BrainMets
==

/Brain Mets, /BrainMets

Recent review in Clinical Lung Cancer, July 2014:

http://dx.doi.org/10.1016/j.cllc.2014.04.008

DEGRO Recommendations (dose 18Gy-20Gy-22Gy, SRS for up to 4 mets)

Kocher, Strahlenther Onkol. 2014 Jun;190(6):521-32. doi: 10.1007/s00066-014-0648-7. Epub 2014 Apr 9.  Stereotactic radiosurgery for treatment of brain metastases. A report of the DEGRO Working Group on Stereotactic Radiotherapy.

http://www.ncbi.nlm.nih.gov/pubmed/?term=24715242

Incidence: 170,000-300,000 (2001)

Up to 30% of all CA pts get brain mets.

Mean age: 60 yrs

Median survival w/o treatment: 1 mo (Zimm S, Cancer 48:384-394, 1981)

w/ steroids: 2 mos

w/ WBI: 4 mos (Sundstrom, Ann Med 30:296-299, 1998)

MCC: lung 50% (MedSurv 13wks), breast 15-20% (MedSurv 24wks), unknown 10-15%, melanoma 10%, colorectal, lymphoma, RCC (hemorrhagic), (but not prostate)

Often Solitary: Breast,colon, renal.

Often Multiple Mets: Lung, melanoma

Often hemorrhagic: RCC, melanoma

Sx: HA, focal neuro sx, only 10-20% have sz,

Gaspar, IJROBP 1997, RTOG /RPA Brain Mets /PEAK of 7.1 mos:

controlled Primary, Extracranial dz, Age65, KPS70.

Class 1: PEAK

 Median Survival 7.1 mos

Class 2: all others

 Median Survival 4.2 mos

Class 3: KPS<70

 Median Survival 2.3 mos

/RTOG 9104: Mini-Mental Status Exam can predict outcome for brain met pts.

Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):59-64.

PMID 10924972

Lack of decline of MMSE below 23 was seen in long-term survivors, with 81% at 6 months and 66% at 1 year of patients maintaining a MMSE above 23.

 

Steroids, min dose

AntiSeizure meds, only if sz. Don't give prophylactically, EXCEPT melanoma, concurrent leptomeningeal disease.

Chemo for BrainMets:

Usually at failure.

TMZ, Xeloda

/WBI /WBRT

For multiple brain mets,

Non-randomized studies show WBI (w/o surgery) improves survival from 1 mo to 4 mos (from 3 to 6 months (JH)).

Steroids improves survival by 1 month.

Improve HA in 70%

Improves CN dysfunction in 40%

After WBI, only 40% of deaths are from brain mets.

WBI dose fracitonation: 300x10=3000

Use lower fractionation if pt going to get more chemo: 250 to 3750.

Side Effects of WBI: somnolence syndrome, dementia ...

No standard fractionation,

DeAngelis (NSU 1989) says increased dementia if >300/day.

/Rades, Strahlenther Onkol. 2008 Jan;184(1):30-5.

Comparison of short-course versus long-course whole-brain radiotherapy in the treatment of brain metastases.

Compared 400x5, 300x10, 200x20.

No OS diff.

IMRT Boost to mid 50's @ 200/d if occipital

Need 66Gy for local control of 1 cm lesion.

/Solitary Brain Met

Always try surgery first, if can be done safely! (non-eloquent)

Can't omit surgery:

/Patchell1, NEJM 1990: +/-surgery + WBRT, "(median, 40 weeks vs. 15"

RT: 300x12

48 pts

Improved OS 40wks v 15wks

11% of resected lesions were NOT mets.

Improved LR 20% v 50%

Annal of Neurology 1993

Still need PostOp WBI after resection:

Many studies show PostOp WBI still improves LOCAL CONTROL.

/Patchell2, JAMA 1998 – Need PostOp WBI after resection of solitary brain met.

95 pts.

Surgery +/- WBI

RT: 180x28=5040.

