An interview with Dr. Jorg Dietrich of Massachusetts General Hospital
The title of the article is a mouthful: “Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy.” It made its debut online on Nov. 19, 2008, in the online version of the journal “The Oncologist.” (Many of the most tradition-bound peer-reviewed medical journals now publish shorter, “express” versions of their articles online first. Abstracts – a short summary of the main points – are often available free on PubMed)
But the article, by Dr. Jorg Dietrich at Massachusetts General Hospital in Boston, and colleagues at Stanford University and at the MD Anderson Cancer Center in Houston, contains a thought-provoking theory about what might be causing some symptoms of chemobrain (Dr. Dietrich, a physician who also has a PhD, is a clinical fellow in neuro-oncology at the Stephen E. and Catherine Pappas Center for Neuro-Oncology at Massachusetts General in downtown Boston.)
Let’s be clear: the researchers never actually use the term chemobrain. By most accounts, that is too colloquial and imprecise for scientists. And it is not entirely descriptive, either, because Dr. Dietrich and his team found that people treated with radiation also had problems with memory and thinking. They use terms like neuro-cognitive deficits and cognitive dysfunctions. But the symptoms they are talking about are unmistakably chemobrain: Forgetfulness, difficulty concentrating, trouble staying organized. An overall feeling of “spacing out.” (And, yes, the researchers did use that highly non-technical term!)
The researchers found that adults reported cognitive symptoms soon after they started chemo. “Frequently,” Dr. Dietrich and his colleagues wrote, “these symptoms persist after completion of therapy and are a cause of considerable distress for individuals who are unable to return to their previous academic, occupational, or social activities, or are able to do so only with significant additional mental effort.” These symptoms, they note, can persist, or even emerge later.
So what might be causing this? Tests in the lab and reviews of brain scans found damage to regions in the brain where newborn cells are developing. This view of the brain is relatively new, according to researchers. “We have learned in the past decade that, contrary to our initial belief, the brain has the potential to repair itself.”
But inflammation caused by radiation, and the toxic drugs used in chemotherapy, can strangle these newborn cells in the crib, essentially.
The image I am using here – strangling a newborn – is a bit crude and perhaps sensational, intended to signal the importance of this process of re-creation that is needed to maintain the brain’s structure. Dr. Dietrich, in an interview, uses a more elegant metaphor: a fertile field where crops can thrive. “If you essentially cut off the water source for a cornfield, you will not be able to grow anything in the years to come,” he says from his office at Mass. General. “This is essentially what happens. If you stop the production of newborn cells, you will have to deal with the consequences years down the road. Because you wipe out an essential proliferating pool of cells that is needed. Some are the stem cells to just rebuild what is lost. If you don’t have these tools available, then essentially no more repair mechanisms can take place.
“A simple way to put it is an early aging process that has been triggered. Because that is exactly what happens during aging, you lose some of these potentials to repair, and with these kinds of treatments you actually let the organism prematurely age.”
Here, in Q&A format, is more of my interview with Dr. Dietrich. (And, as an aside, he is an articulate man who seems passionately committed to listening to his patients, and to speaking with them honestly about their illness, the treatments available, and what to expect.)
Q. You found that both chemotherapy and radiation affect these newborn cells, which you call neural progenitor cells, in the brain. What is damaging the cells? And do chemotherapy and radiation cause different sorts of problems?
A. The radiation [studies] are a little older, and I think they have paved the way for allowing the chemotherapy studies on the toxicity on the human brain. The mechanisms of how radiation affects the human brain are somewhat different than toxicity from chemotherapy. We know that patients who are exposed to radiation treatment show signs of inflammation. And inflammation itself in the brain may cause a whole cascade of negative side effects.
One of the most important side effects that we see, in terms of symptoms, is cognitive impairment that may propagate even years after radiation treatment has been finished. Radiation may impact the rejuvenation of brain cells and mainly has negative effects on the newborn neurons. We have learned in the past decade that the brain is actually able to repair itself to some degree, contrary to what was originally thought.
This alone was a revolutionary finding — to see that there are certain areas in the brain called germinal zones that are on a daily basis engaged in providing a source for newborn cells of all lineages. These newborn cells become neurons, which are key for the neuronal network. They also become the support cells, called astrocytes and oligodendrocytes. They are suffering, and may not allow the neurons even to work properly.
Q. So for people who get radiation therapy, it is inflammation that causes serious problems?
A. Inflammation is one of the consequences of radiation to the brain. And it is probably one of the key reasons why cells in the germinal zones of the brain stop dividing and why the generation of new neurons is impaired.
Q. And that can affect memory?
A. Yes. One of the target areas that suffers most under radiation treatment is the hippocampus formation, which is critically important for storing and retrieval of memory.
Q. How is chemotherapy different?
A. With chemotherapy, it looks like some of the mechanisms are very different because inflammation may not play an important role at all.
Unlike with radiation, chemotherapy appears to compromise the generation of newborn neurons and glia cells throughout the brain, although these effects are most notably in the germinal zones and so called white matter tracts – bundles of cells and fiber tracts that connect different areas of the brain. In this regard, chemotherapy is probably more broadly targeting all [cell] lineages at the earliest stages. And with that, the network system, the overall brain function, and just the ability of the brain to do its job cannot be fully maintained. I think this is one of the key differences between both treatments.
