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Plaque Radiotherapy for Uveal Melanoma
- 1. Strategies to Minimize Radiation Maculopathy Yonah Ziemba SKMC, MS3 Radiotherapy for Uveal Melanoma:
- 2. Outline I. Patient presentation II. 3 Treatment Options: Plaque vs Proton Beam vs Enucleation III. 3 Clinical Questions, 3 Major Studies IV. Back to the Patient
- 3. • US incidence 1,500 cases/year. • White >> Black, Men > Women • Melanoma is the most common primary intraocular malignancy in adults, at 75%. • #2 = Retinoblastoma. Only 13%. Epidemiology
- 4. Patient Presentation • JK is a 51y/o gentleman presenting w 3 mo of intermittent photopsia in the left eye. • Exposure to arc welding. • Choroidal lesion measuring 10 x 8 mm in left eye noted on Fundus exam. • Visual acuity was 20/20.
- 5. Fundus Exam
- 7. • Work-up: fundus exam, ultrasound and fluorescein angiography. • Measurements: diameter by fundus exam, thickness by ultrasound • Biopsy: not done until after radiation for risk of seeding. Diagnosis
- 8. 3 Treatment Options • Enucleation Last resort • Proton Beam Useful when > 5 mm thickness • Plaque Brachytherapy Useful when < 5 mm thickness
- 9. • prior to 1970 • refractory cases Enucleation
- 11. Proton Beam
- 12. Plaque
- 13. Plaque
- 14. • Most common form of treatment • Good for thin tumors, not thick tumors Plaque • Commonly Iodine-125 T1/2: 59.4 d Av Energy: 35.5 keV • Not possible over optic nerve due to anatomy
- 15. 3 Clinical Questions I. Is radiation effective? II. Does radiation cause vision loss? III. Can prophylaxis prevent vision loss?
- 16. • Question: Is Radiotherapy as effective as enucleation? • Design: Randomized multi-center clinical trial of iodine 125 brachytherapy vs enucleation. • Conclusion: No difference in survival between I-125 brachytherapy vs enucleation. • Impact: Brachytherapy usually first line treatment. JAMA Ophthalmology, Dec 2006
- 17. JAMA Ophthalmology, Sept 2000
- 18. J of Ophthalmology Vol 121, Jan 2014
- 19. Back to our patient… • JK’s melanoma was treated with iodine-125 plaque. 7185 cGy to the apex and 17,023 cGy to the base of the tumor. • 3355 cGy was delivered to the fovea and 4235 cGy to the optic disc. • To minimize maculopathy, JK received anti-angiogenic treatment. • Bevacizumab injections • Photocoagulation (laser)
- 20. • Lesion reduced to a 3 mm scar Before After 2 Year Follow Up
- 21. • Patient retained perfect 20/20 vision! • Attributed to the anti-angiogenic treatment. • Case was published as a success story in Retina Today. Retina Today, March 2013
- 22. Conclusions I. Wills Eye protocol for work-up of non-metastatic melanoma differs from other tumors: - No biopsy, CT or MRI - Diagnosis via fundus exam - Thickness measured by ultrasound II. Isodose patterns of Plaque vs Proton: - Plaque ➞ Steep gradient ➞ Thin tumors - Proton Beam ➞ Wide plateau ➞ Thick tumors. III. Radiotherapy cures ocular tumors, yet causes maculopathy IV. Bevacizumab expected minimize maculopathy - Too early for long term studies
- 23. Thank you!
Editor's Notes
- Presented to Rad Onc department Fri Oct 16, 2015, end of Rad Onc clerkship Updated after presentation based on feedback Thanks residents & faculty Flipped model for student to talk to experts. If I make mistake, please correct Wills Eye experience Major diff btwn Wills Eye tumor workup vs Rad Onc Dept: Diagnosis w/o biopsy Possibility for prophylaxis MRI/CT depends on institution. Not recommended by ABS-OOTF. But needed if metastasized. ~~~~~~~~~~~~~~~~~~~~~~~~~ The American Brachytherapy Society - Ophthalmic Oncology Task Force / Brachytherapy The fundus diagram should be created as to demonstrate the tumors clock hour orientation within the eye, its longitudinal and transverse diameters, and its largest basal diameter. It should include measurements from the tumor to the fovea, optic nerve, lens, and opposite eye wall. This information is typically derived from judgments correlating the ophthalmic examination, ultrasound findings, and photographic images. The ABS-OOTF agreed (Level 2 Consensus) that neither CT nor MRI currently offers superior tumor measurements.
