 months (SS to WBRT+SRS)
*** Conclusion: WBRT+SRS significantly improves control of brain disease; WBRT alone does not provide effective and lasting control

### Non-Randomized

* Multi-institutional; 1996 - PMID 8641923 -- "A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis." (Auchter RM, Int J Radiat Oncol Biol Phys. 1996 Apr 1;35(1):27-35.)
** Multi-institutional retrospective. 122 patients, single resectable met, KPS >=70. Median follow-up 31 months
** RT: WBRT (dose range 25-40 Gy, median 37.5 Gy) + SRS (dose range 10-27 Gy, median 17 Gy)
** Local control 86%, median survival 56 weeks, 1-year OS 53%
** Conclusion: WBRT + SRS is viable, should be tested in a randomized setting
* Multi-institutional; 2001 (1988-98) - PMID 11567817 — "Radiosurgery for patients with brain metastases: a multi-institutional analysis, stratified by the RTOG recursive partitioning analysis method." (Sanghavi SN et al, Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):426-34.)
** Retrospective, multi-institutional. 502 pts, WBRT + RS, stratified by RPA class I-III. Compared with historical controls receiving WBRT alone. Number of metastases not specified (but all metastases were treated with RS).
** Overall MS 10.7 months. Addition of RS boosted median survival (16.1, 10.3, and 8.7 for Class I, II, and III) vs WBRT alone (7.1, 4.2, and 2.3).
** Addition of RS may improve survival in selected pts. Benefit seen in all RPA classes.

## Radiosurgery +/- WBRT

Open trials:
* NCCTG-N0574 protocol link
** Open trial by North Central Cancer Group and ACOSOG
** SRS +/- WBRT in patients with 1 to 3 cerebral metastases:
*** Primary endpoint: overall survival
*** Secondary endpoints: time to CNS (brain) failure, QOL/duration of functional independence/long-term neurocognitive status, post-treatment toxicity.

