Carol L. Shields, MD, FASRS, and Jerry A. Shields, MD

In the 1940s and before, most eyes with uveal melanoma presented with a blind, painful eye, often from neovascular glaucoma, and were managed with enucleation. The beginnings of the development of globe-sparing treatments (plaque radiotherapy [brachytherapy]) for eyes with uveal melanoma were underway. Hungerford published that the first successful brachytherapy for uveal melanoma was by Foster-Moore in 1929 in London, England, using a radon seed inserted into an eye with melanoma.[1] Bechrakis et al, however, believed that Deutschmann from Hamburg, Germany, was the first to place brachytherapy on an eye with melanoma as early as 1915.[2] Later, in London, Stallard, working with his physicist, Innes, modified the technique of brachytherapy and placed radon seeds into a wax mold so that they could be positioned onto the ocular surface (rather than into the eye) and then later removed.[3] This was the beginning of plaque radiotherapy as we know it.

Meanwhile in the United States, Havener from Columbus, OH, along with his radiation oncologist, Batley, was exploring the use of radon seeds for uveal melanoma in the late 1960s.[3] They sutured tubing with gold seeds that were filled with radon gas to the eye for an apex dose of 6,000-8,000 rads. The gold coating permitted the gamma rays from radon decay to penetrate into the melanoma while inhibiting the alpha and beta rays, as reported by Newman et al in 1970.[4] This device had a short half-life of radon at 3.8 days so the device was not usually surgically removed. While these developments were progressing with radon, Hyla (Henry) Bristow Stallard was simultaneously exploring the use of Cobalt 60 radiotherapy.

In 1966, Stallard published on the first 100 cases of choroidal melanoma treated with “plaque” radiotherapy (Figure 1).[5] He opened his scientific report with these comments:

“It is evident from current ophthalmic literature that there is still an unawareness of the possibility and the value of radiotherapy for some patients with malignant melanoma of the choroid, despite the publication of several papers and lectures about this matter. So this paper is submitted as a reasonable excuse for publishing the results of the first hundred patients with malignant melanoma of the choroid treated by radioactive applicators between 1939 and 1964”.  

Stallard employed either Radium (n=1, 1%) or Cobalt 60 (n=99, 99%)–loaded applicators that were sutured to the sclera overlying the choroidal melanoma with a 1 mm margin on all sides and he calculated the radiation dose to the apex of the tumor was between 7,000 and 14,000 rads, although 11% received 28,000 to 42,000 rads. These apical doses are far beyond the current apical dose of 7,000 centiGray (rads). Further, most patients had only one application of radiation, but 23% had two applications and 1% had three applications of radiotherapy. Tumor regression with globe conservation was achieved in 69 (69%), enucleation was necessary in 16 (16%), and death from metastasis/uncertain outcome in 15 (15%). He commented on treatment complications of macular exudation, punctate retinal hemorrhages, cataract, and scleral necrosis, all of which can occur with current radiation techniques. He also reported visual acuity outcomes of 20/100 or worse in 30 of 69 eyes (44%).[5] Stallard is credited as the first to develop the curvilinear design of the Cobalt 60 radioactive plaque for uveal melanoma.

There is more to know about Stallard. He was a talented middle-distance British runner, and he participated in the 1924 Paris Olympics during his medical student years.[6] Needless to say, he won the Bronze medal in the 1500-meter run and crossed the finish line in a collapse from severe right foot pain, later diagnosed as a ruptured ligament and a stress fracture of the scaphoid bone. He was remembered in the 1981 epic British film, Chariots of Fire. One final caveat about this “giant” in our field is that he transported the unshielded radiation plaques in his hip pocket as he rode his bicycle to the hospital. He later developed osteogenic sarcoma of that same hip, likely from radiation exposure, and subsequently died in 1973.

Later reports on Cobalt 60 plaque radiotherapy for uveal melanoma from Wills Eye Hospital in Philadelphia, PA, USA found that most treated tumors regressed to a thin scar and but there was an inability to shield this radioisotope and thus, there was a relative high frequency of side effects.[7] In the early 1980s, the Cobalt plaque was rarely used in Europe and the USA, as less intense radioisotopes of Ruthenium 106 in Europe 8 and Iodine 125 in the United States [9,10] were explored.  

Ruthenium-106 is a beta radiation device that can be shielded and was introduced to Europe by Lommatzsch in the 1960s.[8] This radioisotope currently remains the most commonly used for brachytherapy in Europe. The main limitation is that the dose to the sclera is relatively high, at risk for scleral necrosis and only thin tumors (≤5-7 mm in thickness) are suitable.[3,8]

Iodine-125 is a gamma radiation device that can be shielded and was introduced to the United States by Packer [9] and Shields [10] in the 1970s. This radioisotope currently remains the most commonly used for brachytherapy in the USA. These devices can be customized to fit basal dimension up to 20 mm and thickness up to 13 mm. The position of the radiation seeds with their distribution activity can lead to conformal radiotherapy fields (Figure 2).

