15th EURETINA Congress, Nice · Klinik für Strahlentherapie und Radioonkologie Why radiation therapy – results from trials on AMD Different indications wet and/or dry macular degeneration,

12.06.2015 Frank Zimmermann

Room Clio, 10:00 – 11:00 am

Klinik für Strahlentherapie und Radioonkologie

15th EURETINA Congress, Nice

Stereotactic Radiotherapy for Wet AMD using micro-collimated low-voltage X-ray:

Mechanisms and Synergy with anti-VEGF


Therapeutic approaches

• Local Anti-VEGF injections o Lucentis® o Avastin® o Macugen® o Eylea®

• Photodynamic / Laser therapy

• Radiation therapy

• Combined radiation therapy and Anti-VEGF


Why radiation therapy – vascular effect in tumors

With single doses beyond 12 Gy, vascular effects by obliteration is dominant Song CW et al. Technical Basis of Radiation Therapy 2012


Why radiation therapy – vascular effect in AVM

Regions of vascular constriction due to abnormal proliferation of surviving endothelial cells: hyaline and calcium deposits, thrombosis – obliteration in 80 % Single doses of > 16 Gy and smaller volumes with better results Levy RP et al. Neurosurg Clin N Am 1990; Andisheh B et al. J Neurosurg 2009


Results from radiosurgery: vascular malformation

Obliteration and reduced risk from AVM with 17.5 – 25 Gy


Why radiation therapy – results from trials on AMD

Conflicting interpretation Best-corrected visual activity loss vs. reading ability vs. improved vision vs. visual acuity stabilization vs. daily living tasks dependent on vision vs. SF-36 questionaire Different techniques and poor precision in some techniques high energy photons, protons, brachytherapy Different concepts Single doses of 1 – 4 Gy, total doses 7.5 – 24 Gy, or HDR 12 – 15 Gy Rbrady et al. IJROBP 1997; RAD Study Group, Ophthalmology 1999; Bergink et al. Graefe’s Arch Clin Exp Ophthal 1998; Valmaggia et al. Am J Ophthalmol 2002; Evans et al. Cochrane Coll 2010; Dugel et al. Opthalmology 2013; Kishan et al. IJROBP 2013; van Houtte et al. Cancer Radiother 2014


Why radiation therapy – results from trials on AMD

Different indications wet and/or dry macular degeneration, different disease extent Side effects no retinopathy, no optical neuropathy, no malignancy, but 15 % mild retinopathy at 5 years Small, non-significant advantage in favour of treatment, but biased for non-blinded trials Short follow-up !!!

Rbrady et al. IJROBP 1997; RAD Study Group, Ophthalmology 1999; Bergink et al. Graefe’s Arch Clin Exp Ophtahl 1998; Valmaggia et al. Am J Ophthalmol 2002; Trikha et al. Retina 2011; Dugel et al. Opthalmology 2013; Kishan et al. IJROBP 2013; van Houtte et al. Cancer Radiother 2014


Risk in radiation therapy – results from high doses

With doses beyond 20 Gy: focal area of photoreceptor loss and retinal pigment epithelial atrophy

Trikha et al. Retina 2011


Why radiation therapy – biological rationale

Regression and inactivation of subretinal neo-vasculature Reabsorption of fluid and blood Reducing the risk of further leakage and bleeding Causing subretinal fibrosis and vascular obliteration

Brady et al. JROBP 1997


Why radiation therapy – biological rationale

Comparison of biological efficacy - 4 x 4 Gy in 4 minutes each - 12 Gy in 11 minutes - 16 Gy in 4 minutes For α/β-value of 4 Gy for vessels range from 30 – 100 Gy Need for risk reduction for late effects by high precision If RT, than precise with ~ 16 Gy


Why combined therapy – clinical rationale

The EXCITE Study - Phase-III-randomized trial - 353 patients - After 3-months: monthly > quarterly injections at 12

months Side effects (EXCITE and SUSTAIN studies): - 12 % conjunctival hemorrhage - 15 % eye pain - 7 % increased intraocular pressure - 1 % retinal hemorrhage Schmidt-Erfurth U et al. Ophthalmology 2011; Holz FG et al. Ophthalmology 2011


Greec στερεός stereós: „rigid, fix, constant, 3 dimensions“ τάξις táxis: „disposition, installation, arrangement“

Definition: Precise technique for small target area and steep dose decrease for optimal normal tissue protection

Stereotactic radiation therapy – new concept


High single dose Aim: strong local tissue reaction and small vessel obliteration by

endothel proliferation with fibrosis High precision 3D-coordinate system with high precision ( error < 1 mm ) Image / camera control to verify the precision Exact, robust and reproducible patient positioning and navigation

of the beam

Short treatment Only 1 session

Definition and prerequisite: radiosurgery ( single fraction stereotactic radiation therapy )


Quality assurance of stereotactic radiation therapy

3 robotically positioned 100 kV photon beams Test with modern algorithm in bulbus sizes of 20 – 28 mm Doses to - Lens - Optic nerve - Distal tip of central retinal artery - Retina outside target volume - Ciliary body

No significant variations: doses below critical levels !

Cantley J et al. Phys Med Biol 2013


Adjustment of the patients head



Eye stabilization

Taddei PJ et al. Phys Med Biol 2010


Fine adjustement of the I-Guide



Beam orientation Virtual dose distribution

Taddei PJ et al. Phys Med Biol 2010



Dose distribution with 24 Gy

Hanlon J and Lee C American Ass Phys Med 2009; Moshfeghi DM et al. Br J Opthalmol 2011



Dose distribution with 24 Gy

Hanlon J and Lee C American Ass Phys Med 2009


Prerequisite for intervention

Clear patient selection: - Actively leaking - < 4 mm

Extensive explanation also about alternatives Explanation of risk: early and late effects in detail

Jackson TL et al. Retina et al. 2015


Clinical effect

Pretreatment Intervall of injections: 4 weeks After 12 months Intervall of injections: 8 weeks


High biological effect Close interaction with anti-VEGF High precision / safety Comfortable, non-invasive treatment

The new aspects


Open for questions !

Merci beaucoup de votre attention

… questions?

12.06.2015Frank Zimmermann��Room Clio, 10:00 – 11:00 amTherapeutic approaches�Why radiation therapy – vascular effect in tumorsWhy radiation therapy – vascular effect in AVMResults from radiosurgery: vascular malformationWhy radiation therapy – results from trials on AMDWhy radiation therapy – results from trials on AMDRisk in radiation therapy – results from high dosesWhy radiation therapy – biological rationaleWhy radiation therapy – biological rationaleWhy combined therapy – clinical rationaleStereotactic radiation therapy – new conceptDefinition and prerequisite: radiosurgery �( single fraction stereotactic radiation therapy )Quality assurance of stereotactic radiation therapyAdjustment of the patients headQuality assurance of stereotactic radiation therapyFine adjustement of the I-GuideQuality assurance of stereotactic radiation therapyQuality assurance of stereotactic radiation therapyQuality assurance of stereotactic radiation therapyPrerequisite for interventionClinical effectThe new aspectsOpen for questions !��Merci beaucoup de votre attention

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15th EURETINA Congress, Nice · Klinik für Strahlentherapie und Radioonkologie Why radiation therapy – results from trials on AMD Different indications wet and/or dry macular degeneration,