The ocular oncology duo of Shields and Shields shoots for lofty goals. “I want to cure — even prevent — melanoma; too many people die unnecessarily from it,” said Carol Shields, MD, codirector with husband Jerry Shields, MD, of the Oncology Service at Wills Eye Hospital, Philadelphia, Pennsylvania. Together, they personify the pre-eminence of the unit Jerry founded 44 years ago.

Defeating ocular melanoma may sound far-reaching, but it is likely within the reach of these clinicians/researchers/superheroes who have meticulously recorded their lives’ work in thousands of published papers, textbooks, and lectures the world over. Their trials, errors, and ultimately successes define the very purpose of ocular oncology and continue to shape its reach.

“They are the best known ophthalmologists in the world,” declared Julia Haller, MD, ophthalmologist-in-chief at Wills. “They literally have written the book on ocular oncology. They inspire the rest of us with hard work, productivity, clinical excellence, research.” As if that didn’t quite cover it, Haller added, “They are immortal, godlike, superhuman. Yet, they are also accessible, collaborative, and fun – the last ones to leave the dance floor at a party.”

On a chilly December afternoon the Shieldses sat down with Retinal Physician to discuss the convergence of their careers and the future of their field. Carol began, “I always wanted a meaningful life that would make a difference in the world. The best way to do that was to become a physician.” Having done various rotations during medical school at the University of Pittsburgh, she considered specializing in dermatology. But a brother — one of 8 siblings, five of whom are doctors — suggested ophthalmology. “He said, ‘It’s a great field with interesting surgical procedures, and good hours.’ I trusted his advice.”

During her second year of residency, Carol examined a 35-year-old female who thought her vision was blurred from a displaced contact lens. Carol discovered something very different: melanoma. “My very next rotation was oncology; I sat in on her eye removal. The next rotation was pathology, and I actually saw her eyeball under the microscope. She ‘grabbed’ me 3 times. I said, ‘I’ve got to do something about this.’ That patient propelled me into ocular oncology.”

Jerry came from a humble farm background in Kentucky. Two of 8 siblings finished high school; most dropped out to work the soil. So, it was a shock to his family when Jerry headed to college. “I noticed smart kids talked about medical school, so I figured I might as well give it a try,” he said, chuckling. After putting himself through medical school at the University of Michigan, Jerry considered a psychiatry residency, but was drafted and sent to Vietnam as a field doctor with the Marine Corps.

“I was literally in a field, never saw a hospital,” he said.

Having passed sleepless nights in a bunker targeted by Viet Cong mortars and small-arms fire, Jerry turned to his bunker mate and announced, “I want to go into a specialty where I won’t be up all night.” Paging through a booklet about various residencies he carried with him, he saw ophthalmology and thought, “I bet ophthalmologists get to sleep. Case closed.” He wrote to Wills, which welcomed him into a residency once he finished military service.

Though his objective in the early 1970s was to finish the residency, move to Colorado, and live in the Rockies, a retina fellowship intervened. “I saw patients with retinal diseases at a time when ophthalmologists did their own tumor work,” recalled Jerry. “When they saw cancer, they removed the eye. That was the end of it. But new techniques were emerging in diagnostics and treatments and I wanted to pursue them. I started a small practice at Wills treating just tumors; it was one of the first ocular oncology units in the country.”

Jerry studied enucleated eyes, and began to comprehend a previously unrecognized variety of eye tumors. “We developed new techniques, like radioactive phosphorus testing to detect tumors and determine malignancy,” he recalled, “and improved known techniques to the point where we no longer had to remove eyes. Patients were thrilled. I began to lecture, and tumor referrals started coming.”

When Carol joined the practice in the late ’80s, ocular oncology was still an odd duck in the medical community. “Oncologists dealt with lungs, colon, skin, but none with eyes. There was no organized subspecialty for ocular cancer, so we worked to build it. Jerry turned the crank of the effort, greased the wheels and set the vehicle in motion,” said Carol. “He developed better diagnostic methods, starting with the P32 test, and began treating cancers using plaque radiation. As he worked, Jerry kept meticulous case reports.” (Jerry interjected, “If I saw 10 patients with retinal pigmentation epithelial ademona, I wrote exactly what each looked like, how I managed each one, what the outcomes were.”) “That was significant,” stressed Carol. “It became the essential building block to bigger studies.”