### Randomized

* EORTC 22952-26001 (1996-2007) -- Randomized, Surgery/SRS +/- WBRT
** Randomized. Pts with 1-3 mets ≤ 3.5 cm (≤ 2.5 cm for 2-3 lesions), and no or stable systemic disease or asymptomatic primary tumors, PS 0-2. Treated with surgical resection (160) or SRS (199). Randomized to: adjuvant WBRT 30/10 or observation. Primary endpoint: PS deterioration to >2.
** 2009: ASTRO Abstract #9 -- "Adjuvant Whole Brain Radiotherapy vs. Observation after Radiosurgery or Surgical Resection of 1–3 Cerebral Metastases - Results of the EORTC 22952-26001 Study." (Kocher M)
*** 359 pts (353 elig.). Surgery for 160 pts (96% solitary), SRS for 185 pts (multiple in 33%).
*** Median time to PS progression: 10 months (obs) vs 9.5 (WBRT), no diff. Intracranial progression (@6 months and 24 months) 39.7% and 54.2% (obs) vs 15.2%/31.2% (WBRT). Reduction of local failure (31.3% vs 16.4%) and elsewhere intracranial failures (32.4% vs 17.6%). Neurological cause of death in 43% vs 25%.
*** Conclusion: Adjuvant WBRT reduces the frequency of intracranial relapse at both initially treated and new sites and reduces the risk of neurologic death. However, it fails to prolong functional independence and overall survival.
** 2011 PMID 21041710 -- "Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study." (Kocher M, J Clin Oncol. 2011 Jan 10;29(2):134-41.)
*** Median time to PS progression (to >2) 10 months (obs) vs 9.5 (WBRT), NS. Similar OS: 10.9 vs 10.7. WBRT reduced the 2 yr relapse rate at initial sites and new sites. Neuro cause of death in 44% vs 28%.
*** Conclusion: "After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival."
* MD Anderson (2001-2007) -- SRS vs SRS + WBRT
** Randomized. Stopped early due to significantly worse cognitive outcome in WBRT+SRS arm. 58 of expected 90 patients. RPA I-II (KPS >=70), 1-3 brain mets (57% single). Arm 1) SRS (dose per RTOG 9005; median 19 Gy) vs. Arm 2) SRS first (median 20 Gy) + WBRT 30/12. No concurrent chemo. Primary endpoint neurocognitive function using HVLT-R recall test at 4 months
** 2009 PMID 19801201 -- "Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial." (Chang EL, Lancet Oncol. 2009 Nov;10(11):1037-44. Epub 2009 Oct 2.). Median F/U 9 months
*** Outcome: Significant decline in 4-month recall SRS 24% vs. SRS+WBRT 52% (SS). Functional brain assessment no difference. 1-year LC 67% vs. 100% (SS); 1-year distant brain control 45% vs. 73% (SS). 1-year CNS DFS 27% vs. 73% (SS). Median OS 15 months vs. 6 months (SS). Salvage much more aggressive in SRS only arm
*** Toxicity: SRS 7% Grade 4.
*** Conclusion: Patients treated with SRS + WBRT were at greater risk of memory decline at 4 months. Recommend SRS as initial treatment
* Japan JROSG 99-1 (1999-2003) -- SRS vs SRS + WBRT
** Randomized. Stopped early due to low likelihood of showing a difference. 132 of expected 188 patients. 1-4 mets, size < 3cm. RPA I-II (85% RPA II). 50% active extracranial disease. 11 centers in Japan. Arm 1) SRS alone (dose if <2cm 22-25 Gy, if 2-3cm 18-20 Gy) vs. Arm 2) WBRT 30/10 followed by SRS. SRS dose reduced by 30%. Primary endpoint OS
** 2006 PMID 16757720 — "Stereotactic Radiosurgery Plus Whole-Brain Radiation Therapy vs Stereotactic Radiosurgery Alone for Treatment of Brain Metastases: A Randomized Controlled Trial." (Aoyama H et al. JAMA 2006;295 2483-2491.)
*** Outcome: Median OS SRS 8.0 months vs. SRS + WBRT 7.5 months (NS); 1-year OS 28% vs. 38% (NS); CNS death 19% vs. 23% (NS). 1-year LC ~75% vs. ~90% (SS); 1-year distant brain control 36% vs. 59% (SS). Decreased need for salvage brain treatment (10 pts vs 29 pts) with WBRT. No difference in neurocognitive measures
*** Conclusion: SRS alone can be a reasonable strategy, with close monitoring and salvage retreatment
** 2015 PMID 26181254 "Stereotactic Radiosurgery With or Without Whole-Brain Radiotherapy for Brain Metastases: Secondary Analysis of the JROSG 99-1 Randomized Clinical Trial." (Aoyama H et al. JAMA Oncol. 2015 Jul;1(4):457-64)
*** Secondary Analysis of the 88 Lung Cancer patients (n=132) based on diagnosis-specific Graded Prognostic Assessment (DS-GPA)
*** Outcome: Significantly better OS was observed with the addition of WBRT + SRS in patients with favorable prognosis. In the GPA 2.5-4.0 group (favorable prognosis pts) WBRT + SRS vs SRS alone, median survival time of 16.7 months vs 10.6 months (P = .04). However, no such difference was observed in the unfavorable GPA 0.5-2.0 group (P = .86). 5 yr OS dramatically better in favorable prognosis pts (24% vs 4% - P value not provided).
*** Conclusion: The important role of WBRT for patients with BMs from NSCLC with a favorable prognosis should be considered

### Non-Randomized

* Pittsburgh; 2005 PMID 15803013 -- "Radiosurgery with or without whole-brain radiotherapy for brain metastases: the patients' perspective regarding complications." (Kondziolka D, Am J Clin Oncol. 2005 Apr;28(2):173-9.)
** Retrospective. 200 patients treated with SRS +/- WBRT (69%). Patients perspective via questionnaires
** After WBRT: hair loss 88%, excess fatigue 95% (5% SRS), short term memory 72%, long-term memory 33%, concentration 61%, depression 54%. WBRT + SRS 63% thought they had side effects vs. SRS 34% (SS)
* Multi-institutional; 2002 PMID 12062592 -- "A multi-institutional review of radiosurgery alone vs. radiosurgery with whole brain radiotherapy as the initial management of brain metastases." (Sneed PK, Int J Radiat Oncol Biol Phys. 2002 Jul 1;53(3):519-26.)
** Retrospective. 10 institutions. 569 patients (268 RS alone vs. 301 RS+WBRT)
** Median survival: no difference
** Conclusion: Omission of WBRT doesn't seem to compromise length of survival
* Heidelberg; 1998 (Germany) PMID 9817276, 1998 — "Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases." Retrospective data from Pirzkall (JCO 1998) found no difference in survival in 236 pts treated with SRS versus SRS + WBRT, who had 1-3 brain metastases. In subset of patients WITHOUT extracranial disease, omitting WBRT decreased median survival from 15.4 months to 8.3 months

