Brain Tumors

From the Physician’s Desk 
. . .an Interview with Dr. Mark Kieran

As the director of the pediatric brain tumor program at Dana-Farber Boston Children’s Cancer and Blood Disorders Center, Dr. Mark Kieran leads a program dedicated to clinical care, survivorship and the development of clinical trials. As a physician investigator, he divides his time each day between the research lab and seeing children in the clinic. He combines his experiences and knowledge to explore novel therapies to treat pediatric brain tumors.

How do clinical trials for brain tumors differ for children from adults?

Our approach is somewhat different. Treating children with brain tumors is not simply treating cancer in small adults. Children don’t have the same mutations that cause adult brain tumors, and they don’t respond the same way as adults. Part of that may be due to the fact they haven’t had as many years to develop certain eating, drinking or social habits that affect one’s health. We also have to worry about the use of chemotherapy and radiation, agents that kill dividing cells, in pediatric patients since many of their normal cells are also dividing as part of their growth and development.

What type of research is currently underway to treat pediatric brain tumors?

Cancer isn’t just one disease. It’s thousands of diseases, which makes treating cancer infinitely more complex than we ever thought. We are trying to understand the more than 300 types of pediatric brain tumors out there. We do that by identifying the gene abnormalities, or mutations, that cause cells to lose control. The next step is to develop drugs that target those mutations. Typically, drugs are first tested in adults to determine the optimal dose and schedule, and then tested for activity. If the results start to look promising, then the process is repeated in children (since the dose may be different). During the clinical trial, we learn if the drug is tolerable in patients and whether the target (the specific mutation the drug was made to attack) works. Unfortunately, many tumors have a built-in knowledge of how to get around the drug, similar to many bacteria that are naturally resistant to an antibiotic. If the drug doesn’t work, perhaps it needs to be combined with another one in order to overcome the resistance.

Doctors treating pediatric brain tumors realize cure is not an “all or none” phenomenon. It isn’t just about surviving. We are very cognizant of the quality of cure, which means we take into consideration the survivorship aspect — the child’s functional ability after having a brain tumor — and modifying or developing treatments to accommodate that. Certain types of treatment, such as chemotherapy and radiation therapy, kill cancer cells, but they also kill healthy cells. The result is that the child can lose neurological or cognitive functionality. We are investigating more efficient, less toxic, therapies that target the mutations that cause brain tumors without harming other parts of the brain.

What are your thoughts on current research for adult brain tumors?

The approach described previously for pediatric brain tumors is not significantly different for adults. We strive to understand the underlying causes of the patient’s cancer and then develop more specific agents that target those specific abnormalities. The issue is that most of the mutations in adults and children differ, not the approach. The one special issue is that for young children, where major cognitive function is still developing, we have to be careful not to severely damage this function. This is especially important for radiation therapy to the developing brain.

Is it possible to regain functional ability that is lost after brain tumor treatment?

The ability to recover from the damage caused by a brain tumor and its treatment depends on a number of factors. Some neurologic damage is permanent in both adults and children. Because children are still developing, their brains tend to be more pliable than those of adults; thus, other parts of the brain can be trained to learn functions that they would not normally carry out. In both age groups, it is possible to develop a workaround, or retrain the brain. For example, when a healthy brain tries to solve a problem, it uses certain pathways. It knows that it must go from A through a specific pathway to B, where it can solve the problem. However, if the pathway to B is damaged as a result of the tumor or therapy, we can sometimes teach patients how to go from A to C and then from C to B to arrive at the correct answer.

What guidance do you provide about making the decision to enroll in a clinical trial?

There was a time when doctors made all the treatment decisions, including whether to enroll a child in a clinical trial, and the child’s parents went along with it. Today, whether we are talking about parents and their children or adults advocating for other adult members of the family, we know how important it is for families to be a part of the decision. There are cultural, religious and social issues to consider. For experimental therapies that are unproven and have potential toxicities, patients and families must weigh the risks with the potential benefits. To help people make the difficult decision, it is our responsibility to educate them. We need to ensure they understand that clinical trials are experimental, that they come with potential benefits but also potential risks.

Even with all of this information, every situation is unique. You could have two sets of family members whose loved ones have the same diagnosis and prognosis, and you may get two completely different decisions. There is no right or wrong decision. Ultimately, the decision they make at the time that feels right to them is going to be the right one, and we will support it.

What progress have you seen in the treatment of pediatric brain tumors, and what do you expect for the future?

The most common pediatric brain tumors are low-grade gliomas. We’ve been able to determine the mutations that cause the majority of these tumors, and we now have multiple clinical trials using precision medicines that attack those mutations. The cure rate for many of these tumors now approaches 95 percent. That is a great number, unless you happen to be part of the other five percent. We still have a lot to learn, but we are in this for the long haul and as our knowledge of the tumors increases, so does our ability to make the size of the tumors decrease.

Because there are so many types of brain tumors, we haven’t learned everything about every tumor, but we are working diligently. In the 20 or so years that I’ve concentrated on pediatric brain tumor research, we’ve seen many advances. For many years, we didn’t make much progress with diffuse intrinsic pontine gliomas (DIPG). The most malignant of the pediatric brain tumors, DIPGs were typically diagnosed by just a clinical exam and MRI — no biopsy — which meant we knew nothing about the tumor itself. In the past five years, we’ve developed the capability to biopsy a critical part of the brain without doing damage. With a biopsy sample that is about the thickness of a strand of hair, we’re able to sequence the entire tumor’s genome, thereby discovering the mutations that caused the tumor. Finding therapies that treat those mutations is now ongoing. With those new treatments, I believe we are on the cusp of changing what has been the worst outcome in all of pediatric oncology.

It’s an exciting time in cancer research for both children and adults with brain tumors. I feel confident that the advances made in my generation are just the beginning. I envy the next generation of oncologists because they will be the ones who will have the tools to truly understand the biology of tumors, what causes them and the combinations of therapies that can stop them.

 

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