Evangelos S. Gragoudas, MD; Anne Marie Lane, MPH; Frances Wu, MD; Ivana K. Kim, MD, FASRS

Prior to proton irradiation for treatment of choroidal melanoma, enucleation or the use of several kinds of radioactive plaques had been employed for many years. In 1975, Dr. Evan Gragoudas’ team at Massachusetts Eye and Ear administered the first proton treatment on a patient with choroidal melanoma.  

The physical characteristics of these high-energy charged particles have several advantages: minimal scatter, a well-defined range in tissues that is finite and energy-dependent (Bragg peak), and the particles’ ability to be collimated into small beams.[1,2]

Monkey experiments first showed that proton treatment was feasible for the eye and that there was an extremely sharp demarcation between the radiation field and adjacent tissues[3,4] (Figure 1).

When the first patient was treated in 1975, the tumor was localized through surgical placement of tantalum rings on the sclera around the borders of the melanoma, which were defined by transillumination[5,6] (Figure 2).

Tantalum was used because it was being employed for securing scleral buckles at the time, and the MIRA Company helped design a marker that could be used for tumor localization.

Dr. Gragoudas’ team developed a treatment planning program to model the radiation dose distributions in the eye according to the gaze direction. The team used this program to find the gaze direction for the treatment that would best minimize radiation exposure to sensitive structures such as the optic nerve, the macula, the cornea, and the lens[7] (Figure 3).  

During treatment, the patient is immobilized with a bite block, and a lid speculum is used to keep the lids away from the radiation field (Figure 4). Treatment is monitored in a control room through a television screen that shows a magnified view of the anterior part of the eye (Figure 5). The treatment lasts about 1 to 2 minutes and can be stopped if there is excessive eye movement. Most treatments go uninterrupted.  

For tumors anteriorly located on the iris or ciliary body, a light beam coaxial with the central axis of the protons is used to position the beam relative to the tumor and tantalum markers are unnecessary. This is what Dr. Gragoudas termed light-field treatment[8,9] (Figure 6).

Since 1975, over 4000 patients with intraocular melanomas have been treated with protons at Mass. Eye and Ear in collaboration with Massachusetts General Hospital, and more than 40,000 patients have been treated worldwide. Figures 7 and 8 demonstrate the tumors before and after treatment (Figure 7, choroidal melanoma; Figure 8, iris melanoma).

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A major advantage of protons is that one can treat patients with tumors that are very large[10] or close to the optic nerve[11,12] (Figures 9-10).  

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Some entertaining facts surround the first treatment performed by Gragoudas’ team. The institutional review board (IRB) asked Dr. Gragoudas to state in the consent form that there was a possibility that the proton beam could extend beyond the eye and kill the patient. He had to spend a lot of time trying to convince the IRB that this was not going to happen, but in the end, he gave up and included that statement.

Also, it was surprisingly hard to find a suitable chair for the patient; it couldn’t be so soft that the patient would sink into it, and it had to be adjustable. Dr. Gragoudas ended up finding an old dental chair, which is still in use for proton beam therapy. Finally, the team was fortunate to have an ideal first patient—one from Colorado who had been seen at 2 other centers, both of which had recommended enucleation.  When the patient learned through a former fellow of Dr. Gragoudas’ that the doctor was working on a new modality for tumor treatment, the patient came to Boston. He was told that they were not ready for treating patients yet, and still needed some necessary equipment. The patient turned to Dr. Gragoudas and said, “Dr. G, I will be at the hotel; when you are ready, give me a call.” Two weeks later, the patient was successfully treated. The team received an update many years later, and was pleased to hear that the patient was still alive, and his eye was intact with good vision.

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Appendix

Figure 1: Fundus photographs of a monkey retina after high dose proton radiation demonstrating the sharp margin between radiated and adjacent retina (upper right shows acute reaction, upper left shows atrophic scar). Lower left and right: Histopathology revealed intact outer segments (left) at the border and normal vasculature (right) just adjacent to the radiated area. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 2: Tantalum rings sutured to the sclera at the edges of the tumor which is seen by transillumination. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 3: A beam’s-eye view of the eye model from the planning program, showing the modeled tumor in red and the aperture design in green giving a 3.0 mm margin on the tumor (left). Isodose curves are shown in a vertical plane through the eye parallel to the beam direction. The tumor is shown in red and the yellow cone represents the optic nerve (right). Images courtesy of J. Michael Collier, PhD, Radiation Oncology Department, Mass General Hospital.