- Road map Need info from [parts II and III to choose treatment plan in IV Orient audience by referring to this road map to for each slide in presentation Judy Tykocinski
- More than 500 cases are treated at TJUH Will Eye Hospital. Greater than 1/3 US cases. Remarkable! RB gets the bad rap, but really is it’s only most common ocular tumor in children but not common in adults. (RB also disproportionally well-known because of important molecular gemetic research on RB gene)
- Before images, quick review of anatomy: Uvea is the middle layer of the eye, between impermeable retina and sclera. I know the lesion is un choroid since below retinal BVs. Causes tumors to be flat. Back portion of Uvea called “Choroid” Choroid contains melanocytes which supply the black pigment to absorb light. All ocular melanomas arise from Uvea, and most from Choroid. Ophthalmologists call it Uveal mealnoma, popular press calls it Ocular Melanoma Interchangeable for this presentation Define disc/cup vs optic nerve Define Fovea (Macula is bigger) Draw optic disc, fovea and lesion Pigmented gray = Melanin! Retineal vessel above lesion -. confirms choroidal location Measure diameter by Optic disc Is lesion medial or lateral? Cartoon diagram ➞ Disc is always closer to midline b/c points to Optic Chiasm ➞ photo is left eye. Lesion is Superomedial , 11o’clock ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Notice panorama, contrast to tunnel vision of direct ophthalmoscope. Photographer couldn’t capture entire lesion because inner front surface of globe is an impossible angle. Rarely breaks through Epithelium. Would enter vitreous chamber, bad bad sign, Rule of 3s, like tic toc toe board: Eye has 3 layers: sclera, uvea, retina Eye has 3 chambers: Anterior, Posterior and Vitreous Thus Uvea has 3 parts: choroid, Ciliary body, Iris
- Fluorescein angiography: Late phase, arteries are black against backround of fluorescence leakage from tumor forms “Halo” = ring of hyperautofluorescence = leakage B-scan ultrasonography is primary way to measure thickness. Note hollowness Fundus exam + ultrasound is considered equal or better than MRI or CT for ocular lesions. Thickness is very important for prognosis and determines treatment modalities. Shows acoustically hollow tumor mass of 4.7 mm. ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~
- Biopsy not used for diagnosis or initial treatment, Risk of seeding and not necessary. confirmed by American Brachytherapy Society consensus guidelines Biopsy via FNA is occasionally done for genetic molecular testing, which can guide pharmaceutical treatment, only after irradiation. ~~~~~~~~~~~~~~~ One of the most important papers published for Ocular Melanoma Only possibly since WIlls Eye has such high volume Play-off of famous ABC’s of Melanoma A - Asymmetrical Shape B - Border C - Color D - Diameter
- Can’t use X rays so close to optic nerve and brain, but proton beam and plaque have minimal dose volumes Enucleating = removing surgically, like amputation Patient sometimes think, if I’d be blinded by radiation anyway, why not enucleate? “Blind” can still see! Just can’t read chart, < 20/200 Walk down hallway, day/night cycles, depression Dr Shields: Life > Eye > Vision
- Prior to 1970, all eyes suspected of melanoma were enucleated, then brought to pathologist for final diagnosis. Up to 30% were reported to be false positives after enucleation. What a shame! In the photo, eye was enucleated d/t melanoma. Perhaps more than 10 mm thick. Note “mushrooming”: bulk is is btwn choroid and retinal pigment epithelium, but stem broke thru into Vitreous chamber. Bad sign.
