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August 09, 2017

Hope Comes in Many Forms for Patients With Cancer

For many with glioblastoma, there’s no clear path after standard therapy, but scientists are exploring an array of new options.
BY Tara Haelle
PUBLISHED July 21, 2017
It is frustrating not
having more tools
to try to attack
and make sure
it doesn’t come
back, and I think
that’s what the
doctors feel, too
— there’s a limited
number of tools
they can use.” <br>
— MICHAEL YUTKIN,
patient
It is frustrating not having more tools to try to attack and make sure it doesn’t come back, and I think that’s what the doctors feel, too — there’s a limited number of tools they can use.”
— MICHAEL YUTKIN, patient
PHOTO BY MARIESAM SANCHEZ 
Some people first learn they have brain cancer after they have suffered a violent seizure or nearly stopped breathing. Sen. John McCain learned about his tumor after telling his doctor at a routine check up that he’d been tired and seeing double. That led to the discovery of a mass that doctors thought was a blood clot but turned out to be glioblastoma, a malignant, fast-growing cancer that arises from stem or stem-like cells in the brain. McCain was diagnosed July 14 with the cancer, which can affect thinking, emotions, personality and even the body’s ability to perform basic functions.

In 2017, about 24,000 people will learn they have brain cancer, the National Cancer Institute estimates.

Michael Yutkin probably didn’t think “brain cancer” when he was on a business trip in Chicago in August 2012 and woke up with “the worst headache of my life.” Nevertheless, it turned into the worst health challenge of his life.

He went to the emergency department, and a scan found a bleed on his brain with a mass behind it. A few days after his wife and two young children flew in from his home in Irvine, California, a craniotomy and a biopsy led to a diagnosis of glioblastoma, a grade 4 glioma, in his right occipital lobe.

Yutkin, now 44, enrolled in a clinical trial at UCLA testing the effectiveness of Velcade (bortezomib) — a targeted drug already approved for multiple myeloma — while receiving the standard of care: surgery to remove as much of the tumor as possible, followed by radiation and chemotherapy with Temodar (temozolomide).

McCain, too, is considering standard-of-care treatment with radiation and chemotherapy.

Yutkin took both Temodar and Velcade over the next two years and responded well to treatment. Things seemed to be going well for him, but six months after he stopped taking Temodar, a drop in his platelets forced him to also stop taking Velcade. Almost a year later, his cancer progressed. More radiation and Temodar brought it under control, and Yutkin’s MRI scans looked stable from December 2016 through this June, when tumor enhancement was seen.

Yutkin has no new symptoms, and he and his doctors are waiting for one of two vaccine/immunotherapy trials to open. In the meantime, with so few effective therapeutic options for glioblastoma in general, Yutkin exists in a sort of limbo.

“Right now, I’m not on chemo or anything, but that’s one of the most frustrating things,” he says. “I want to be fighting this as much as possible to make sure it doesn’t come back, and until or if there’s ever a recurrence, there’s really nothing for me to be on.” 

He recently began a ketogenic, or low-carb, diet through UCLA to feel like he was doing something potentially beneficial, and he has followed a supplements program put together by Nutritional Solutions, in Utah. He also believes that daily exercise has helped him in his battle. Beyond those efforts, Yutkin simply stays focused on his family and tries not to think too much about the disease — there’s not much else he can do. 
 
Among the treatments ROBERT MITCHELL is using for his glioblastoma is Optune, which applies tumor-treating fields directly to the head. - PHOTO BY AMELIA BEAMISH
Among the treatments ROBERT MITCHELL is using for his glioblastoma is Optune, which applies tumor-treating fields directly to the head. - PHOTO BY AMELIA BEAMISH
“It is frustrating not having more tools to try to attack and make sure it doesn’t come back, and I think that’s what the doctors feel, too — there’s a limited number of tools they can use,” he says. 

Indeed, despite big strides in therapies for many other cancers, advances for glioblastoma have not kept up. The long-term prognosis is typically bleak, with five-year survival rates below 10 percent. The standard of care has evolved only marginally in recent decades. Radiation quadruples survival from three months to 12 months, and Temodar adds a few more months, which improved median survival from 12 months to nearly 15 months when it came out.

