UCSF Uveal Melanoma Program: Outcomes with Proton Beam Radiation Therapy Kavita K. Mishra, M.D., M.P.H. UCSF Comprehensive Cancer Center

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1 Disclosures UCSF Uveal Melanoma Program: Outcomes with Proton Beam Radiation Therapy No disclosures Kavita K. Mishra, M.D., M.P.H. UCSF Comprehensive Cancer Center UCSF Uveal Melanoma Program: Ocular Melanoma Outcomes with PBRT Kavita K. Mishra, Inder K. Daftari, Jeanne M. Quivey, Theodore L. Phillips Uveal Melanoma Treatment Overview UCSF Proton Therapy Program Outcomes Local Control & Survival Complications Conclusions * American Cancer Society Statistics 2009 ( 1

2 Anatomy Uveal tract is the vascular supporting layer of the eye 80% choroid, 10-15% ciliary body, <5-10% the iris MRI or CT Clinical sx/ Exam Ultrasound A & B Clinical and Diagnostic Studies FNA bx Figure 1. Eye Anatomy. Terese Winslow, Terese Winslow Medical Illustration Fundus photography Fluorescein Angiography Local Therapy: Key Points Small tumors: serial observation Two-thirds do not grow Medium tumors: RT (particles, plaque, SRS) vs surgery (enucleation, local resection ± RT) Comparable survival rates RT allows for excellent LC and preservation of natural eye and its function Particle RT: Consistently best LC outcomes with long follow-up Large tumors: surgery vs RT Radiation Therapy Overview LC 5y 95% ( %) 15y 95% Particles Plaques SRS 89.7% (81-96%) Shorter f/u, [1 to 3y 83-98%] Enuc 5y 10% (0-25%) 12% (4-20%) [1 to 3y %] 5y Useful vision (<20/200) Relevant Issues: Follow-Up Dose distribution Eye fixation Treatment times Side effects 40-65% 37% (23-73%) [shorter f/u, 21-50%] Excellent LC with long f/u Uniform dose distribution 1-2 min rx time SE minimized Lower LC vs. particles in studies Not advised for large or peripapillary/ macular tumors Modified from Mishra et al, Uveal Melanoma, in Textbook for Radiation Oncology (in press) Shorter f/u Dose inhomogeneity Eye fixation/ monitoring variable Longer rx times Higher body dose 2

3 UCSF-LBNL Trial Only prospective RCT to date of particles vs plaque LC & ENUC rate better with particles UCSF-Tumori Update 15 year data from patients treated showed significantly higher late local failures in brachy pts Particles vs Plaques Char et al, Ophthalmology 1993 and 2002 UCSF-LBNL trial (n=184) Charged Particle (f/u 42 mos) Local Control 100% (p<0.001) Plaque I-125 (f/u 41 mos) 87% Enucleation 9.3% 17.3% CSS 92% 92% Stereotactic Radiosurgery Doses include Gy (1 fx) to 50% idl; Gy multifx Issues: Method of eye fixation/monitoring for typical duration (up to one hour) Relatively short f/u vs other RT modalities Higher doses to normal structures (i.e. ipsi lacrimal gland, contralateral eye, thyroid, peripheral organs/ whole body)* Greater tumor inhomogeneity compared with either proton therapy or plaque It would take a randomized trial to show SRS equality in control and superiority in complications compared with protons. * Zytkovicz A, et al: Peripheral dose in ocular treatments with Cyberknife and Gamma Knife radiosurgery compared to proton radiotherapy. Phys Med Biol. 2007;52(19):5957. Charged Particle Therapy UCSF Eye Therapy Program 1975: Proton Therapy at Harvard Cyclotron 1977: Helium Ion Therapy commenced at LBNL 184 inch cyclotron by Castro and Quivey Particle techniques yield best reported radiotherapy results to date Ocular model computer program developed by Goitein and Miller 1994: Eye Therapy transferred to proton beam at Crocker Nuclear Lab (CNL) 76 inch cyclotron Proton Patients include: Intraocular Melanoma1,143 Conjunctival tumors 16 Benign disease 32 Other misc. 17 3