- Implant put in at surgery attached to muscles for ocular mov’t prosthesis made later by ocular artists to match good eye Can’t tell from casual contact
- Pic 1: X-rays: everything in their path gets at least some entrance /exit radiation. Protons slow down as they penetrate tissue and deposit most of their energy right before they stop. If you hit a patient with protons going at the right velocity toward the tumor, you spare healthy tissue. Graph based on experimental data from Harvard Cyclotron. 70% entrance dose, 0% exit dose. Pic 2: Even dose over a large plateau which compasses the entire tumor volume, then falls off sharply. Good for thick tumors > 5mm. Even in the artist’s drawing, treatment volume is much larger than tumor. This would be unacceptable clinically. Proton beam can not be concentrated in less than 5 mm Therefore not good for thin tumors. ~~~~~~~~~~~~~~~~~~~~~~ ~~~~~~~~~~~~~~~~~~~~~~~ Proton beam prescription dose : 56 GyE in five fractions GyE = Gray equivalent = dose in Gy × Relative biological effectiveness of protons 1.1 Photon machine $4 million vs Proton machine 100 million ~~~~~~~~~~~~~Exerpt from Radiobiology for the Radiologist by Eric Hall FIGURE 25.4 Dose distribution used for the treatment of choroidal melanoma at the Harvard cyclotron. Note the sharp edges to the beam and the rapid falloff of dose outside the treatment volume. (Courtesy of Dr. Herman Suit.) FIGURE 25.3 The way the Bragg peak for a proton beam can be spread out. Curve A is the depth-dose distribution for the primary beam of 160-MeV protons at the Harvard cyclotron, which has a half-width of only 0.6 cm. Beams of lower intensity and shorter range, as illustrated by curves B, C, D, and E, can be added to give a composite curve S, which results in a uniform dose of more than 2.8 cm. The broadening of the peak is achieved by passing the beam through a rotating wheel with sectors of varying thickness. (Adapted from Koehler AM, Preston WM. Protons in radiation therapy. Comparative dose distributions for protons, pho- tons, and electrons. Radiology. 1972;104:191–195, with permission.) The Advantage of Protons The basic principles of physics and biology imply that the dosimetric advantage of protons should translate into a clinical gain. These principles are as follows: 1. For the same dose to the target volume, pro- tons deliver a lower absorbed dose to normal tissues than do high-energy x-rays. 2. There is no clinical advantage to be gained by irradiating normal tissues that do not har- bor malignant cells. 3. There is little difference in the radiobiologic properties of protons used for therapy and high-energy x-rays; this includes repair, OER, and response through the cell cycle. The only relevant difference, therefore, is the dose distribution. 4. Ionizing radiations damage normal tissues as well as tumors, with the severity of the dam- age increasing with dose. The consequence of these principles is that, for the same tumor dose, protons will deliver a lower dose to a smaller volume of normal tissue than high-energy x-rays. It is difficult to imagine that this can be other than a marked advantage, and the clinical results lean in that direction. Nevertheless, a comparison of clinical results between protons, intensity-modulated radiation therapy, and conventional conformal radiotherapy is somewhat controversial because of the lack of phase 3 clinical trials.
- Note lens, optic nerve and plaque. Isodose lines show a very steep gradient. See red annotation. Sclera is within field The steep gradient is within the tumor. (contrast to proton beam) Dose fell from 70 to 20 in the first 4 mm! Extremely hot at base of plaque, dose is much higher than apex. Plaques not feasible for lesion > 5 mm thickness since most of the dose falls away. ~~~~~~~~~~~ Add “spacer” to protect. Image from Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 4, pp. 1227–1242, 2005 Dose prescription: minimum tumor I125 dose 85 Gy; dose rate 0.60–1.05 Gy/h.
