Ophthalmic tumors Wolfgang Sauerwein
Today s menu Introduction and some basics on uveal melanoma Brachytherapy for intraocular tumors Proton therapy for intraocular tumors Proton therapy for conjunctival melanoma High energy beams and PBS in ocular tumors? Controversial issues irradiation of retinoblastoma radiotherapy of the orbit in small children Folie 2 2 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors Rare diseases In Germany 800 new cases per year (>500 of them treated in Essen) What is different to normal radiotherapy? Very small treatment volume (electron equilibrium??) Very close to important functional structures Treated in dedicated centers with different equipment Special techniques are mandatory Folie 3 3 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors: Target volumes the entire eye (metastases) Localized tumor in the eye (melanoma, retinoblastoma) the retina and the vitreous (retinoblastoma, lymphoma) the orbit (retinoblastoma, melanoma ) others (iris, conjunctiva ) Folie 4 4 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors: Irradiation techniques Brachytherapy 90 Sr 106 Ru 125 I Folie 5 5 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors: Irradiation techniques External beam radiotherapy photons et electrons Folie 6 6 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors: Irradiation techniques External beam radiotherapy protons Folie 7 7 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ophthalmic tumors: Irradiation techniques External beam radiotherapy X rays Folie 8 8 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Brachytherapy INTRAOCULAR TUMORS Folie 9 9 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Irradiation of a tumor in the eye: uveal melanoma Protection of the optic nerve, the papilla and the macula, the orbit Dose >100 Gy Techniques - brachytherapy using radioactive plaques - protons Folie 10 10 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Survival rate Chromosome 3 status predicts survival Tumour related survival of 374 enucleated patients (1998 2008) Tumors with partial monosomy 3 Tumors with disomy 3 AI monosomy 3 Folie 11 11 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Months after treatment of the primary tumour
Metastases in uveal melanoma risk factors genetics localization size extra-ocular growth Folie 12 12 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ru-106 plaques -irradiation with a background of /Bremsstrahlung maximal energy of rays: 3,53 MeV half-life: 366 days steep dose gradient: in 6 mm depth ~ 10% of dose rate at the surface big choice of different applicators prescribed dose: at the sclera 700 (- 1500 )Gy at tumor apex >130 Gy indicated for tumors 6 mm height Folie 13 13 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ru-106 plaques Folie 14 14 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125 plaques Photon irradiation mean energy 27-35 kev Half life: 60 days in 10-12 mm depth 10% of dose rate at the surface Plaques have to be produced at the hospital (8-12 seeds/plaque) Prescribed dose: at the sclera 300(- 500 )Gy at tumor apex >80 Gy Indication for tumors 8-12 mm height Folie 15 15 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125 plaques plaque in stainless steel with Persepex inlay Folie 16 16 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125 / Ru-106 bi-nuclide-plaque 3 2 1 Folie 17 17 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dosimetry for b-emitters Relative dosimetry difficult but we know how to do Absolute dosimetry real challenging only feasible together with the national standard laboratories (PTB, NIST) Folie 18 18 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distribution of a 106 Ru-plaque tumor: 8 mm dose: apex: 100 Gy base: 2200 Gy sclera opposite: 1Gy Folie 19 19 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distribution of a 125 I-plaque tumor: 8 mm dose: apex: 100 Gy base : 440 Gy sclera opposite: 15 Gy Folie 20 20 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distribution of a bi-nuclide plaque tumor: 8 mm dose: apex: 100 Gy base 1200 Gy sclera opposite: 9 Gy Folie 21 21 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125 / Ru-106 bi-nuclide-plaque Advantages as compared to a 125 I-plaque > contact dose < integral dose > dose to the tumor < dose to structures at risk For tumors with height 7 11 mm Folie 22 22 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Modified peneasy/penelope simulation CCB plaque, 7.5 mm apical height tumour Strahlenther Onkol (2013) 189, 68-73 Folie 23 23 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Modified peneasy/penelope simulation Cumulative dose-volume histograms Folie 24 24 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Strahlenther Onkol (2013) 189, 68-73