Carol, too, plowed ahead, perfecting diagnostic and treatment techniques, and undertaking research using statistical methods. “I dragged the field forward by asking, ‘What is the best treatment for a particular type of cancer? Who does best with that type of cancer? Should we be radiating an eye or using another treatment?’” Taking over retinoblastoma (the most common pediatric intraocular malignancy) and much of the melanoma work, Carol organized the practice so that “every patient who walked through the door was coded on a record,” she said. “When we wanted to look at 300 cases of disease XYZ, we could pull those charts and immediately track how each patient did with our various therapies. This allowed us to do mega-data analysis on thousands of patients.”

As raw data provided fodder for deeper research, word of their work spread. Invitations to lecture at important conferences were extended to Jerry and Carol, and referrals from around the globe started arriving. “Before Carol joined us, we had a small clinic here at Wills; very few tumors were sent in. When Carol came, she improved our practice with her publications. She really put us on the map,” said Jerry. Dr. Haller concurred: “They became the world’s ‘go-to’ people in ocular oncology.”

Earlier on this December day, Carol completed 18 surgeries on patients “from Egypt, Saudi Arabia, and 4 from China. They come from all over.” But not only surgeries demand precious time; the practice blends clinic, surgery, and vital continuing research.

Lawrence Yannuzzi, MD, professor of clinical ophthalmology at Columbia University, marvels at the Shieldses’ capacity for Herculean research loads. “It is hard to comprehend the sheer volume of work they have published — and without NIH grants,” he said of his friends and colleagues. “Research money is scarce so the Shieldses do it on their own. The work they produce is original, lasting, and innovative. Their observations are now standards in the field.”

The couple confirmed research is both a necessity and a passion. “What we do is so different and unique that we must publish results so doctors understand exactly why they are referring patients,” said Carol. Their love of research is nurtured by dogged dedication. Rising daily at 4:00 a.m., they beat an early path to Wills where preclinic hours are spent answering emails, reviewing cases, and writing reports. “We work hard Mondays through Thursdays,” Carol said, “then carve out Fridays for research. There’s an excitement to it. I feel like Magellan rounding the Cape of Good Hope, never knowing what’s on the other side. I love being the explorer.”

Admittedly the Shieldses have taken a financial hit to do research. “It is our contribution to science,” said Carol. They have founded their own Eye Tumor Research Foundation, built on donations from patients and families, to assure work continues unfettered. “They’ve helped us a lot,” said Jerry.

Fruits of research have been many. Those that spring immediately to Carol’s mind are improved treatments for intraocular tumors in retinoblastoma, many of which she co-pioneered. In the 1970s, treatment choices were but two — removal of the eye or irradiation (often causing secondary cancers). In the 1990s, intravenous chemotherapy was introduced. In the early 2000s, “We studied and employed intra-arterial chemotherapy, using a catheter to deliver exactly the right combination of chemotherapy into the ophthalmic artery, sparing systemic complications,” said Carol, noting it was a bit of an uphill climb. “Intra-arterial chemotherapy had been used to treat osteosarcoma of the limbs, but it got a ‘thumbs down’ in the literature because it caused so much limb ischemia. So when we first wanted to use intra-arterial chemotherapy for eye tumors, everyone said, ‘No. It’s too toxic.’”

Persisting, Carol found a fellow “explorer” in Robert Rosenwasser, MD, head of neurosurgery at Jefferson University Hospital in Philadelphia. “He said, ‘I’ll do it with you. Let’s try 20 patients,’” recalled Carol. “It has been crazy good, saving more eyes than anything else.”

In 2010, Carol continued to develop another technique, intravitreal chemotherapy. “It allows us to inject a potent dose of melphalan, a killer chemo, into larger, advanced tumors, directly in the eye. It wipes out the tumor, without going systemic. Living through this chemotherapy evolution has been thrilling,” said Carol, “but scary. Whenever we try a new therapy, we don’t know if the eye will tolerate it, if there will be complications, if the child will die in the process. It’s like jumping off a cliff with a half-opened parachute. But we’ve landed safely; we can cure most cases of retinoblastoma with some chemotherapy method.”

