research into possible way to reverse chemo brain toxicity
 

UR Study Reveals Chemo’s Toxicity to Brain, Possible Treatment



Researchers have developed a novel animal model showing that four commonly used chemotherapy drugs disrupt the birth of new brain cells, and that the condition could be partially reversed with the growth factor IGF-1.

Published early online in the journal Cancer Investigation, the University of Rochester Medical Center study is relevant to the legions of cancer survivors who experience a frustrating decline in cognitive function after chemotherapy treatment, known as chemo brain.

“It is not yet clear how our results can be generally applied to humans but we have taken a very significant step toward reproducing a debilitating condition and finding ways to treat it,” said Robert Gross, M.D., Ph.D., professor of Neurology and of Pharmacology and Physiology at URMC and principal investigator of the study.

Chemo brain is a newly recognized condition. The URMC team found surprising data about how the four drugs impact the brain, Gross said, and they are the first to report that the experimental insulin-like growth factor, IGF-1, may be beneficial.

The study was funded by a Department of Defense grant to Gross and by the National Cancer Institute to co-investigator and lead author, Michelle Janelsins, Ph.D., research assistant professor of Radiation Oncology at the James P. Wilmot Cancer Center.

More than 11 million Americans are living today after receiving a cancer diagnosis. Many of them have endured chemotherapy and although the side effects during treatment are well known, the lingering neurological effects are more puzzling. Patients often report memory lapses, trouble concentrating, confusion, difficulty multi-tasking and slow thinking for weeks, months or years after treatment ends.

The URMC team hypothesized that cognitive problems might stem from chemo destroying the ability of brain cells to regenerate in the hippocampus, which is primarily involved in memory formation and mood. They sought a way to find the mechanisms at work and to manage the adverse effects on the brain before, during and after chemotherapy treatment.

Researchers also hypothesized that chemotherapy drugs known to cross the blood-brain barrier would be a bigger threat to brain cells than drugs that do not cross the blood-brain barrier. To test the hypothesis, they investigated the effects of routinely used doses of cyclophosphamide and fluorouracil, which do cross into the brain, against paclitaxel and doxorubicin, which do not.

Unexpectedly, all four drugs caused a significant breakdown in brain cell proliferation in the animal model. A statistical analysis of cell regeneration showed a 15.4 percent reduction in new brain cells following fluorouracil, a 30.5 percent reduction following cyclophosphamide, a 22.4 percent reduction following doxorubicin, and a 36 percent reduction following paclitaxel.

“It could be that all of the chemo drugs cross into the brain after all, or that they act via peripheral mechanisms, such as inflammation, that could open up the blood-brain barrier,” Gross said.

“Neurogenesis can also be altered by stress, sleep deprivation and depression, all of which are common among cancer patients,” added Janelsins. “More thorough studies are needed to understand the interplay of these factors and the long-term effects of chemotherapy on the brain.”

Researchers conducted a second study of a single high dose of cyclophosphamide, a mainstay of adjuvant chemotherapy for breast cancer, because chemo brain is a frequent complaint of people receiving this drug. The single high dose resulted in a 40.9 percent reduction in newly divided brain cells, the study said.

In previous studies the experimental growth hormone IGF-1 had demonstrated that it could generally promote new brain cell development within the central nervous system. Thus, investigators chose to test its effect in the animal model.

They administered IGF-1 prior to and following a conventional cyclophosphamide multiple-dose regimen, and a single, high-dose of cyclophosphamide. The IGF-1 seemed to increase the number of new brain cells in both models, but was more effective in the high-dose model, the study concluded.

The research team plans to conduct additional studies which will allow them to further test the impact of IGF-1 and other related interventions on the molecular and behavioral consequences of chemotherapy.

A multidisciplinary group of scientists participated in the study. The research grew from discussions between URMC cancer investigators and experts in epilepsy, who also study damage to the hippocampus region and wondered about a connection to chemo-brain. In addition to Gross and Janelsins, collaborators included Wilmot Cancer Center faculty Joseph A. Roscoe, Ph.D., Gary R. Morrow, Ph.D., Charles E. Heckler, Ph.D., and Pascal Jean-Pierre, Ph.D.; Lisa A. Opanashuk, Ph.D., and Bryan D. Thompson, of the Department of Environmental Medicine; and Michel J. Berg, M.D., of the Department of Neurology.