Surgical technique Additional mattress suture Correlation of ophthalmoscopy and transillumination Folie 25 25 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Follow up after Ru-106 brachytherapy juxta-papillary melanoma 8 mois 33 mois Folie 26 26 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Local recurrences after Ru-106 P<0.001 N=1069 Tumor thickness < 4 mm 4-7 mm > 7 mm mois Folie 27 27 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Visual acuity after after Ru-106 vision N=898 Blindness = CF and less N = 2536 juxtapapillary midperiphery periphery/cb months Folie 28 28 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 months
Visual acuity after I-125 Shields et al. 2000 Folie 29 29 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Ru-106: limits scleral necrosis incomplete destruction Tumor height Folie 30 30 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125: limits Complications Long standing exsudative retinal detachment Radiation cataract Radiation induced optic neuropathy Radiation retinopathy, ocular ischemia, neovascular glaucoma Folie 31 31 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125: limits Folie 32 32 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
I-125/Ru-106 bi-nuclide-plaque results N=100; mean follow-up 30 months Secondary enucleation in 15 eyes, 2 because of recurrent tumor growth Complications: Cataract 66% Retinopathy 47% Radiation papillopathy 44% Scleral staphyloma 15% Secondary glaucoma 11% Folie 33 33 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Retinoblastoma brachytherapy 106 Ru vs. 125 I Essen (2005) Shields et al (2001) Treatment period 1979-2005 1976-1999 Treated tumors 175 ( 106 Ru) 178 ( 125 I) Mean age [months] 23 (0.2 150) 12 (1 96) Tumour diameter [mm] 7.5 ( 1.5 22) 7.7 ( 1-18) Tumour height [mm 3.7 ( 1-7.6) 4.1 ( 0.5 12) Distance to optic disk [mm] 7.2 ( 0 21) 6.4 ( 0 17) Retinal detachment 22 / 175 31 / 178 Vitreous seeding 37 /175 15 / 178 Primary brachytherapy 56 / 175 60 / 178 Mean duration of radiation 69 h 68 h Mean dose apex / base (rounded) 138 Gy / 419 Gy (NIST) 42 Gy /155 Gy Tumour recurrence / mean interval 4.6 % / 12.9 Monate 17% / 8 Monate Radiation retinopathy 12 % 26 % Folie 34 34 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Proton treatment of ocular tumors Folie 35 35 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
% of dose Depth dose distribution 100 protons Cobalt photons 25 MV 50 electrons 10 25 Depth (cm) 03.09.2014 Sauerwein Folie 36 36 PTCOG 53 Shanghai 2014
% of dose Depth dose distribution Dose distribution in the Bragg peak: not convenient to treat a tumor. The peak needs to be enlarged, (or spread-out, or modulated) 90 50 20 Folie 37 0 37 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
% of dose Depth dose distribution Dose distribution in the spread-out Bragg peak: 90 now suitable to treat a tumor with safety margins 50 20 Folie 38 0 38 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Wedge filter The dose distribution can be optimized by a wedge filter sparing the macula while maintaining a sufficient safety margin Folie 39 39 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Bolus eyelid assumed at "-x" mm "0" mm deformation of isodoses by eyelid profile proton beam excessive irradiation due to eyelid at "-x" mm eyelid profile eye optic nerve Folie 40 40 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Bolus eyelid assumed at x" mm eyelid profile proton beam no deformation of the isodoses bolus eye optic nerve Folie 41 41 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
3D Conformation of the proton beam diode wedge-filter Y bolus X modulator Z Folie 42 42 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 collimator
dose distributions Dose distribution of a 106 Ru plaque For a tumor of 8 mm Dose distribution of a 125 I plaque 60 Gy 30 Gy 12 Gy Dose distribution of a proton beam Folie 43 43 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 60 Gy 30 Gy 12 Gy
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Preparation of the patient: positioning of markers CT scan after clipping always included Folie 45 45 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Positioning devices for the patient Folie 46 46 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