4 Proton Beam Therapy Proton Beam Planning Pt dx and transfer care to ocular/radiation oncologist Pt decide PBRT; Tantalum ring placement in OR Simulation in Rad Onc w/ immobilization device and orthogonals Treatment at CNL Planning w/ EYEPLAN software; anterior structure sparing technique* 56 GyE in four daily fx of 14 GyE *Daftari et al, IJROBP 1997, 39: Input: 1.Ultrasound tumor and eye measurements 2.Clinical exam and drawings 3.Fundus photograph 4.Surgical T-ring drawing with relation to tumor, limbus, inter-ring distances, etc. 5.MRI 6.Angiogram 7.Other DVH Use eye position, beam parameters, margins, etc. to ensure tumor coverage and minimize dose to critical structures Fundus photo digital superimposition - Prototype software tested at UCSF UCSF-CNL Proton Treatment Schematic of Beam Setup 4

5 Beam Line Apparatus Flat Panel Imaging Beam line Patient in seated treatment position Proton Treatment Field Imaging UCSF Uveal Melanoma Program Important advances in planning and treatment protocol Beams eye view Lateral view Excellent local control rates have been maintained with proton therapy for patients with uveal melanoma: 98% at 2 years and 96% at 5 years Daily alignment with electronic portal imaging Clinical use of flat panel imaging pioneered Our current clinical practice, including delivering 56 GyE in four fractions and focusing on sparing of the lens and ciliary body, has yielded low enucleation and NVG rates without sacrificing a high LC rate compared with historical data. 5

6 Results: Local Control 5y 96% Results: Enucleation & NVG % Free from NVG: 5 yr = 84.3% (95% CI: %) % Free from ENU: 5 yr = 94.0% (95% CI: %) Time to NVG by Dose to Ciliary Body & Optic Disc Kaplan-Meier estimates LC: 2 yr = 98.1% (95% CI: %) 5 yr = 95.6% (95% CI: %) <30% vol ciliary body to get 28 GyE <100% vol optic disc to get 28 GyE Results: Time to Failure/Complications Results: Overall Survival 5y 85% Of those that had failures/complications Median time to local failure: 25.5 months Median time to NVG: 21.6 months Median time to enucleation: 25.4 months Median time to distant metastasis: 36 months Median time to death after DM: 3.1 months OS (%) 50 K-M estimates Overall Survival: 5 yr = 84.8% (95% CI: %) Months from Treatment 6

7 Results: Prognostic Factors Recurrent Disease No patients with small tumors recurred locally. Univariate Cox regression analysis for LC: + Ciliary body involvement (p=0.007), Largest diameter (p=0.001), Shorter distance to fovea (p=0.001), Shorter distance to disc (p<0.001), Female gender (p=0.033) were significant for worse LC. Multivariate LC: LOCAL CONTROL p HR [95% CI] Distance to disc [ ] Largest diameter [ ] OVERALL SURVIVAL Largest diameter < [ ] Older age at Dx < [ ] Initial local control is high, hence relatively rare to retreat Enucleation is considered standard of care Marucci et al, 2006: 31 pts retreated of 2788 UM pts total at Harvard Cyclotron 7 in-field recurrences, 19 marginal, 2 ESE, 4 out of field Additional CGE (total CGE) Some degree of field overlap (40-100%) Mean f/u 50 mos after retreatment Marucci et al., IJROBP, 64:1018, 2006 Uveal Melanoma: Conclusions Acknowledgements Radiotherapy is the treatment of choice for most ocular melanomas. Particle Treatment is superior to plaque treatment. Proton beam radiotherapy has less complications than helium ion therapy. Need RCT and longer follow-up to evaluate relative outcomes and toxicity for SRS. Overall survival rates are comparable between surgery and RT. Important advances in proton planning and treatment have resulted in excellent LC and low complication rates. UCSF Uveal Melanoma Team Inder K. Daftari, PhD Charlie Pascal, Development Engineer Dolores Andy Sevier, RTT R.P. Singh, PhD Pamela Akazawa Paula Petti, PhD Vivian K. Weinberg, PhD Ramji Rajendran, MD Jeanne M. Quivey, MD Theodore L. Phillips, MD Mack Roach III, MD, Chair Crocker Nuclear Laboratory Tim Essert Randy Kemmler Anthony Wexler, PhD Ocular Oncologists Devron H. Char, MD Robert Johnson, MD Susanna Park, MD Paul Stewart MD Tony Tsai, MD 7