Currently, the radioactive seeds are positioned on a gold shield to provide tumor treatment within 5 days with an apex dose of 7000 cGy.[10-13] Iodine-125 plaque radiotherapy was selected for conservative management of uveal melanoma in the Collaborative Ocular Melanoma Study (COMS) and demonstrated similar survival to enucleation for medium-sized tumors.[14] Shields et al have shown Iodine-125 plaque radiotherapy provides favorable tumor control with low risk for local recurrence for iris, ciliary body, and choroidal melanoma, even those adjacent to the optic disc (Figure 3) and for those of small, medium, and large size.[10-13] The specifics for iris melanoma radiotherapy are clearly described in the literature (Figure 4).[13] Other isotopes like Iridium 192 and Palladium 10315 have been explored for management of choroidal melanoma as well.

Beginning with its origins in the mid-1900s with H.B. Stallard in London, plaque radiotherapy has played a central role in treatment of uveal melanomas. Innovations in plaque design and radiotherapeutic advances have led to our current applications and approach. Almost a century later, plaque radiotherapy remains the most common treatment for patients with uveal melanoma.

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References

1. Hungerford JL. Current trends in the treatment of ocular melanoma by radiotherapy. Clin Exp Ophthalmol. 2003;31:8-13

2. Bechrakis NE, Blatsios G, Haas G, et al. Short review of the history of radiotherapy for intraocular tumours. Klin Monbl Augenheilkd. 2015;232:834-7. [German].

3. Brewington BY, Shao YF, Davidorf FH, Cebulla CM. Brachytherapy for patients with uveal melanoma: Historical perspectives and future treatment directions. Clin Ophthalmol 2018;12:925-34.

4. Newman GH, Davidorf FH, Havener WH, Makley TA.  Conservative management of  malignant melanoma – 1: Irradiation as a method of treatment for malignant melannoam of the choroid. Arch Ophthalmol 1970;83:21-6.

5. Stallard HB. Radiotherapy for malignant melanoma of the choroid. Br J Ophthalmol. 1966;50:147–55.

6. Bullock JD. Henry B. Stallard, MD: The 1924 Paris Olympics, and Chariots of Fire.  Surv Ophthalmol. 2011;56:466-71.

7. Cruess AF, Augsburger JJ, Shields JA, et al. Regression of posterior uveal melanoma following Cobalt-60 plaque radiotherapy. Ophthalmology. 1984;91:1716-19.

8. Lommatzsch PK. Results after beta-irradiation (106Ru/106Rh) of choroidal melanomas: 20 years’ experience.  Br J Ophthalmolol. 1986;70:844-51.

9. Packer S, Iodine-125 radiation of posterior uveal melanoma. Ophthalmology 1987;94:1621-6.

10. Shields JA, Shields CL. Management of posterior uveal melanoma: Past, present, and future: The 2014 Charles L. Schepens lecture. Ophthalmology 2015;122:414-28.

11. Shields CL, Sioufi K, Srinivasan A, et al. Visual outcome and millimeter incremental risk of metastasis in 1780 patients with small choroidal melanoma managed by plaque radiotherapy. JAMA Ophthalmol 2018;136:1325-33

12. Shields CL, Sioufi K, Robbins J, et al. Large uveal melanoma (≥10 mm thickness): Clinical features and millimeter-by-millimeter risk for metastasis in 1311 cases. The 2018 Albert E. Finley Lecture. Retina 2018;38:2010-22.

13. Shields CL, Shah S, Bianciotto CG, Emerich JE, Komarnicky L, Shields JA.  Iris melanoma management with Iodine-125 plaque radiotherapy in 144 patients: Impact of melanoma-related glaucoma on outcomes.  Ophthalmology 2013;120:55-61.

14. Collaborative Ocular Melanoma Study (COMS) Group. The COMS randomized trial of Iodine 125 brachytherapy for choroidal melanoma. V. Twelve-year mortality rates and prognostic factors: COMS report no. 28. Arch Ophthalmol 2006;124:1684-93.

15. Finger PT, Lu D, Buffa A, et al. Palladium-103 versus Iodine-125 for ophthalmic plaque radiotherapy. Int J Radiat Oncol Biol Phys 1993;27:849-54.

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(Milestone essay published 2022)

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Additional Resources

Hear from Carol L. Shields, MD, FASRS, on her remarkable career in a Leaders & Legends interview at https://retinahistory.asrs.org/video-interviews/carol-l-shields-md-fasrs.