Cognitive functioning in breast cancer patients

A new study on chemotherapy and its effect on the brain will be presented at the annual conference of the nation’s chief oncology group in Orlando. ASCO — the American Society of Clinical Oncology — has posted brief synopses of research, known as abstracts, online. (The meeting starts May 29. Late-breaking abstracts will be posted May 31.) The list is searchable by key word, and is good raw material for someone who wants to dive more deeply into the science of cancer and its treatment. At most conferences, new research is presented in several formats: as posters that are pinned up on boards in a large room, as an oral presentation on stage in front of an audience, or in a smaller panel or talk. The rigors of scientific research demand statistical analysis that may seem befuddling, even to those who took statistics in college. And researchers may use terms that seem arcane. But Google can be a powerful tool, making it relatively easy to search for definitions. Look for authoritative, official websites that have information vetted by doctors or researchers or science writers. For basics on cancer, or on study methodology, the National Cancer Institute website, found here, is clear and authoritative. Dig deep, and you can find an explanation for many medical and scientific terms.

One study being presented at the ASCO conference addresses cognitive functioning in breast cancer patients during and after chemotherapy. The study, done by researchers at the University of Rochester Medical Center in New York, was an outgrowth of another study of the antidepressant Paxil, which I blogged about here. Researchers looked at the changes that breast cancer patients reported over four cycles of chemotherapy, and then looked at how they were doing two years later. In all, 84 patients completed questionnaires about whether they experienced heavy headedness, muddled thoughts, difficulty thinking, trouble concentrating, or forgetfulness. (Patients filled out the questionnaires seven days after each treatment.) In all, 58 patients answered questions after all four cycles. Cognitive difficulties were highest after the first chemotherapy cycle, and were significantly improved by the third and fourth cycles.

But the researchers also found that there was an increase in cognitive difficulties AFTER the last cycle for a few patients — but not enough to be statistically significant. In other words, a very few patients found that their cognitive problems worsened after chemotherapy ended. Some patients reported improvements, and some reported no change.

The conclusion? The University of Rochester research suggests that cognitive difficulties related to cancer treatment are most pronounced after initial cycles of chemotherapy treatment, and that they improve during the treatment course.  As always, this research is simply a guidepost along the pathway, one more dollop of information that may ultimately lead to a deepened understanding of chemobrain. Better testing is needed — paper and pencil tests that allow doctors and patients to track symptoms, paired with brain scans and tests that measure other biological processes.

“Further studies need to include objective neuropsychological examinations and biological correlates of cognitive functioning to understand the extend of cognitive decline due to chemotherapy,” the researchers say.

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2009 Oncologists’ Meeting – Preview

ASCOOncologists gather in Orlando on May 29 for the annual meeting of the American Society of Clinical Oncology. ASCO posts short takes of studies, known as abstracts, online. I’ve combed through the list in order to highlight a few that touch on chemotherapy and cognitive dysfunction. I’ll present them here in small bites.

The first, from researchers at the University of Rochester Medical Center, examines the effectiveness of pharmacological interventions to control chemobrain symptoms. The researchers do not actually use the term chemobrain, of course. They call it cancer-related cognitive dysfunction, or CRCD. “Cancer and its treatment impact important areas of cognitive function such as attention and memory, which are essential to patients’ effective psychosocial functioning and quality of life,” the researchers report in their study, entitled “Neuroprotective effect of SSRI among 781 cancer patients receiving chemotherapy.”

From 17 percent to 75 percent of cancer patients report some difficulty with thinking and memory during and after treatment, the authors note. But few studies have looked at whether drugs prescribed for other ailments might help. This study, which is scheduled to be presented at the ASCO convention on Saturday, May 30, studied whether the antidepressant Paxil (paroxetine hydrochloride) helps with memory problems. Paxil, manufactured by GlaxoSmithKline, is an SSRI — selective serotonin reuptake inhibitor — that is commonly prescribed to treat anxiety disorders, among other conditions. (SSRIs help balance the level of serotonin, a neurotransmitter, in the brain.) The researchers gave patients a test to measure their memories. Patients who were tested ranged in age between 22 and 87 — a range that captures the brain in all its seasons. Of the patients tested, 574 were women, and 207 were men.