Decreased local recurrence 10% v 46%.

Decreased any brain recurrence rate 18% v 70%.

Decreased distant recurrence 14% v 37%

Decreased neurologic death 14% v 44%.

No OS diff (43-48 wks)

No diff in Functional Independent Status.

WBI decreased salvage tx 63% v 8%.

No benefit of post-op WBI in renal cell, sarcoma, melanoma?

Wong, Re-RT to WBI 200x10

After WBI, Only 40% of deaths are due to progressive CNS disease.

/Multiple brain mets

/SRS /RS Stereotactic Radiosurgery: for brain mets, AVMs

For mets < 3cm.  Suh doesn't do RS for more than 4 mets.

Can RS replace surgery?

Tradeoffs between Surgery vs RS:

Surgery:

Can do for any size,

acute removal, fast sx reslution,

histologic confirmation

rapid steroid taper

easy to follow pts

SRS:

min invasive

can treat deep lesions

lower cost than surgery

BUT, no histo confirmation, can only do for <3cm, longer steroids

Surgery vs RS decision:

Choose Surgery if:

tumor>35mm, +mass effect, single lesion, superficial, need tissue.

Choose RS if: deep, <35mm, poor surg risk, no mass effect, multiple lesions w/ good systemic control, radioresistant histo (RCC, melanoma).

/SRS Dose

Schomas UChicago's current recommendations:

<1cm 20-22Gy (w/ WBI),

1-3cm 18-20Gy

>3cm 14-16Gy

/SRS Technique

Prescribe to 50% for GK, 70-80% for linacs.

Winston-Lutz test is gold std for isocentric accuracy for Linacs.

Aim for <0.5mm.

Aim for >500 degrees of arc

CTV=GTV

PTV=CTV + PTVmargin

BlockMargin

MF

PTV=0, BlockMargin=0

now prescribe to volume: 100% of PD goes to 95% of PTV

Make sure IDL fall of 10% every 1mm, or 100% to 50% in <5mm.

CM

Going back to prescribing to MaxDose

PTV 1mm, Block 2mm

MF and CM

Both now prescribe to volume: 100% of PD goes to 95% of PTV

CTV=GTV

PTV=CTV + PTVmargin

?  =PTV + BlockMargin  (What do you call this final volume?)

PTVMargin BlockMargin

MF 0 0 (MaxDose is about 150%)

CM 1-2mm 1-3mm (MaxDose is 110-130%)

SW:

PD=20Gy to 95% of PTV.  Aim for MaxDose of 120% (24Gy)

Contour tight

PTV Margin = 1mm

Block Margin = 1.5mm?, 0mm?

~5 arcs, >500 total arc degrees

HD MLC w/ 2.5mm leaves

/SRS DVH

Brainstem Max <14-15Gy,  (CM: 1%<15Gy, or 5%<12Gy)

/SRT: for tumor bed post Brain met Resection:

CM

tumor bed <3cm 7-8Gy x 3

tumor bed >3cm 6Gy x 5 QOD, (After prior SRS, 4.5-5Gy x 5)

Yuan, Red 2008, "doi:10.1016/j.ijrobp.2007.12.039"

SRT Hypofractionation Regimens for large brain tumors

Without WBI,

if cavity>3cm, 700x5, 600x5, PS says 500x5, 600x3.

if cavity<3cm, SRS 15Gy (Pittsburgh)

After WBI,

if cavity >3cm, 700x3

if cavity <3cm, ***

UCI did 22-27.5 Gy in four to six fractions.

Minniti, Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):623-9. doi: 10.1016/j.ijrobp.2013.03.037. Epub 2013 May 15.

Multidose stereotactic radiosurgery (9 Gy × 3) of the postoperative resection cavity for treatment of large brain metastases (>3cm).  (2mm margin)

PMID: 23683828

SRS studies:

RTOG /9508 (/Andrews, Lancet 2004) "U10CA37422, Stat U10 CA32115)"

WBRT v WBRT+RS. 1-3 mets.

