Marlana Orloff, MD, Associate Professor of Medical Oncology at the Sidney Kimmel Cancer Center of Thomas Jefferson University Hospital in Philadelphia, has created an unusual niche for herself in the world of oncological clinical care and research. She specializes in rare melanoma subtypes—specifically, ocular melanoma.
“I'm not an ophthalmologist,” clarified the born-and-raised suburban Philadelphian. “As a medical oncologist, I don't see the patients when they initially present with vision changes.” But what she does have is access to, and a working relationship with, some of the best minds in ocular melanoma—including pioneering husband-and-wife Wills Eye Hospital clinicians Carol and Jerry Shields, both MDs, and considered by many to be the best-known ophthalmologists in the world. The Shields pioneered new techniques, like radioactive plaque treatments that allow patients with cancer of the eye to keep their eyes. Prior to their work, eyes were simply removed.
“So how this works is, they [the team at Wills Eye, and other ocular oncologists] do the initial diagnosis and then we pick up where they leave off. Because unfortunately, despite their amazing, revolutionizing way of treating a primary tumor in the eye, half the patients will develop metastatic disease,” said Orloff.
Finding Her Path
Married to her high school sweetheart, and mother of four children, Orloff said her career direction seemed to be obvious to others, even at an early point in her education. “In eighth grade I was named ‘Most Likely to Be a Doctor,’” she recalled with a laugh. She began her undergraduate work in pre-med at New York University on the fateful day now known simply as “9/11.” It was so jarring to the freshman that she transferred home to the pre-med program at the University of Sciences in Philadelphia. Later, she went on to graduate from Penn State College of Medicine, Hershey, and then completed a residency at Jefferson, where she has remained.
Orloff originally thought she wanted to do reconstructive plastic surgery, based on high school volunteerism with Operation Smile, which provides surgical medical missions to patients with cleft palates and lips in underserved countries. “I thought I wanted to do that sort of work, and then it turned out that I hated the OR,” she admitted. After considering specializing in infectious diseases, Orloff was eventually drawn into oncology, thanks to it being an area of medicine with opportunities for cutting-edge research and multidisciplinary clinical exposures.
“I loved research, and I loved working with patients and having an engaging continuity with them. Oncology allows for that kind of experience—you're with patients during the highest of highs and the lowest of lows,” she noted, “but ocular oncology wasn't even on my radar screen at that point. I was considering lymphoma, because I had been paired with a great lymphoma doctor during fellowship.” It was at about that time in her career development that immune checkpoint inhibitors for skin melanoma gained FDA approval. “I started hanging out in melanoma clinic because these immunologic agents were so exciting and interesting. And then, one day, I happened to get a consult on a patient at Wills Eye Hospital.”
Not sure how to proceed, Orloff contacted, Takami Sato, PhD, MD, at Jefferson, who, she said, “...has revolutionized medical oncology management of uveal melanoma. He told me to see the case, then tell him about it.” What followed next was a series of research projects under Sato, increased interaction with patients in his clinic, and being offered a position to stay on.
Taking a Leap
It was an intellectual leap for the medical oncologist to enter the world of ocular oncology. “Although ocular melanoma has ‘melanoma’ in its name, it is a distinctly different disease,” informed Orloff. “It is not something you learn about in a fellowship. It's not something that's written about in many books. It was as much of a ‘learn-on-the-job’ situation as there ever could be. But fortunately, with Takami Sato, and the Shields, and another Wills Eye ocular oncologist, Sara Lally, MD, I learned from the best.”
Furthermore, as the field of ocular oncology has grown and matured, particularly in the last 10 years, Orloff has similarly expanded her ability. “I feel like I have grown up alongside some of the leaps and bounds that are being made.”
Now dividing her time between teaching, research, and clinical practice, Orloff noted that many oncologists may only see one case of uveal (ocular) cancer in their entire lifetime.
“There are about 2,500 to 3,000 new cases diagnosed annually in the U.S., and half of them will recur. We see patients who already have gone through primary treatment,” she noted. “We follow them very carefully because we need to pick up any metastasis early. Once patients become metastatic, they are referred to us. We always tell them, ‘Even though this is a rare cancer to the rest of the world, it is not rare to us. It's what we do all day, every day.’ In fact it is what Dr. Sato has been doing for decades.”
Metastatic uveal cancer spreads through the bloodstream, “...and where the tumor starts in the eye is a blood-rich area,” said Orloff of the disease. “However, we do not fully understand why it seems to spread to the liver first. It goes to the liver in 90+ percent of the cases. And liver failure due to metastasis is the cause of death in 90+ percent of the cases as well.”
Metastatic uveal melanoma behaves very differently than metastatic skin melanoma. “The reason they are both called ‘melanoma’ is the cell of origin; under the microscope they look similar,” explained Orloff. “But the mutations that drive uveal melanoma are very different from skin cancer.