Patients also often take Avastin (bevacizumab), a drug that interferes with the growth of blood vessels that feed tumors. This reduces swelling and lengthens time to tumor progression. While the drug doesn’t add to overall survival in this population across the board, it has been associated with better longevity in certain subgroups. 

“In three decades, after hundreds and hundreds of clinical trials and untold millions of dollars of both government and private-sector research dollars, we made an advance of three to five months of median survival,” says Howard Fine, M.D., the founding director of the Brain Tumor Center at Weill Cornell Medical Center in New York City. 

Meanwhile, “We’ve seen the prognosis shift dramatically in other cancers in a very short period of time,” says Andrew Chi, M.D., Ph.D., director of neuro-oncology at NYU Langone’s Perlmutter Cancer Center and co-director of Langone’s Brain Tumor Center. “With the amount of discovery that we’re doing today, (that progress) is really going at an exponential rate.” 

But the lag in progress in treating glioblastoma is certainly not for lack of trying — and researchers have only redoubled their efforts to find new therapeutic options. Few cancers have as many diverse experimental therapies in clinical trials as glioblastoma. 

THE TRICKIEST TUMORS 

The challenges associated with glioblastoma start with its name. 

“A term like glioblastoma is actually very nonspecific and nonaccurate,” Chi says. “It’s made up of different diseases, and if you look at them from a genetic perspective, some have a relatively good prognosis and others have a very poor prognosis from the outset.” 

More than 2,000 to 3,000 glioblastoma tumors have been sequenced by the research community to date and "almost none of them are totally alike,” Fine says. He expects the terminology to change over the next decade, with clinicians referring to these tumors, and basing their treatments, more on their genetic classifications than on older pathological terminology such as "astrocytomas" or "oligodendrogliomas." 

This extreme heterogeneity means that glioblastoma genetics vary greatly from person to person, and even within an individual. A drug that only kills 99 percent of the tumor likely won’t work in the long term, making it hard to find a drug that kills even one person’s tumor, Chi says. 

The disease’s presence in the brain presents the biggest obstacle. “The brain is the size of two fists,” explains Rimas Lukas, M.D., associate co-chief of the Neuro-Oncology Division at Northwestern University. “That’s not a gargantuan organ, so a tumor doesn’t have to be very big to take up a lot of real estate.” 

And, like real estate, different parts of the brain are more valuable than others when it comes to daily functioning. In another area that would be neurologically devastating.”  Even then, tumor size is deceptive: Glioblastoma tumors are so widely invasive that what shows up on a patient’s first MRI does not accurately represent how far cancer cells have already traveled or how integrated into healthy brain tissue they may be, limiting surgery’s effectiveness. 

“You can do wide resections in other organs, such as the lungs, colon or breast, and take out large parts if it’s invasive,” Chi says, but “you can’t take out half the person’s brain and have them be a normal person.” 

Even before surgery, glioblastoma interferes with normal brain functioning, and can therefore cause a disproportionately large amount of disability relative to other cancers. 

“A small growth in the brain can lead to such significant neurological dysfunction, whether it’s cognitive and thinking, motor, personality or memory, that it really impacts the ability to function in basic activities, quality of life and even the ability to tolerate treatment,” Chi says.  

Finally, a unique feature of the brain can actually give glioblastoma an edge. The blood-brain barrier, a protective membrane which filters out many of the compounds that might reach other organs, is intended to protect the brain, but it can partially protect the tumor, as well. 

“It prevents most drugs from even getting into the brain,” Fine says. “Even if you have the magic bullet, if you can’t get the bullet to the bad guy, it doesn’t do you any good.” 

GENOTYPES MATTER 

Despite the genetic diversity within glioblastoma, subtypes exist in which a specific gene or set of genes are expressed throughout all tumor cells, essentially defining that tumor’s behavior, Chi says. 