WBI 250x15=3750

RS 24,18,15 Gy (per 9005)

RS improved median survival time (6.5 v 4.9 mos) for those w/ 1 met.

RS improved KPS (@6mo 43% v 27%), LC (82% v 71%), edema, tumor response.

RS decreased need for steroids

Posthoc subset analyses:

Also survival advantage for RPA Class I (11.6 mo v 9.6mo), largest met > 2cm (6.5 v 5.3), SCC or NSCLC (5.9 v 3.9)

RTOG 0320

Brain mets

Consent for toxicities:

Can we skip WBI and do RS alone? 2 trials:

Sneed says don't need WBI.

Aoyama says need WBI.

(Regine says need WBI.)

CM skips WBI for breast CA primary, RCC.

/Sneed, UCSF, IJROBP 2002 Jul 1;53(3):519-26. PMID: 12062592

1-4 Unresected brain mets. Retrospective.

RS+/-WBI

Found no OS diff.  No diff in FFP at 1 yr.

Authors concluded that you can omit/delay WBI.

BUT, closer examination shows that the pts in the WBI+RS group had more severe disease (67% v 42% had >1 met) than those in RS alone group.

WBI improved LC 63% v 42%?

37%? (vs 7%) of RS pts needed salvage tx.

/Aoyama, JAMA 2006, " C000000412" JROSG

RS+/-WBI

132 pts w/ 1-4 brain mets

Adding WBI did not improve OS. (8 mo)

WBI improved LC 89% v 73%, improved DBF (distant brain failure) 42% v 64%.

No significant difference in deterioration in neurocognitive fcn between groups.

Says still need WBI.

/Chang, Lancet Oncol 2009;10:1037-44, ASTRO 2008 "4ED72AF7-E164-43B"

SRS +- WBI

Closed early at 58 pts.

Worse learning and memory at 4 mos,

Better LC and DBF.

Better neurocognitive function.

Improved survival!  (unplanned analysis)

/EORTC 22592-26001  /Kocher, JCO 2010.

(S or SRS) +-WBI

300 pts

No OS diff.

WBI...

Improved PFS

Improved intracranial failure

Improved: Relapse at primary or other site

Improved 2yr LC: 27% v 59% (?)

Improved: intracranial progression causing death

Prognostic factors: Her2, ER/PR

/Pirzkall, JCO 98, AND U Kentucky says

Delaying WBI decreases survival.

NCCTG 0574 " http://clinicaltrials.gov/ct2/show/record/NCT00377156?term=NCCTG+0574&rank=1&show_locs=Y"

For 1-3 brain mets

RS+/-WBI

Opened 2006, Est Close 7/2011

Accrued 37 of 152 pts as of 9/11/09

Neurocognitive endpoint.

---

Do which first: WBI or RS?

Regine does RS first so can get off steroids.

/RS Dose?

If no WBI,

RTOG /9005, /Shaw, Red 2000, "PII S0360-3016(99)00507-6"

SRS trial for previously treated recurrent brain tumors:

    MaxDose LC

<2cm  24Gy 90%

2-3cm 18Gy 80%

3-4cm 15Gy 70%

Keep CI < 2.

Prescribed to 50-90% isodose line.

If brain met >3-4cm, 8Gy x 3 SBRT in brain.

Dose for RS alone (No WBI)

Fuss does 22Gy for either primary or reRT.

RS dose after WBI:

Fuss does 15Gy

Shehata, Red 2004, U of Kentucky treated <2cm to 20Gy (w/ WBI), (NOT 22Gy!)

"doi:10.1016/j.ijrobp.2003.10.009"

1. adding WBI did better.

2. 20Gy had better LC than <20Gy.

3. >20Gy had worse G3-4 neurotoxicity

/Schomas, UChicago, AJCO 2005.  " DOI: 10.1097/01.coc.0000143017.69880.04"

157 brain mets in 130 pts from UChicago.

