Panel DebateCavernous Malformations - Why does Everyone Remain Confused?

Gábor Nagy MD PhDNational Institute of Clinical Neurosciences, Budapest,

Hungary

Andras A Kemeny MD FRCSThornbury Radiosurgery Centre, Sheffield, UK

Cavernoma (CCM) Radiosurgery –The Unanswered Questions

• Is it effective?- No radiological evidence, only large patient statistics (of heterogenous quality) suggest it

Is it a real alternative of open surgery?

• Is it safe? – Conflicting evidence in the literature regarding

safety Is it a real alternative of observation in non-

operative cases?

1. Natural History of Cavernous Malformations – What Counts as a Bleed?

• Symptomatic hemorrhage: a clinically significant acute/subacute event associated with evidence of concurrent hemorrhage (Al-Shahi Salman, 2008)

Natural History of Cavernous Malformations –Annual Hemorrhage Risk and Morbidity

• Annual bleed rates 0.25-3.1 %• Most series agree in an increased annual re-bleed rate: 4.1-40 %• It is unknown, whether such an increase is temporary

(“clustering” - Barker, 2001) or longer lasting (Hasegawa, 2002)• Series suggest the existence of “high risk” (i.e. multiple bleeds)

and “low risk” (i.e. bleed never or only once) lesions

• Deep eloquent CCMs do worse: higher bleed risk with higher morbidity – At least 1/3 of the patients are left with persisting neurological deficit after each bleed

Time Dynamics of Rebleeding

(Nagy et al., 2010 )

(Hasegawa et al., 2002)

Understanding Natural History of CCMs Is the Key for Proper Management and Data

Interpretation

Definition of clinical hemorrhage

Rebleed rate is higher than the rate of first bleed

Deep eloquent lesions behave more aggressively than superficial (hemispheric)

2. Management Strategies”Considerable uncertainty exists amongst cerebrovascular experts as to optimum management of cerebral cavernomas.”(in Al-Shahi Salman et al.: Current treatment practice for cavernous malformations:International survery. 154th SBNS Meeting, Dublin, 2009)

E.g. Brainstem with 2 bleeds• Surgical removal (59%)• Radiosurgery (14%)• Observation (7%)• (20% unsure)

What is the optimum management of this lesion?

(young pt, single bleed, no neurological deficit)

Management Dilemmas

Lack of Evidence„We have limited these therapeutic guidelines to studies of CCMtreatment involving at least 20 adults, that examined surgicalresection and/or stereotactic radiosurgery, in which a group ofadults receiving treatment was compared to either another groupreceiving a different treatment or to a conservatively-managed(untreated) group of adults. …We recommend that decisions about the treatment of adults withCCM that have already caused one ICH or FND be made on a case-by-case basis, given the absence of randomised trials orobservational studies with dramatic effects specific to theseadults.”

Samarasekera et al. Guidelines for the management of cerebralcavernous malformations in adults. 2012http://www.cavernoma.org.uk/opus473/final_CCM_guidelines_2.pdf

3. Principles of Modern CCM Radiosurgery

• Importance of patient selection and data analysis (properinterpretation of natural history)- Difference between hemispheric and deep eloquent- Difference between first and rebleed

• Modern treatment protocols- High conformity (GK, MRI-based planning)- 12-15 Gy (<20 Gy) margin dose- Within the hemosiderine ring- Avoid DVA- At least 3 months after the last bleed

Nagy&Kemeny, J Neurosurg Sci, 59:295-306, 2015

Critical Review of Radiosurgical Literature

Nagy&Kemeny, J Neurosurg Sci, 59:295-306, 2015

Analysis of Modern Radiosurgical Data –Bleed Rate

• Lesions with multiple prior bleeds (n = 197)- 32.26% pretreatment (95% CI: 29.15-35.37; 281 repeated hemorrhages in 871 person-years)- 8.28% within the first 2 years after SRS (95% CI: 5.27-11.29; 27 repeated hemorrhages in 326 person-years)- 1.51% thereafter (95% CI: 0.53-2.5; 9 repeated hemorrhages in 595 person-years)

• Lesions with no more than 1 prior bleed (n = 108)- 5.71% within the first 2 years after SRS (95% CI: 2.24-9.49; 10repeated hemorrhages in 175 person-years)- 1.6% thereafter (95% CI: 0.03-3.17; 4 repeated hemorrhages in 250person-years)

Nagy&Kemeny, J Neurosurg Sci, 59:295-306, 2015

Analysis of Modern Radiosurgical Data –Persisting Morbidity

• Morbidity related to post-treatment hemorrhages- 5.66% (95% CI: 3.41-7.92; n = 406)- Deep eloquent: 5.3% (95% CI: 1.43-9.18; n = 132)- Mortality: 0.84% (95% CI: 0.26-1.41; n = 958)

• Morbidity related to adverse radiation effects- Deep eloquent: 4.16% (95% CI: 2.09-6.22; n = 376)- Hemispheric: 0.82% (95% CI: 0-2.44; n = 122)- NO MORTALITY

Nagy&Kemeny, J Neurosurg Sci, 59:295-306, 2015

Observation(sum of series)

Microsurgery(573 patients)*

Gamma Knife(958 patients)**

Better or same <60% 70.9% 89.7%Permanentmorbidity

40% 26.5% 9.46%(5.3+4.16)

Relatedmortality

2-20% 2.6% 0.84%

Rebleed rate(per year)

30% (longterm rate is debated)

2% 1.51%(2 years after trt)

Management of Deep Eloquent CCMs

*Sum of surgical series >100 pts (Wang et al. 2003; Abla et al. 2011; Pandey et al. 2012)

** Sum of GK centers applying modern methodology(Nagy&Kemeny, 2015)

“Unfortunately, it is not likely to change the polarization thatexists in the radiosurgical community regarding this particularindication. A prospective trial is truly needed and long overdue tosettle this debate.” (Sheehan & Schlesinger, 2010)

“A CCM study group met over a 2-year period and designed arandomized trial comparing resection and radiosurgery for high-risk malformations. Unfortunately, after 1 year had passed, not 1patient had been entered into the study.” (Kondziolka & Lunsford,2010)

“It is of course uncertain how feasible such a trial would be interms of patient recruitment. We suspect, … that many patientswould not wish to be randomized to a study in which one arm had noactive management. … we … are working on setting up a prospectivenational data collection and this may pave the way for a casecontrol study.” (Nagy et al, 2010)

Perspectives – Should We/Can WeRandomize?

Perspectives: Prospective Data Collection

Prospective national/international CCM database

Standardization of CCM radiosurgery

Nagy&Kemeny, Neurosurg Clin N Am 24:574–89, 2013Nagy&Kemeny, J Neurosurg Sci, 59:295-306, 2015

Acknowledgement• Neurosurgeons at the National Centre for Stereotactic

RadiosurgeryMatthias W.R. RadatzJeremy G. RoweJohn Yianni, Dev Bhattacharya• Neurosurgeons at the Department of Neurosurgery, Royal

Hallamshire HospitalUmang J. PatelAdam RazakStuart Stokes• NeuroradiologistsTimothy J. HodgsonStuart C. Coley• RadiographerWendy Burkitt