Breaking the Blood-Brain Barrier

AS THE CALENDAR turned to September 2014, Leslie Falduto was feeling at the top of her game. The cancer survivor was running six miles, three days a week. Her oncologist had recently told her she was doing great. And at work, Falduto, a registered nurse, was returning to her favorite post, the neonatal intensive care unit.

Talking about her diagnosis of stage III breast cancer in September 2008 still made her feel anxious. But in the world of cancer, five-year survival is one of those measures that is supposed to make you think, OK, maybe now I can pop the champagne. And Falduto, a mother of two from St. Paul, Texas, had passed that marker the year before.

But on Sept. 7, when she went to leave the neonatal unit, an odd thing happened. “I couldn’t remember how to open a door,” recalls Falduto, 38. After that, “I couldn’t remember how to walk.” Her right leg started shaking uncontrollably. Then, she passed out. When she awoke, Falduto was in the emergency room, where she was told she’d had a seizure. A neurosurgeon requested an MRI. The scan revealed a tumor the size of a pingpong ball—metastasized breast cancer—deep in her brain.

Learning that cancer has metastasized, or spread, means coming face-to-face with the reality of an incurable illness. Learning that the cancer has spread to the brain—the place, in essence, that makes each of us who we are—can be even more unsettling.

“I think there are levels of ​metastasis, and the brain is the one that everyone really fears the most,” says CJ Corneliussen-James, a co-founder of METAvivor, an Annapolis, Maryland–based organization focused on research and support for patients with metastatic breast cancer.

“When you think about brain metastases, you are thinking in terms of: Now my clock is really ticking,” says Corneliussen-James, who was diagnosed in 2006 with metastatic breast cancer that had spread to her lung. “And you are [also] concerned that you will lose the ability to function or think.” For people living with metastatic disease “who have been around people with brain metastases, that is less of a fear. But for [metastatic patients] who have not had any interaction with someone with brain metastases, there is much more fear about what will happen and how they will cope.”

Forging Their Way

Brain metastases are the most common form of brain tumor in adults. No precise statistics are available, but according to the American Brain Tumor Association, between 100,000 and 170,000 cancer patients in the U.S. learn their cancer has spread to the brain each year. A patient’s risk of developing brain metastases depends primarily upon where the cancer started. Lung cancer is the most common source of brain metastases in men and women, followed by breast cancer in women and melanoma in men, and colorectal cancer in both men and women. Overall, though, melanoma is more prone than other cancers to spread to the brain.

Cancer cells can spread to the brain by traveling through the bloodstream, but they must cross a major obstacle: the blood-brain barrier. The blood vessels that make up the barrier are lined with endothelial cells and act like a strainer: They let in small molecules like the hormones and nutrients the brain needs while keeping out larger toxins and bacteria.

Because of the blood-brain barrier, most cancer cells that try to cross to the brain don’t make it, which is one reason that brain metastases aren’t as common as, say, bone metastases. But some cancer cells do get through the barrier. Once a cancer cell gets into the brain, it typically latches onto the wall of a blood vessel, which it can use to fuel its growth.

During the past five years, oncologists have reported seeing an uptick in cancer patients with brain metastases—and it’s not clear why. “One theory is that new treatments are better at controlling disease outside of the brain,” says DeeDee K. Smart, a radiation oncologist at the Center for Cancer Research at the National Cancer Institute in Bethesda, Maryland. This is allowing people to live longer, which could be giving more time for brain metastases to develop. “The other theory,” she says, is that as people are living longer, they “are now going through more chemotherapy regimens,” which may lead cancer cells to develop new types of mutations that change how, when and where they spread. This is because chemotherapy drugs typically used to reduce or eliminate metastases in other organs are made of molecules that are usually too large to get through the blood-brain barrier. “The brain becomes a sanctuary site for cancer cells, a place they’re hiding out,” says Smart.

Researchers had hoped that some new smaller-molecule therapies would be able to squeeze through, and their hunch proved correct when studies showed that BRAF inhibitors and checkpoint inhibitors—systemic therapies being studied in patients with melanoma—not only extended survival but reduced the size of brain metastases.

“Now not only do we have drugs that work in melanoma,” says Jeffrey Weber, an oncologist who directs the Donald A. Adam Comprehensive Melanoma Center at the Moffitt Cancer Center in Tampa, Florida, “but they work in the central nervous system—in brain metastases [caused by melanoma]—and that is revolutionary.” And they may do the same for brain metastases caused by other cancers, too.

Treatment Mainstays

For most patients with brain metastases, treatment will typically involve surgery or radiation or both. The side effects patients experience mainly depend on which treatment they receive, how it is delivered, and what part of the brain is affected.

For decades, whole-brain radiation therapy has been the primary treatment for patients with multiple brain metastases, because it can both extend progression-free survival and reduce symptoms such as paralysis and pain caused when tumors press the brain against its skull. But whole-brain radiation, which is typically given daily for two to three weeks, can also diminish a patient’s short- and long-term memory, problem-solving skills, attention span, word recall and other cognitive abilities—decreasing quality of life.

For some patients with one to three small brain metastases, stereotactic radiosurgery, which targets the tumor with narrow high-dose beams of radiation, may be an option. (The radiation technique is called radiosurgery, but it is not a form of surgery.) Because the narrow beam avoids healthy tissue, stereotactic radiosurgery reduces the risk of side effects. But studies have found that patients who receive this type of radiation are more likely than those who receive whole-brain radiation to see their brain metastases return.