“Skin cancer is notorious for first traveling in the lymph nodes. Uveal melanoma does not. It's more of a hematogenous spread. It differs in its immune makeup. A patient's prognosis, after uveal melanoma spreads to the liver, is not great. Median survival is less than 2 years. But at Jefferson, we try to pick up patients very early in metastasis, and we can offer them 2 years and often more, thanks to the treatment options we can offer.”
Orloff said, at the time of this writing, there are no drugs approved by the FDA specifically for uveal melanoma. “However, we borrow treatments from skin melanoma, or develop other treatments unique to uveal melanoma, and because the metastasis goes to the liver first, we do a lot of liver-directed therapy.” Noting she works very closely with a group of interventional radiologists who perform the liver-directed procedures, Orloff said, “David Eschelman, MD, Carin Gonsalves, MD, and Robert Adamo, MD, have dedicated much of their careers to taking care of metastatic uveal melanoma patients.”
Though clinical trials in rare cancers are typically hard to come by, there are actually several new clinical trials in uveal melanoma currently. “That really is where and how we are going to find therapies to prolong life for these patients, and hopefully one day a cure,” Orloff predicted.
Registering patients into those trials can be tricky. With half of uveal melanoma cases developing metastatic disease, there are usually no more than 1,500 such individuals identified in a given year.
“With Jefferson being a referral center, we see patients from all 50 states. When we have therapies that require monthly or even weekly treatments, patients may fly in weekly from California, or Texas, or wherever,” said Orloff. “It's logistically challenging. However, if they are in a clinical trial, often there are ways to get them support for travel and lodging. We also have an amazing nurse navigator, Renee Zalinsky, RN, and a team of nurses, nurse practitioners, and physician assistants who operate like travel agents making arrangements for the patients, coordinating their cancer care with flights and hotels.”
Orloff is currently involved in research efforts of note. “First, I am interested in better understanding the epidemiology of this disease,” she explained. “Even though it is called melanoma, it is not caused by the sun. We do not see that UV footprint that we see in skin melanoma. We do not know what causes it. Even though we can treat a lot of the cancer, it would be so much better if we could prevent it.”
For a long time, uveal melanoma was thought of as “something that just happens,” commented Orloff. “However, in the last 6 or 7 years, we have started to uncover small subsets or accumulations of patients with eye melanoma who lived or worked or went to school in the same location. For a cancer that is so rare, we normally would not expect a group of cases happening in the same town.
“Further, the median age of onset is allegedly around 60 years of age. But we became aware of a group of high school girls who were all diagnosed with eye melanoma who lived in Huntersville N.C. And a group of young women who graduated from Auburn University in Alabama. We've also identified a group who live along the Susquehanna River in New York.”
Orloff and team published a paper detailing their initial work in this space (Am J Ophthalmol 2020; doi: 10.1016/j.ajo.2020.07.012). Though there have not been any definitive conclusions from the investigations of the accumulations, there has now been acknowledgement that rare cancers are often under-reported in cancer registries. As a result of this realization there has been huge push for better registries in uveal melanoma.
“There is now a parallel registry effort. There is a patient registry, created through CURE Ocular Melanoma, into which patients worldwide can enter information about their eye cancer. This registry will help us understand some of the epidemiology—lifestyle, environment, etc.—and how that contributes to, or is affected by, the diagnosis,” detailed Orloff. “The patient registry also links to a parallel academic registry where a treating physician can enter information pertaining to that patient's disease. We hope this registry will help advance more of the scientific questions.”
Another of Orloff's primary interests is in the management of the disease. “Whether it is in the adjuvant setting, after patients are diagnosed with a high risk of tumor in their eye, or after the disease metastasizes,” said Orloff. “A lot of this work is ongoing in clinical trials trying to investigate novel therapies and approaches—both systemic therapies and liver targeted treatments.”
One promising drug, tebentafusp, is furthest along in clinical development. It was first tested in all melanomas, including skin and eye. Unexpectedly, there were some responses in the eye melanoma patients which triggered a series of uveal melanoma trials. Tebentafusp has now been the first systemic therapy to prolong survival in uveal melanoma when compared to other available therapies in a randomized study. Approval of this drug and its use in the clinic will certainly be practice-changing. This is a very hopeful time for uveal melanoma.
Indeed, Orloff looks to the future of ocular melanoma with a sense of cautious optimism. “I do think we've turned a corner,” she said, earnestly. “I think there are some therapies still in clinical trials that are showing real promise. I think our understanding of the disease has come a long way, so we're being smart in the drugs we are investigating.”
The “big take-away,” said Orloff, for oncologists who do not treat ocular cancer is “...to understand that uveal melanoma is a very rare subtype of melanoma that is distinctly different from skin melanoma, and patients must be treated as such. Patients should be referred to clinical trials whenever possible, and to centers that specifically deal with ocular cancer, because if they get the right treatment they can have very a meaningful survival.”
Valerie Neff Newitt is a contributing writer.