BANC OPTIQUE 190 cm collimator tube RX dégradeur modulateur faisceau dans l'air chambres plates simulation lumineuse croisillon chaise de traitement 181.3 cm feuille de kapton 0.13mm faisceau sous vide collimateur Ø 50mm collimateurs Ø 5mm capteur d image diode tube RX Béton baryté 1.8m 210 cm Folie 47 47 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 182.5 cm
treatment DIODE DIODE WEDGE FILTERS WEDGE FILTERS BOLUS VIDEO CAMERA COLLIMATOR Folie 48 48 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Challenge for treatment planning: Does the model represent the reality? All the calculations made on a relatively simple mathematical model of the eye. + + The anatomy may differ from the model. To be accurate, the validity of the model has to be checked by CT and the model to be modified if necessary. Folie 49 49 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 CT-scan
If the model is not accurate, you will not hit the target Underdosage of real tumor Wrong model Folie 50 50 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Positioning: same tumor, 3 different positions I II III Folie 51 51 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distributions for the three different positions lateral view 20% 50% 90% Folie 52 52 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 wide angle fundus view
20% 50% 90% Folie 53 53 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Outcome of Uveal Melanoma treated in Nice (n= 2500) Percent 100 80 60 40 20 0 100 80 60 40 20 Overall survival All Patients < 14.6 mm f > 14.6 mm f P = 0.0002 Local control 67% 0 10 20 30 40 50 60 70 Months 82% 73.8% 98% T1 & T2 84% T3 & T4 P = 0.003 100 80 60 40 20 0 100 80 60 40 20 Disease free survival < 5 mm thick > 5 mm thick P < 0.0001 0 10 20 30 40 50 60 70 80 Months Enucleation-free survival T1 & T2 T3 & T4 P = 0.0008 90 % 66 % 0 Folie 54 54 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 0 10 20 30 40 50 60 70 80 Months 0 0 10 20 30 40 50 60 70 80 Months
Intraocular tumors: indications for different treatment modalities Type of applicator/ irradiation 106 Ru applicator mixed 106 Ru/ 125 I 125 I protons Maximal tumor thickness allowing an adequate dose distribution 5-7mm (depending from applicator) 6-10 mm (important influence of the activity) 10-15 mm (depending from applicator) Homogeneous dose distribution always possible Depth dose distribution behind the target volume (% of dose at the apex) 1 mm: ca. 60% 5 mm: ca. 10% ca. 75 % ca. 10 % ca. 80-90% ca. 30-50% ca. 50% 0 Dose in healthy tissues prior the target volume (% of dose at the apex) 0 0 0 ca 30-60% Lateral dose distribution 1 mm: ca. 20% ca. 30-50 % ca. 20-60% (% of dose at the apex) 5 mm: ca. 3% ca. 5-10 % ca. 5-25% ca. 50% 0 Folie 55 55 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Tumors of the conjunctiva: orphan diseases non-hodgkin lymphoma malignant melanoma squamous cell carcinoma extremely rare lesions: adeno-squamous carcinoma rhabdomyosarcoma others Folie 56 56 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Complex target volume Complex geometry The problem of the fornix The problem of the depth Organs at risks in the neighborhood Target volume is also organ at risk Folie 57 57 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose? No systematic dose finding studies Different tumor entities need different doses Due to the geometry there is always a dose gradient in the target volume to be considered Folie 58 58 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Why protons? ballistic precision of the proton beam homogeneous irradiation of a complex treatment volume (necessity to treat large volume of bulbar and tarsal conjunctiva while sparing the internal structures in the eye) steep dose gradients at the edges and depth: protection of healthy structures Folie 59 59 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Proton irradiation of conjunctival tumors distal shape of the irradiated volume: reproduces the relief of the beam entrance 20% Proton beam Clip Folie 60 60 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Treatment technique Protection of intraocular structures Bolus: (gel+plexiglas-slice) 20% Proton beam Plane beam entrance: distal shape of the irradiated volume is flat Clip Folie 61 61 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Treatment technique Bolus Folie 62 62 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Treatment technique Semi-hemispherical plexiglas-compensator reduces the proton energy and modulates their range to protect healthy structures Folie 63 63 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 shielded volumen