Radiation oncologists have explored whether whole-brain radiation therapy should be used along with stereotactic radiosurgery in patients with one to three small tumors. But a phase III trial presented at the 2015 American Society of Clinical Oncology Annual Meeting indicated that the combination was not beneficial. The trial, which enrolled more than 200 patients at 34 cancer centers between 2002 and 2013, found that patients who received both treatments did have a reduced risk of their brain metastases returning or growing, but they had more cognitive problems and did not live longer.

Challenging Side Effects

Median survival following treatment for brain metastases has gradually increased to about 11 months today from three to six months just a decade or two ago. (In other words, half of all patients now live more than 11 months, while half live less than 11 months.) Some patients are now living for two years or even longer. As life expectancy lengthens, identifying the patients who have the greatest likelihood of developing side effects is increasingly important.

“What we want,” says Smart, “is to be able to say to a patient, ‘You have this percent of risk of having this amount of [cognitive] decline at this point after radiation that will last for this amount of time, or that you are [in] the 1 percent who will get dementia from aggressive treatment.’ But we don’t have good predictive monitoring tools.”

It is not uncommon for fears about these side effects to lead patients and caregivers to question the benefits of radiation. But the alternative isn’t any better, says Smart. “We know by far the worst thing is to have uncontrolled tumor growth,” she says. “So whenever we talk about toxicity of treatment, the biggest thing we need to keep in perspective is the toxicity of undertreating the brain metastases.”

If brain metastases are left untreated, she says, patients—especially those with more than three brain metastases—are unlikely to live more than a month after diagnosis and will typically require high doses of medication to manage pain from brain swelling and seizures. So Smart tries to offer patients and their families some reassurance about the side effects associated with treatment. For most patients, “what we see in terms of potential side effects are things like immediate recall, those ‘Where did I put those keys?’ moments. … And in most patients, these are transient effects that occur in the first few months, and in the majority of people they improve.”

For Colleen Duffey, “Where did I put that?” moments are now routine: In February 2014, two years after an initial diagnosis of metastatic breast cancer that had spread to her liver, throbbing head pain sent Duffey to the emergency room. The doctors there contacted her oncologist, who requested a CT scan. The cancer had spread to her brain.

“That was the scariest it had ever been,” Duffey, now 35, recalls. The scan showed multiple metastatic sites, and she was treated with whole-brain radiation. “It was exhausting mentally and physically,” she says. “I lost my hair completely. And because of the swelling in my brain, I had to be on steroids, which caused me to gain a lot of weight.”

The treatment’s side effects became most evident when Duffey, who has a degree in mechanical engineering, returned to her position as a systems engineer at Lockheed Martin. “Doing the work that I do, you have to be on your game, and I just was not remembering things,” she says. “And it was harder for me to learn new things because I couldn’t retain the information as well as I used to. … I worked extra hard to keep up and I always passed my evaluations, but for me it was just too much.”

Five months after she returned to work, Duffey resigned. It was a decision that deeply affected her sense of self. “I’m an engineer and I’ve always been known for my intelligence,” she says. “That’s always been such a large part of my personality, and to see myself losing that was hard. … I have a lot of short-term memory loss. And I also often can’t remember the word I want. Or I’ll decide to make something like chicken pot pie and then, when I get to the store to buy the ingredients, have no idea what I had decided to make. So, I’ve learned a lot of tricks and will write everything down. Otherwise I know I’ll just forget it.”

For her part, Falduto, who now works for a health insurance company, began to grasp the extent of the side effects she was facing when she met with a physical therapist a few days after her neurosurgeon removed the 1.5-inch tumor that had caused her seizure in the neonatal intensive care unit. A former ballet dancer, Falduto says she didn’t think much of it when “the physical therapist told me to stand by the wall and lift up my left leg.” But when she tried, she says, “I fell over.”

To remove the metastasis, Falduto’s surgeon had to take a route to the tumor that affected her proprioception—the way the brain senses body position and movement. As a result, Falduto’s recovery required extensive relearning of activities and motions that had been second nature. “When I went for a walk,” she says, “I’d have to think ‘Right leg. Right leg. Right leg.’ I had to relearn how to scramble eggs and I had to teach myself how to write again. My thoughts would stop midsentence. I would say something like, ‘Thank you for … ’ and then just stop.”

While she was recovering from the surgery, Falduto also received three treatments of stereotactic radiosurgery, which she knew could cause additional side effects.

But by working steadily with the physical therapist, she continued to improve, learning how to walk around objects, gauge how deep a step was, and stop running into walls. She also did a lot on her own. “I’d force myself to bake a cake to practice learning how to read and process the steps needed to make it,” she says. She also spent hours practicing her penmanship in one of the cursive writing books her 8-year-old son brought home from school.

Feelings of frustration were common. “I went from playing tennis and running to not being able to walk across my living room floor without being terrified of tripping over something.” Even now, Falduto says, “there are still some glitches.” For example, she’ll find herself making errors when writing checks, or she’ll trip over her sons’ toys. But, she says, when that happens, “I’ll say, ‘There goes the proprioception.’ ”

On the medical front, Falduto, whose medications currently include Herceptin (trastuzumab), Perjeta (pertuzumab) and Zometa (zoledronic acid), sees her oncologist every six weeks and her neurosurgeon every six months, and she has a one-year follow-up with the radiation oncologist on the books. She gets MRIs of her brain every three months and a PET scan of her spine and lung, where metastases were also found but are now stable, every six months. She also started running again and recently participated in a mini–boot camp. “I’m getting back to my old self,” says Falduto. “I’m starting to look forward to the future.”

Duffey is receiving Kadcyla (ado-trastuzumab emtansine) and adhering to a similar schedule of appointments and scans while enjoying her time as a stay-at-home mom. Like Falduto, she has begun to exercise again, doing Pilates and weight training a couple of times a week. Most important, she says, “The last time I saw my neurosurgeon he told me my brain looks great.”

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