- Pics = plaque, transillumination and post surgery Plaque usually has 1 or 2 mm margins General or local anesthesia Cut muscles so eyeball hangs out Localize melanoma with transillumination, mark with marker One millimeter spacer. dummy plaque is confirmed using intraoperative ultrasonography, , suture plaque to sclera in pre-placed sutures Close up, and place lead eye shield. Patient usually discharged in 24 h. Patient returns for plaque removal in 4–7 days. FNAB at plaque removal if genetic molecular testing is desired.
- Our patient JK had thickness 4.8 mm, so would qualify for plaque
- Before deciding to give JK plaque, need to answer these 3 questions Next 3 slides are 3 studies addressing the Qs
- Other studies show similar results for proton beam
- All 3 lines eventually reach zero by 20 yrs. Sad. Poor visual acuity = 20/200 = legally blind. ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ Risk of maculopathy vs dose: - Risk increases with radiation dose of more than 4.5 G - Then increases linearly - Plateaus at 40 Gy (in study of proton beam radiation) 4.5 Gy: Parsons JT. Int J Radiat Oncol Biol Phys 1994;30:765–73. 40 Gy: Gragoudas ES, Ophthalmology 1999 Some factors that predicted poor vision: Tumor less than 4 mm to foveola Radioisotope iridium 192 vs iodine-125 Dose rate greater than 260 cGy/h to tumor base Age/ pre-treatment vision/ Diabetes
- Intro Bevacizumab is anti-vegf, anti-angiogenic treatment, blocks growwth of BVs Developed for colorectal Cancer, to cut off tumor blood supply The ophthalmologists realized that many eye disease pathogenisis involved new BV growth, Inject Bev directly into eye very effective treatment Revolutionized treatment of Age-related Wet macular degeneration (AMD) For the first time, we can not only slow AMD progression but actually reverse course, vision improves Cochrane Database Meta analysis included 12 RCTs including a total of 5496 participants found to be effective World health Organization lists Bev as “essential drug for any healthcare system” under Ophtho drugs rather than anti-neoplastics. While there are very strong studies showing efficacy of Bev for AMD, studies for radiation maculopathy are much weaker Study Limitations: Not randomized. Disease progression is 20 years, as shown in previous slide. So what use is 2 yr data? To address this, Authors used macular edema as endpoint, assuming it predicts vision loss. (like judging outcome of baseball after first inning!) In truth, real reason Ophthomolgist recommend Bevicuzimab so strongly is not based on these weak studies, rather clinical judgement based on similiarity to AMD ~~~~~~~ ~~~~~~~ Controversy of FDA approval of Bev for AMD Bottom line, bevacizumab recommended by experts for prophylaxis against radiation maculopathy. Continue to struggle with insurance companies, who reject coverage saying it’s only an experimental treatment. Our patient was billed than $3,600 + 800 out-of-pocket for his anti-angiogenic treatment. Why isn’t bevacizumab (Avastin) approved by FDA for any ocular dx? Because there is a similar drug called Ranibizumab which is designed for eye, same manufacturer and much more profitable, so manufacturer won’t apply Bevacizumab (Avastin) : $150 x 12 = $1,800 Ranibizumab (Lucentis) (O/U pocket): $2,000 x 12 = 24,0000 Ranibizumab (Lucentis) (20% Medicare co-pay): $400 x 12 = $4,800
- Prescription dose was 7000 cGy, why 17,000 to base? Because of gradient of plaque radiation, only way to get dose at apex is with extremely hot base Important to gauge dose to fovea since we will follow the patients visual acuity/snellen chart Function of fovea is measured by Snellen chart, needed for reading Function of rest of eye is measured by visual field test, needed for driving (stop signs and changing lane)
- Thickness from 4.8mm to 3.3! Not hollow anymore! But what about vision?…..
- 20/20 vision is rare Even though full effect is 20 yrs, it begin to decline before 2 yrs Success attributed to bevicuzimab treatment.
- “Ocular work-up for non-metastatic tumor treated at Wills Eye differs from other tumors” After metastasis, treated at Bodine Cancer center rad onc dept. with different protocol, including MRI, CT scan Other institutions would do MRI, CT even as part of initial work-up. This can be a politically sensitive conflict, best to stay away from it.