Asked to pinpoint a project of current interest, Jerry described an emerging advancement in early diagnosis. “We have begun giving talks about invisible intraocular tumors. We can now use newer imaging techniques to find tumors that are clinically invisible – too small to see with a microscope. Using optical coherence tomography, we can diagnose flat melanoma in the eye when it can’t even be visualized with an ophthalmoscope.” He added some patients with unsolved visual complaints may in fact have melanomas that are “very tiny, subclinical lesions. When patients come to us now, we can discover these problems early on with OCT and other methods. That is very exciting.”

The future of ocular oncology holds a lion’s share of promise. Carol expressed great expectations for the use of viral therapy. Serving on the scientific advisory board of Aura Biosciences, she works alongside CEO Elizabet de los Pinos, PhD, who Carol described as “incredible, bright, enthusiastic. I want to cure melanoma, and I want to do it with her.”

One Aura product, AU-O11, “is the hottest cutting-edge technology coming to ocular oncology,” proclaimed Carol. “We inject nanoparticles into the eye. Attracted to the melanoma, these nanoparticles carry a chromophore, allowing them to suck up laser light. When we shine a laser on them, melanoma cells have immediate necrosis. It’s very precise and doesn’t cause much collateral damage or vision loss, as far as we know. We are still in Phase 1 trials; we need to test safety and efficacy. But it could be groundbreaking.”

The Shieldses also look to emerging screening tests for cancers with genetic mutations in the blood, such as germline retinoblastoma, some retinal capillary hemangioblastomas, vascular tumors, and uveal melanoma.

“We are hopeful laboratory testing will locate pathways in the mutated gene of concern that could ‘turn off’ tumors,” said Carol. “I predict there soon will be blood screenings for newborns to find mutations for tumors that could be prevented by early detection and intervention. Right now, we are doing treatment after the fact. But that is not good enough. If we can put someone on the moon, and invent driverless cars, we can prevent cancer. The next generation of oncologists will be preventing cancer, not treating it.”

The Shieldses’ fight against ocular oncology has spread across oceans and continents, and has informed diverse populations and cultures. “A large proportion of people doing this work are fellows we have trained and sent back to homelands on every continent,” reported Jerry with justifiable pride. “Patients all over the world reap the benefits of our work.” Carol added that in addition to the global force of ocular oncology subspecialists they have trained, “We are now developing more granular subsubspecialists in specific tumor types.”

Despite having accomplished those 18 surgeries earlier, Carol reflected on the most meaningful moment of her day. “It arrived by email from John Cropsey, MD, a missionary ophthalmologist in Burundi, Africa, who trained at Wills. The United States and Europe enjoy 98% to 99% survival with retinoblastoma, but in Africa — no. Survival is just 40% to 50%. Kids are dying from a cancer that can be cured in developed nations. John and I have many conversations going about what to do with this child or that child. It is making a difference for Africa.”

Wanting “to make a difference in the world” is, after all, where Carol’s story started. “I have been courageous, even a little fearless, working with retinoblastoma at the height where it is now. It’s the single-most-cured pediatric cancer. That is what I hope to be remembered for,” she said thoughtfully.

Jerry has been the pioneer, the catalyst, Carol added. “The rest of us are just spinoffs, trying to improve on what he established.” In recognition of his contributions, Jerry was recently named the inaugural recipient of the distinguished Brady-Shields Endowed Chair in Ocular Oncology at Wills Eye Hospital.

“We’ve only just begun. There are bigger things to come; in our lifetime, we will prevent retinoblastoma and melanoma,” Carol said.

Pressed to attend another meeting, both doctors rose to say goodbye. Halfway through the doorway, Carol turned and added, “When Jerry and I consider our ultimate accomplishment, it is the fact that we are parents to 7 healthy, wonderful children, most already in medical school. They are, without a doubt, our greatest contribution to the universe.” RP