Figure 4: Patient seated in front of the proton beam collimator awaiting treatment. Immobilization of the head is achieved with plastic mask and bite block secured in a headholder. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 5: Dr. Gragoudas monitoring a patient’s eye position during radiation treatment at the Harvard Cyclotron. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 6: A light beam coaxial with the central axis of the proton beam is used to position the tumor relative to the beam during treatment. The eyelids are held open with a lid speculum. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 7: Patient with macular tumor and 20/25 vision at diagnosis (left).  Four years after PBI, vision is 20/30 with mild radiation maculopathy (right). Images courtesy of Dr. Ivana K. Kim, Ocular Melanoma Center, Mass Eye and Ear.

Figure 8: Case of iris melanoma before (left) and 1 year after treatment (right) with visual acuity of 20/20. Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 9: Large tumor involving the optic disc before treatment (left).  Significant regression of the tumor is seen, and patient has visual acuity of 20/200 after treatment (right). Images courtesy of Dr. Evangelos S. Gragoudas, Ocular Melanoma Center, Mass Eye and Ear.

Figure 10: Patient with tumor almost encircling the optic disc and 20/20 vision at baseline (left).  Six years after PBI (right) the vision is 20/30.  Images courtesy of Dr. Ivana K. Kim, Ocular Melanoma Center, Mass Eye and Ear.

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References

1.    SuitHD, Goitein M, Tepper J, Koehler AM, Schmidt RA, Schneider R. Exploratory studyof proton radiation therapy using large field techniques and fractionated doseschedules. Cancer. 1975;35(6):1646-1657.doi:10.1002/1097-0142(197506)35:6<1646::aid-cncr2820350626>3.0.co;2-1

2.    Koehler AM, Schneider RJ, Sisterson JM.Range modulators for protons and heavy ions. Nucl Instrum Meth. 1975;131(3):437-440. doi:10.1016/0029-554X(75)90430-9

3.    Gragoudas ES, Zakov NZ, Albert DM, ConstableIJ. Long-term observations of proton-irradiated monkey eyes. Arch Ophthalmol. 1979;97(11):2184-2191. doi:10.1001/archopht.1979.01020020502020

4.    Constable IJ, Roehler AM. Experimentalocular irradiation with accelerated protons. Invest Ophthalmol. 1974;13(4):280-287.

5.    Gragoudas ES, Goitein M, Koehler AM, et al.Proton irradiation of small choroidal malignant melanomas. Am J Ophthalmol. 1977;83(5):665-673. doi:10.1016/0002-9394(77)90133-7

6.    Gragoudas E, Goitein M, Koehler A, et al.Proton irradiation of choroidal melanomas: preliminary results. Arch Ophthalmol. 1978;96(9):1583-1591. doi:10.1001/archopht.1978.03910060217006

7.    Goitein M, Miller T. Planning proton therapyof the eye. Med Phys. 1983;10(3):275-283. doi:10.1118/1.595258

8.    GragoudasES, Goitein M, Koehler A, et al. Proton irradiation of malignantmelanoma of the ciliary body. Br JOphthalmol. 1979;63(2):135-139. doi:10.1136/bjo.63.2.135

9.    Oxenreiter MM, Lane AM, Aronow MB, et al.Proton beam irradiation of uveal melanoma involving the iris, ciliary body andanterior choroid without surgical localisation (light field). Br J Ophthalmol. 2022;106(4):518-521. doi:10.1136/bjophthalmol-2020-318063

10.  Papakostas TD, Lane AM, Morrison M, GragoudasES, Kim IK. Long-term outcomes after proton beam irradiation in patients withlarge choroidal melanomas. JAMAOphthalmol. 2017;135(11):1191-1196. doi:10.1001/jamaophthalmol.2017.3805

11.  Kim IK, Lane AM, Egan KM, Munzenrider J,Gragoudas ES. Natural history of radiation papillopathy after proton beamirradiation of parapapillary melanoma. Ophthalmology.2010;117(8):1617-1622. doi:10.1016/j.ophtha.2009.12.015

12.  Lane AM, Kim IK, Gragoudas ES. Protonirradiation for peripapillary and parapapillary melanomas. Arch Ophthalmol. 2011;129(9):1127-1130. doi:10.1001/archophthalmol.2011.228

(Milestone essay published 2023)