Varian Linac.

Prescribed to 80-95% IDL.

On multivariate analysis: TDmin was only sig factor w/ threshold 12Gy.

5% toxicity rate: edema, RT necrosis.

Schomas UChicago's current recommendations:

<1cm 20-22Gy (w/ WBI),

1-3cm 18-20Gy

>3cm 14-16Gy

=====

/cavity /postop /post op SRS, SRT

/focal RT after surgical resection of brain met?

Scott Soltys, Stanford.  (Hawaii conference, ~2010)

SRS to post-surgical cavity

Soltys, Red 2008

72 pts

No margin.

LC 79% (?)

Ad hoc analysis

The larger the margin, the better the LC.

Try 2mm margins

Starting in 2007, added 2mm margin

Choi Red 2012 "doi:10.1016/j.ijrobp.2011.12.009"

120 cavities in 112pts

1998-2009

PTV increased by about 50%

Now the larger cavities in 3 fx to 24Gy.

Median survival 17mo

Margin was only factor on univariate analysis.

2yr LC 94% vs 83% (p<.05) competing risk analysis

But other possible confounding factors: more experience, better MRI, dose higher now: 24-27Gy in 3 fx, was 21-24 in 3.

TIMING: Now also treating earlier after surgery.  He treats 1 wk after staples out.

MRI at 2 wks post op easier to see, than @ 5 wks.

They looked to see if cavity shrinks more if waiting up to 30 days, but it didn't at 30d, but at 3 mo or 6mo there is cavity shrinkage but we can't wait that long due to recurrences.

Only 26% of cases have cavity larger than pre-resection tumor. Most are smaller.

Necrosis/toxicity not worse w/ margin.

For larger brain mets, local therapy alone is inadequate, high rate of LR.

Cavity boost for >2cm.

Med OS 16 mo.

Risk of distant brain failure higher w/o WBI, up to 50-60%.

They treat SRT on consecutive days.

He uses same SRT doses for intact brain mets.

Roberge, Red 83, 2012  (REVIEW ARTICLES of Cavity SRS)

=

NOW, in 2008, series from Pitt:

/Mathieu, Tumor Bed Radiosurgery After Resection of Cerebral Metastases

April 2008 - Volume 62 - Issue 4 - p 817-824 doi: "10.1227/01.neu.0000316899.55501.8b"

40 pts

LC rates 70-80% (compare to 46% LR rate without RT in Patchell #2)

Add 2mm margin to resection cavity.

Allegheny Hospital: Karlovits BJ, Neurosurg Focus / Volume 27 / December 2009 , "DOI: 10.3171/2009.9.FOCUS09191"

Showed LC rates similar to WBI.

Tufts: Hwang, JNeuroOnc 2009, "DOI 10.1007/s11060-009-0051"

Post-resection GKS vs WBI (retrospective of 25+18 pts)

Showed trend toward improved OS (15mo vs 6.8mo) (p=.08) w/ GKS vs WBRT!

City of Hope: Do, IJROBP, Vol. 73, No. 2, pp. 486–491, 2009, "doi:10.1016/j.ijrobp.2008.04.070"

Showed low 13% LR rate after SRS or SRT.

30 pts, retrospective

1-4 brain mets

/N107C - A Phase III Trial of Post-Surgical Stereotactic Radiosurgery (SRS) Compared with Whole Brain Radiotherapy (WBRT) for Resected Metastatic Brain Disease

Closes 3/1/2014

/WBI /ReRT

OK if no other option, not RS candidate.

Wait >6-9 mo.

Suh does 250x10 for re-WBI.

Sadikov, PMH, Clin Oncol (R Coll Radiol). 2007 Sep;19(7):532-8, PMID: 17662582

72pts got Re-WBI

Initial 400x5, Re-WBI 250x10 or less.

Results: 1/3 improved, 1/3 stable, 1/3 deteriorated.

If ECOG 0-1 lived longer.