Patients were given the memory test after their first chemotherapy cycle and before being given Paxil, and then tested again after they had received four cycles of chemo and had been given Paxil. Some patients received placebos, or inert sugar pills, instead of Paxil. The researchers found a significant different between memory test scores before Paxil and afterward. Not surprisingly, they also found that Paxil relieved symptoms of depression that can also plague cancer patients before, during, and after treatment. (Other studies show that depression and stress can also affect cognition.)

The bottom line? The study says that cancer-related cognitive dysfunction “is a serious problem for patients that can be alleviated by Paxil. Future studies should examine the usefulness of other psychotropic agents and combined behavioral and pharmacologic interventions to control [it].”

Of course, this is one study of many that look at chemobrain. As always, no course of therapy should be undertaken without asking your doctor.

New NCI Bulletin on chemobrain

An image of the brain showing blurred frontal regions associated with complex thought. (Courtesy Arthur Toga, UCLA)

An image of the brain showing blurred frontal regions associated with complex thought. (Courtesy Arthur Toga, UCLA)

The NCI Cancer Bulletin is a font of information (all free, by the way) for a wide array of cancer-related questions. A new post yesterday, “Delving Into Possible Mechanisms for Chemobrain,” suggests that tamoxifen, a drug used to treat breast cancer, can also disrupt cognitive functions. (Tamoxifen, which was approved by the FDA in the 1980s,  is used for breast tumors that are estrogen-receptor positive. The NCI has more information on tamoxifen here.)

Men being treated for prostate cancer are not immune either, NCI writer Eleanor Mayfield reports. Hormonal agents such as goserelin and leuprolide may also cause cognitive dysfunction.

But what is actually happening inside the brain to cause chemobrain? In other words, what is the mechanism?

Two doctors who study chemobrain intensively — one on the East Coast, one on the West Coast — are looking at that very question. Dr. Timothy Ahles at Memorial Sloan-Kettering Cancer Center in New York is crunching data and looking at the role of genetic changes. He has an additional theory, according to the NCI Bulletin: that patients with chemobrain have cells that cannot repair DNA damage caused by chemotherapy drugs.

Dr. Ahles has been focusing on genes for awhile. When he was at Dartmouth Medical School in New Hampshire, before going to Sloan-Kettering, he and colleagues conducted a preliminary study of 80 cancer survivors. They found that patients with a certain form of the gene APOE were at risk for long-term cognitive decline induced by chemotherapy. The 80 survivors, who had been treated for breast cancer or lymphoma, were given a battery of standard neuropsychological tests. Their blood was drawn and tested for the presence of the APOE gene. The study found differences in test results between those who tested positive for the gene and those who tested negative — particularly in visual memory and spatial ability. “The results of this study provide preliminary support for the hypothesis that APOE is a genetic marker for increased vulnerability to chemotherapy-induced cognitive decline,” Ahles writes in the study.

On the West Coast, Dr. Patricia Ganz, at the UCLA Jonsson Comprehensive Cancer Center, points to inflammation in the brain. Inflammation can be caused by surgery, radiation, chemotherapy or immunotherapy, and it may linger after treatment ends. Dr. Ganz is beginning a pilot study to look at strategies and tactics tht breast cancer survivors can use to combat chemobrain.

‘Genius pill’ addictive, study finds

sleepless

This image, from a 2007 article in Time magazine, accompanied a short piece about Provigil, the so-called genius pill. Time put the pill on its list of scariest moments in science.

The up-all-night drug has certainly caught on among students and professionals who want to sharpen their thinking or spend a few additional hours working. I know of colleagues who have used it to handle overseas assignments in distant time zones, to no apparent ill effect.

Now, a small study cautions that the drug could prove addictive. Researchers writing in the Journal of the American Medical Association found that the drug, developed 10 years ago by Cephalon, increases the level of dopamine in the region of the brain involved in feelings of pleasure and reward. Ten healthy volunteers took the drug, then submitted to a PET scan that showed brain activity.

The increase of dopamine is “the signature for drugs that have the potential for producing addiction,” said Nora Volkow, lead author of the study and director of the National Institute on Drug Abuse, told Bloomberg News reporter Marilyn Chases.

Physicians prescribing Provigil should “be alert to the possibility that it could produce addiction,” Volkow said, and the drug “may have more abuse potential than originally believed.”