## Radiosurgery alone

* Freiburg; 2003 (Germany) PMID 12699548, 2003 — "Radiosurgery followed by planned observation in patients with one to three brain metastases." Lutterbach J et al. Neurosurgery. 2003 May;52(5):1066-73.
** 101 pts. Up to 3 mets, 3 cm or less.
** 1-year brain failure free progression rate was 51%. RPA groups predicted survival
* Kentucky; 2002 PMID 11872278, 2002 — " Risk of symptomatic brain tumor recurrence and neurologic deficit after radiosurgery alone in patients with newly diagnosed brain metastases: results and implications." (Regine WF, Int J Radiat Oncol Biol Phys. 2002 Feb 1;52(2):333-8.)
** Retrospective. 36 patients.
** Median OS: 9 months; symptomatic brain tumor recurrence 47%
** Risk of symptomatic brain tumor recurrence after SRS alone: At 18 months, an 80% risk of relapse within the brain with SRS; and neurologic deficit-free survival drops to 50% at 12 months. (stays stable at 18 months)
** Conclusion: Use of primary SRS alone in this setting is associated with an increasingly significant risk of BTR with increasing survival time, as well as increasing neurological deficits
* RTOG 90-05 (1990-1994) - dose escalation study
** 156 pts. Recurrent primary brain tumors or recurrent brain metastases. Previously treated with RT.
** First report (1996) - PMID 8621289 — "Radiosurgery for the treatment of previously irradiated recurrent primary brain tumors and brain metastases: initial report of radiation therapy oncology group protocol (90-05)." Shaw E et al. Int J Radiat Oncol Biol Phys. 1996 Feb 1;34(3):647-54.
** Final report (2000) - PMID 10802351 — "Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05." Shaw et al. Int J Radiat Oncol Biol Phys. 2000 May 1;47(2):291-8.
** Results: maximum tolerated doses were 24 Gy, 18 Gy, and 15 Gy for tumors </= 20 mm, 21-30 mm, and 31-40 mm. The MTD for tumors <20 mm was actually not reached, but they did not increase the dose beyond 24 Gy. Incidence of radionecrosis 11% at 2 yrs. Grade 3-5 neurotoxicity associated with tumor size, tumor dose, and KPS.

## For radioresistant tumors

* ECOG E6397 2005 - PMID 16314647 — "Phase II trial of radiosurgery (RS) for 1 to 3 newly diagnosed brain metastases from renal cell, melanoma, and sarcoma: An Eastern Cooperative Oncology Group Study (E6397)." Manon RR et al.
** Melanoma, sarcoma, renal cell. Maximum of 4 cm tumor.
** Stable disease in 32%, 42% with progressive disease.

## For 4 or more metastases

* Pittsburgh; 2006 (1995-2005) - PMID 16338097 — "Stereotactic radiosurgery for four or more intracranial metastases." Bhatnagar AK et al. Int J Radiat Oncol Biol Phys. 2006 Mar 1;64(3):898-903.
** Retrospective. 205 pts treated with GKRS for 4 or more metastases in one session. Median number of lesions was 5. 17% had GKRS alone, 46% with WBRT, 38% for progression after WBRT.
** Median OS was 8 months. 1-yr LC was 71%. By RPA classificiation, median OS was 18 months (class I), 9 months (II), and 3 months (III). Total treatment volume, rather than number of lesions, was the most significant predictor of survival
** Conclusion: improved survival for pts treated with GKRS compared to historical controls by RPA classification in this retrospective study. Some pts with 4 or more lesions should be considered for GKRS.