Wong (Mayo Scottsdale), Red 1996, "0360-3016(95)02156-6"

86 pts

Resolution of Neuro Sx: 27%

Partial improvement: 43%

Same or worse: 29%

Med OS 4 mo

Toxicities: 5 pts had imaging changes, 1 pt dementia

Cooper (NYU), Radiology 1990, "1989; revision requested July 24;"

52 pts

Criteria for ReWBI:

1) Remained in good condition x 4 mo after initial WBI

2) Has new neuro deterioration

Initial 300x10, ReWBI 250x10

42% improved neurologically

Med OS 5 mo

Bahl (India), JCRT 09, "DOI: 10.4103/0973-1482.57120"

Review of Re-RT for Brain Mets.

WBI, SRS, Brachy.

Re-WBI only recommended for breast CA, KPS>70, age<60, no extracranial.

Contraindications: progression<4mo.

"Delayed neurological toxicity should also not be an issue in these patients as the detrimental effects of disease progression far outweigh the late effects of the treatment."

---------

RTOG 7916

300x10 vs 500x6 BIW, and +/- misonidazole.

859 pts.

No diff in any arm.

RTOG 8528

Dose escalation, hyperFx.

48, 70, 49 Gy/1.69Gy

No diff

RTOG 8905

WBI +/- BrdU

37.5 in 15 Fx.

No Diff.

RTOG 9104 Neurocognitive outcome for pts w/ multiple brain mets, Phase III

160 BID to 5440 vs 300x10

No OS diff.

Uncontrolled brain mets is bad. (??)

/MGd,  /Motexafin Gd

/SMART study, Mehta ASTR2006

WBI+-MGd

No OS diff.

Improved Time to neurologic progression

Helped delay time to neurocognitive decline

Delayed time to loss of functional independence

0230 for brain mets??

WBI + RS + some chemo (temodar? tarceva?)

---

/Radionecrosis

Enlarging enhancement on FU MRIs after SRS/SRT:

DDx: recurrent brain met vs radionecrosis

Try really hard not to do re-SRS because even if it's not radionecrosis this time, very likely will get radionecrosis after re-SRS.

Workup: MRI perfusion & spectroscopy, Brain PET

If specialized imaging suggests tumor recurrence, favor neurosurgical resection if possible, and only do re-SRS if can't resect.

If suggests radionecrosis,

  If asymptomatic -> observe (or low dose steroids) and re-image in a few mos.

  If symptomatic -> 

     trial of steroids

     Avastin

     Resect (last resort) if keeps progressing.

Dangerous to do SRS with (T-DM1, /Trastuzumab Emtansine, /Kadcyla) or other ADCs

BMC Cancer. 2016 Jul 4;16:391. doi: 10.1186/s12885-016-2464-1.

Expansive hematoma in delayed cerebral radiation necrosis in patients treated with T-DM1: a report of two cases.

https://www.ncbi.nlm.nih.gov/pubmed/27377061

Single Case Report:

Journal of Cancer Prevention & Current Research Volume 5 Issue 6 - 2016 Pseudo-Progression in Breast Cancer Brain Metastasis after Initiating Therapy with Ado-Trastuzumab Emtansine Alyssa Johnston*, Tamara Ortiz-Perez, Chandandeep Nagi and Julie Nangia Baylor College of Medicine, USA Received: September 17, 2016

http://medcraveonline.com/JCPCR/JCPCR-05-00185.php

4 patients:

Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema Julie A. Carlson

Neuro Oncol (2014)

http://neuro-oncology.oxfordjournals.org/content/early/2014/02/03/neuonc.not329.full

UCSF 2018

Steve Braunstein

CNS

should we delay SRS?

upfront SRS vs delayed after targeted therapies

/Magnuson JCO 2017 

LOOK THIS UP

Impact of deferred RT in brain mets

350 pts

indicates pt do better w/ upfront SRS

Increased toxicities w/ SRS with Keytruda?

iRANO criteria  /Wen JCO 2017