“That’s a critical point, because if you’re going to develop a drug, you want to make sure every tumor cell has it,” Chi says. He estimates that 95 percent of tumors fall within a clear genetic subtype, although though some controversy exists over how many types there are. One widely accepted number is five. 

“If you factor in the genetic subtype, that predicts survival much, much more strongly than any drugs we’ve ever used,” Chi says, but it also presents an additional challenge in conducting clinical trials with such a diverse cancer. “We don’t want to get tricked into thinking our drugs work when it’s really just a better-behaving tumor, a tumor that has a better natural history or perhaps better responsiveness.” 

Yutkin, who responded well to Temodar because his MGMT gene is muzzled by a process known as promoter methylation, is one example. Those with an IDH-1 mutation also have a better prognosis, which improves even further in a subset of IDH-1-mutated tumors with 1P19Q co-deletion. 

“People with tumors that have (MGMT or IDH-1) mutations do extremely well in general, even with minimal or even no therapy,” Chi says. But only about 9 to 12 percent of glioblastomas have the IDH-1 mutation, and many of these likely grew from a lower-grade glioma, calling into question their status as glioblastoma. 

COMBINING FORCES 

Scientists are exploring a vast array of treatments, some already approved in other cancers and others experimental. 

Combining these therapies is an obvious approach, as 24-year-old Robert Mitchell, living in Syracuse, New York, is doing. Mitchell’s diagnosis came on Aug. 24, 2016, after he was hospitalized because his entire left side went numb. After a surgical resection removed what was possible, Mitchell had a “wafer” placed at the cancer site, which slowly leaks out chemotherapy; he also began radiation treatments and is currently taking Temodar. But in addition, he’s wearing the novel tumor-treating field therapy Optune on his head 18 hours a day, as recommended. Although it could get a bit hot and uncomfortable in the beginning, Mitchell said he barely notices it anymore. 

“It’s just like batteries on your head. You can’t really feel anything,” Mitchell says. He opted not to know much about his tumor, or how much time he may have left, and relies on prayer and hope. “The doctor just told me to go out and enjoy your life, and that’s what I’m trying to do,” he says. “I feel real hopeful about this Optune. I feel like it’s going to work.” 

On the other side of that coin is Meg Turecek, an American living with glioblastoma in the Netherlands. Like Yutkin, she has turned to natural supplements after her Temodar course was cut short at four weeks because of declining platelets. Her diagnosis had followed a major seizure in her sleep on Christmas Eve 2015. She opted for immediate surgery to remove as much of the 9-millimeter tumor as possible and then underwent a six-week course of radiation. She gets quarterly MRIs, the last of which showed tumor shrinkage, but she’s technically on palliative care. 

“It’s not a fun experience for doctors to say there is nothing else they can do,” Turecek says. “My doctors do not offer a prognosis and I don't ask for one. This disease is extremely difficult to predict, even with advanced testing.” She looked into clinical trials, but none were in the Netherlands, and trans-Atlantic flights carried their own risks. Because she had already received the standard treatment, she also didn’t want to risk getting a placebo, which she considers a cruel option in trials for terminal cancer. She turned to alternative medicine “because medical science has nothing for me at the moment.” 

Lukas and Chi advocate for patients joining clinical trials as early as possible — and “most are going to augment the standard of care in some way,” Lukas assures — but they aren’t for everyone. Fine described two types of patients when it comes to considering clinical trials: those who believe that participating would make them feel like human guinea pigs if the trial’s treatment wasn’t definitely better than standard care, and those “who want to go for something new and different because at least there’s promise in the unknown.”

For the latter group, it’s up to oncologists to find the right trials. Despite the huge number of trials, options can be scarce due to eligibility criteria, limited available slots, the stops and starts that can occur for regulatory reasons, and geographical limitations such as Turecek’s. Fine says most drugs and treatments are pretty well tolerated when it comes to side effects, but on the flip side, most don’t work very well, either — at least so far. 

Chi remains confident that that will change. 

“I don’t think that patients should give up hope,” Chi says. “If I didn’t believe that, I wouldn’t be doing what I’m doing today.” 
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