Treatment technique Individual plexiglas-compensator bolus 20% Proton beam Clip Irradiated volume Folie 64 64 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Protected volume
Dose distribution Folie 65 65 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Treatment technique Individual plexiglas-compensator bolus Central shielding 20% Proton beam Clip Irradiated volume Folie 66 66 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Individual collimators and compensators Double boost Partial protection of cornea and limbus Boost Folie 67 67 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Extension /internal canthus
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Dose prescription Large field irradiation 6 fractions of 5.2 Gy (6Gy Co Eq) Folie 69 69 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Small field irradiation 2 fractions of 6.9 Gy (8Gy Co Eq)
Recurrences after proton radiotherapy (N = 20) - 6/20 (30%), 22.1 ± 5.7 months after therapy 3/6 within the target volume (31 Gy) 1/6 within the boost volume (45 Gy) 2/6 outside the target volume Exenteration 2/20 (10%) Metastatatic disease 6/20 (39%) Tumor-related death 4/20 (20%) Folie 70 70 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
survival 100 90 80 70 60 50 40 30 20 10 0 Conjunctival Melanomas Survival Survival at median follow-up 30 months: 80.0% % of survival 0 12 24 36 48 60 72 84 96 108 120 132 Folie 71 71 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 Months
The future of proton therapy for eye tumors? Pulsed beam Pencil beam scanning Image based treatment planning 62-230 MeV Dedicated machine 65 MeV EYEPlan Folie 72 72 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
High energy beams and PBS for small, superficial tumors Collaboration Folie 73 73 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014 work in progress Poster 005
Cyclotrons with continuous beams Folie 74 74 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Synchrotron with pulsed beam w/o RiFi w RiFi DDF 80/20 (mm) 1.0 1.5 DDF 90/10 (mm) 1.5 2.2 Courtesy: Mario Ciocca Folie 75 75 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
PBS for ocular tumors? Spot size: 2 mm MC- simulation Courtesy: Jerome Mandrillon Folie 76 76 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Bilateral retinoblastoma very young children multiple tumors in both eyes hereditary high risk of secondary cancer Folie 77 77 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Secondary malignancies after RT in retinoblastoma Sethi et al. Cancer 2014 Folie 78 78 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distribution 6MeV Photons Folie 79 79 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Retinoblastomkollimator (mit/ohne Zusatzkollimator) Phys. Med. Biol (2012) 57, 7741 7751 Medical Physics (2014) 41 Folie 80 80 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Dose distribution protons vs. photons What is better??? Folie 81 81 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Protons can do better! Folie 82 82 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
RADIOTHERAPY OF THE ORBIT IN CHILDREN Folie 83 83 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Irradiation of the orbit in children Folie 84 84 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
6 years after proton therapy of the orbit retinoblastoma tumor cells in the orbit 3 y old boy follow up 6 years Folie 85 85 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
6 years after brachytherapy of the orbit retinoblastoma tumor cells in the orbit 6 months old boy follow up 6 years Folie 86 86 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Low dose rate brachytherapy of the orbit Strahlenther Onkol (2011)187 322-327 Folie 87 87 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Radiotherapy of the orbit Folie 88 88 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Radiotherapy of the orbit Folie 89 89 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
summary The dose distribution of protons is different from the dose distribution of photons not necessarily better If this difference is used in an appropriate way, it may lead to a benefit for the patient In any case: protons are wonderful Folie 90 90 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014
Joël Herault Pierre Chauvel Dirk Flühs Norbert Bornfeld Lorenzo Brualla Gaëlle Angellier Henrike Westekemper Clare Stannard Jerome Mandrillon Mario Ciocca
Thank you! Folie 92 92 03.09.2014 Sauerwein PTCOG 53 Shanghai 2014