Q. What about patients who receive a combination of radiation and chemotherapy?
A. Some patients only receive one type of treatment and others receive a combination, so the ones who are essentially exposed to both kinds are the ones who are considered to be at highest risk to develop side effects.
Q. What was the biggest surprise in your research?
A. In terms of the chemotherapy treatment, one of the most surprising outcomes I must say is that patients who don’t even have a brain disease, who are treated, let’s say, for breast cancer or for lung cancer, may develop toxicity to the brain over the long term, over the years to come.
Unfortunately, right now, we have no good means of following this, or identifying the patients who are at highest risk, or even to define means of protecting the brain.
Q. Protecting the brain seems so important – are you optimistic that some way can be found to accomplish this?
A. In chemotherapy, there is a good analogy that has been well studied and accepted in the cancer / oncology community, and that is toxicity in the bone marrow.
Bone marrow typically suffers with many forms of chemotherapy treatment. And this is why we closely observe patients on a regular basis to see how the bone marrow behaves. And when the bone marrow suffers and certain lineages like the platelets or the white counts drop significantly, and there is an increased risk of bleeding or infection, then chemotherapy will be put on hold until the bone marrow recovers. This is the standard.
In the bone marrow again, to compare this organ system with the brain, we have ways to protect the bone marrow. We can give support agents to help the bone marrow to repopulate again — growth factors are given subcutaneously [under the skin] by injection or intravenously [into a vein]. And with this the bone marrow is able to get some mileage and rebuild cells quicker and patients are functionally maintained so they can receive further treatment.
Q. That’s a good analogy, one that everyone has heard of or read about. How does this relate to the brain?
A. We feel that similar mechanisms exist in the nervous system. But we currently have no means of thoroughly monitoring damage to the brain in order to say, “Well this patient has now developed a very notable drop in his brain repair capacity. And we need to put chemotherapy for at least a month or so on hold to let the brain recover.”
Q. What does this mean for the whole field of chemotherapy as a cancer treatment?
A. Chemotherapy is one of the hallmarks and cornerstones of cancer therapy and will be in the foreseeable future. But we need to define ways of monitoring patients better, either with imaging or with certain cognitive assessments in order to identify the ones most at risk and then to choose treatments appropriately. In addition, there is a strong need to develop strategies to more effectively protect the brain, especially in patients treated for cancer outside the nervous system.
Q. That’s a goal of your research?
A. Yes, I think that is the main goal, this is the direction we want to try to move the field.
Q. So you are in essence calling for more research to develop better ways to monitor patients treated for cancer in regard to their brain function and to identify both protective and brain repair strategies to be used in affected individuals.
A. Correct, I think there are three big areas where one has to move forward in the future.
One is to define ways to better monitor patients who are at risk and who are developing side effects — dementia, cognitive issues, trouble with concentration and attention, fatigue, all of these are part of a syndrome complex that is explained by the damage to these germinal zones and connecting fiber tracts.
The second point is having protective agents at hand to be used in patients who are receiving chemotherapy drugs that may damage the brain. There is already an array of different agents available and being currently tested in laboratories.
The third point is to routinely employ certain drug screening assays [tests] to identify agents that may potentially be harmful to certain brain cells, even before these agents are used in patients. The scientific knowledge in this area has steadily increased over the past few years and we have learned that potential harmful effects on brain cells may not be identified if less sensitive drug screening assays are used in pre-clinical testing. In other words, as much as novel drugs are rigorously tested for bone marrow or other potential organ toxicity before these drugs are released and approved by the FDA, more sophisticated screening tests will need to be used to identify potential nervous system toxicity.
Q. Some doctors I talked to said chemotherapy does not cross the blood-brain-barrier, and that you’re on the wrong track if you believe it does.
A. Yes, I think this is a misbelief. While certain drugs certainly may cross the blood-brain-barrier easier than others, current research has put this question on a more scientific footing. Our increasing scientific understanding in this area still has to translate into clinical practice and it will have to be accepted in the oncology community that chemotherapy can be a major cause of toxicity to the brain. The good news is that the brain actually has recovery potential. Even if toxicity to the brain develops, this does not mean that this is irreversible damage. As in any other organ system in the human body, the brain has a tolerance level, and the more the brain is exposed to drugs over years, the more irreversible the damage may be.
Q. So what is a patient to do? Patients are willing to do anything to return to their lives, to live. But the implication of a group of long-term survivors who are impaired is quite significant.
A. Yes, this appears to be a problem especially in the children’s population. We have high cure rates in some forms of leukemia – over 70 percent, 80 percent. I think it is important for oncologists and parents who guide the treatments of their loved ones to discuss that certain drugs come with brain toxicities and that these could be expected down the road so there is no surprise.
There has been an increasing awareness about long-term toxicities as a result of numerous clinical reports documenting persistent side effects in children who were treated many years earlier with chemotherapy. In the late 90ies there were a number of papers suggesting that this may also be a problem in adults, especially with prolonged survival. Now, in the past four or five years, the first scientific papers have been published to explain why this damage occurs.
Coming tomorrow: What patients want.