# # #


Researchers Detail Chemotherapy’s Damage to the Brain
82% of Cancer Patients Report ‘Chemo Brain’ During, After Treatment

Re: research into possible way to reverse chemo brain toxicity
 

Thanks, Lani, for the interesting article.

It would be wonderful if a way could be found to reverse chemo brain. So many of us suffer from changes in our brains since chemo, but when we talk to our oncologists about our concerns, they can only tell us that some people complain of chemo brain, but doctors do not know if the disorder is fact or something the patient thinks exists. Patients, myself included, hate to complain too loudly because we are thankful for drugs that can fight cancer so we accept whatever changes we experience (physical changes, too) and try to move forward, although with lesser brain compacity it can be difficult and demoralizing.

I know the before and after (7 years March 2010) cognitive differences I have experienced and no one can convince me that what I am experiencing is from normal changes in brain function due to age, etc. But at the same time I will say "Praise the Lord" and give thanks for being able to duke it out with cancer (past, present, and future) no matter the side effects from the drugs that were used in the fight.

Unexpectedly, all four drugs caused a significant breakdown in brain cell proliferation in the animal model. Many of us have received some or all the the 4 drugs mentioned in this article. I am feeling some sort of relief or satisfaction, knowing that we are finally discovering that these drugs have very likely impacted people who have received them...often for months, weeks, or years after treatment. Even though I knew the changes I was experiencing were not imagined, it is good to see the cause/effect in writing!

One last note...I asked my onc if changes could be seen in an MRI, but he said the MRIs that we use for detecting metastasis, etc., are not the same as an MRI that would show brain function...if I understood that correctly...and that type of MRI is not available in most areas.

Re: research into possible way to reverse chemo brain toxicity
 

Barbara,
There is no doubt that Chemo Brain is real! I am still working on recovering from it, 3-1/2 years past the end of treatment.

One thing that helped me was reading Brainlash by Dr. Gail Denton. (www.Brainlash.com). I tried to talk her into writing a book for chemo brain patients, but she talked me into writing it, with her help. So we've been working on it for about 8 months and hope to have it out in early 2010 (www.BeyondChemoBrain.com).

There are two other books on chemo brain, both out in 2009 (finally!), but both a little hard to read if you have chemo brain...

It's real, you're not stupid or lazy, and it's ok to get help. In a 2007 survey by Hurricane Voices,
Of the 102 respondents 5 or more years out from treatment, 92% were still impacted by cognitive changes—61% at the same level they first experienced following treatment. Only 8% reported that their symptoms had completely ‘gone away.’

You are not alone. Take care.

Carol

Re: research into possible way to reverse chemo brain toxicity
 

It's also very important to get the correct testing and diagnosis.

The traditional psychological tests such as WAIS and WIAT never could detect my cognitive deficit. Only after we had seen a neuropsychologist and gone through up to 19 different tests did we get our suspicion confirmed.

From my experience, it's a 'use it or lose it' situation. The more we use (exercise) our brain, the better (and more) our neurons can be (re)connected. Exercise also can speed up the cell repair (because of more blood supply) and regeneration.

There are specialists using the term 'elasticity' to describe our brain. Our brain can reconnect, rewire, regenerate... Chemo brain is real, but our brain's healing capacity and potential is unlimited.

Re: research into possible way to reverse chemo brain toxicity
 

Well, that explains a lot. I had CMF way back when...AND although I have been on "only" targeted therapy for some time now, lately, I've really noticed another decline in my brain power. It seems that the multi-tasking/integration of several layers at once is really a struggle and frustration.

I wonder if Tykerb plays a part since it crosses the bbb. Thanks for the info!

Re: research into possible way to reverse chemo brain toxicity
 

Thanks for posting this study, Lani. Because I write about chemo brain (and went through it), I read this study with real excitement when it first came out. The science is moving forward and hopefully before too long we'll see some of these successes translated to humans. It's interesting to think that IGF-1 may help reverse the loss of brain cells. Best of all though would be the discovery of more effective drugs that only target cancer cells and leave our healthy cells (including brain cells) in tact. We need to get rid of the worst offenders so that we can beat cancer without our minds turning to mush.

Idelle Davidson
Co-author (with Dr. Dan Silverman at UCLA) of Your Brain After Chemo: A Practical Guide to Lifting the Fog and Getting Back Your Focus. www.YourBrainAfterChemo.com