## Brainstem lesions

* UCSF; 2008 (1991-2005) PMID 17628747 -- "Gamma knife radiosurgery for brainstem metastases: the UCSF experience." (Kased N, J Neurooncol. 2008 Jan;86(2):195-205.)
** Retrospective. 42 pts (44 lesions: 7 midbrain, 31 pons, 6 medulla). Median target volume 0.26 cc; median tumor diameter 0.9 cm. Prescribed dose 16 Gy (50% isodose median).
** Brainstem lesion FFP 90% at 6 months, 77% at 1 yr. 4 pts had brainstem complications. Poor brainstem outcome associated with melanoma and RCC histology and brainstem lesion volume ≥ 1 mL.
** Conclusion: SRS provided excellent local control with low morbidity
* Virginia; 2006 (1989-2005) PMID 17219825 -- "Gamma knife surgery for metastatic brainstem tumors." (Yen CP, J Neurosurg. 2006 Aug;105(2):213-9.)
** Retrospective. 53 patients (8 midbrain, 42 pons, 3 medulla). Mean volume 2.8 cm3 (0.05-21). Prescription dose mean 17.6 Gy (9-25). 37 patients with follow-up imaging
** Conclusion: GKS prolongs survival compared to observation; risks are low
* Marseille, 2006 (France)(1992-2001) PMID 16385327 -- "Brainstem metastases: management using gamma knife radiosurgery." (Fuentes S, Neurosurgery. 2006 Jan;58(1):37-42; discussion 37-42.)
** Retrospective. 28 patients (9 midbrain, 17 pons, medulla 2). Mean max diameter 17.2 mm (10-30). Mean dose 19.6 Gy (11-30)
** Conclusion: GKS valuable modality for safe and effective treatment

## SRS Margins

* Maastricht, 2006 PMID 16814946 -- "A pathology-based substrate for target definition in radiosurgery of brain metastases." (Baumert BG, Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):187-94.)
** Retrospective. Autopsy of 45 patients
** Infiltration present in 48/76 mets (63%). SCLC and melanoma infiltration >=1mm, other tumors <1mm. NSCLC highest percentage of mets with infiltration (70%)
** Conclusion: Margin of ~1mm should be added to visible lesion
* Paris, 2003 PMID 12885447 -- "Radiosurgery for brain metastasis: impact of CTV on local control." (Noel G, Radiother Oncol. 2003 Jul;68(1):15-21.)
** Retrospective. 61 patients. Median KPS 80. 23 no progression of systemic, 38 progressive disease. RT 38 initial SRS, 23 relapse/progression after WBRT. Median f/u 10.5 months
** RT margins: 1994-1995 no margin, mean min GTV dose 14.6 Gy. 1995-2000 1 mm margin (GTV -> CTV), mean min GTV dose 16.8 Gy
** 2-year LC rate: 51% vs. 90% (SS), 8 recurrences vs. 2 recurrences (SS). Margin only multivariate predictor of LC
** No difference in OS, no difference in side effects

## SRS Fractionation

* Toronto; 2007 PMID 17852114 -- "Fractionated (split dose) radiosurgery in patients with recurrent brain metastases: implications for survival." (Davey P, Br J Neurosurg. 2007 Aug 8;:1-5)
** Prospective. 2 SRS protocols, planning based on CT with contrast. 69 patients 2 fractions, 35 patients 1 fraction
** Outcome: Median OS fractionated 7.5 months vs. single fraction 4 months
** Conclusion: Fractionated SRS should be further investigated
* Erlangen, Germany; 2007 (2000-2005) PMID 17960338 -- "Hypofractionated stereotactic radiotherapy for brain metastases--results from three different dose concepts." (Fahrig A, Strahlenther Onkol. 2007 Nov;183(11):625-30.)
** Retrospective. 150 patients with 228 brain metastases. Treated with Novalis. Three different dose schedules: A) 5 x 7 Gy, B) 10 x 4 Gy, C) 7 x 5 Gy. Median PTV 6.1 cm3 (0.02 - 100)
** Outcome: CR 42%, PR 30%, NC 21%, PD 7%. Median OS 16 months
** Toxicity: Dependent on PTV and dose schema; 10 x 4 Gy well tolerated without side effects
** Conclusion: Hypofractionated SRS is effective and safe; if volume >15 cm3, 10 x 4 Gy seem advantageous; but other fractionations have higher response rates

## Guidelines

* Please see the Brain Metastases Guidelines page