How is this relevant to our ongoing examination of chemobrain? Provigil, or modafinil, is sometimes prescribed for patients suffering chemobrain symptoms. In interviews, some patients said it helped them function at work. One researcher at Mayo Clinic in Rochester, Minnesota, is optimistic that modafinil can help patients cope with chemobrain. Dr. Sadhna Kohli, a PhD-MPH who was an assistant professor in Rochester, NY, before she went to Mayo, analyzed surveys of 595 patients with various kinds of cancers who were treated in 2001 and 2002. She found that 82 percent of patients who were receiving chemotherapy for cancer experienced symptoms such as forgetfulness, an inability to concentrate or complete thoughts, or had a sense of fogginess that impaired their ability to reason and remember.

Sound familiar?

Kohli also tested the effects of modafinil in 68 breast cancer survivors over an eight-week period. During the first four weeks of the clinical trial, all 68 women took the drug. For the next four weeks, half continued taking modafinil, and the other half took a placebo pill. Kohli found a significant difference between the two groups. Although the study began as an examination of fatigue, Kohli and her colleagues at the James P. Wilmot Cancer Center in Rochester, NY, did a secondary sweep to look at cognitive function. She found that breast cancer survivors taking modafinil reported improved memory, concentration, and ability to learn.

Does she believe chemobrain is real? “If you talk to patients in the clinic,” she told me in a telephone interview for “ChemoBrain,” “then definitely, I do. Before, they were not being taken seriously. It used to be so subtle in terms of memory and concentration, that physicians didn’t know exactly what it was. But more and more women were complaining of it. We’re going to step back [and look at] what causes chemobrain. We need to know what is going on in the brain.”
She reports that one patient was willing to pay $750 a month out of pocket to get modafinil off label. The pill changed her life, she said.

But any off-label drug use needs to be approached carefully. One physician I talked to said it can be hard for patients to find doctors willing to prescribe stimulants like Focalin and modafinil off label. He viewed off-label prescription as something more apt to be done by an older, more experienced physician.

Cephalon, based in Pennsylvania, also revealed that it is developing a longer-acting version of Provigil for release in late 2009. The new drug, known as Nuvigil, or armodafinil, improved the depressive cycle in bipolar disorder when combined with other drugs, according to a study done by Cephalon.

And, for its part, Cephalon begged to differ with the study results obtained by the drug abuse institute. The chief scientific officer, Jeffry Vaught, told Bloomberg that Provigil’s effect on dopamine is “weak,” and that it is “very different from amphetamines and its abuse potential is very low.”

Scans may give faster answers on chemo

Researchers are exploring a way to peek inside the body of a patient undergoing chemotherapy to see if the treatment is working. Two small but provocative studies looked at the ability of a specialized PET scan to show what a tumor is doing. (PET is an acronym for positron emission tomography, a three dimensional scan common in most hospitals. Patients are injected with a radioactive substance, and the scan “lights up” in active areas. Standard PET scans look for blood sugar consumption.)

A new radioactive substance called fluorothymidine is even more precise: it shows whether cancer cells are dividing. According to Malcolm Ritter, an Associated Press science writer, two studies of patients in Korea and in Wisconsin enabled doctors to see whether tumors were responding to chemotherapy as soon as a day after treatment started.

As Ritter writes:

The hope is that, over time, FLT PET would prove reliable for giving a faster answer on whether an experimental treatment is working. That would save [drug] companies a lot of money, because they could spot ineffective drugs more quickly and not wast further research on them. And the drug company research would produce data to help persuade federal regulators to approve FLT PET for use in tracking therapy.

Lymphoma patients, in particular, are used to getting scans to assess whether their treatments are working. This new technology could provide faster answers for people getting chemo for other kinds of tumors. But it may take time, and larger studies, to change policy so that this “early look” is paid for under Medicaid and Medicare.

Survivor: The Philippines (or, it’s all about healthcare access)

Photo courtesy Caymann Institute blog

Photo courtesy Cayman Institute blog

This is not a recap of the tiresome reality series. Rather, it is a look at the stark differences in cancer survival rates between the United States and the Philippines. Although it is a mere demographic slice, it serves to show how important access to health care can be. And, tucked into this data, there is some evidence that the cost of treatments can make a difference — most likely because it affects access to care.

Acknowledging that comparisons of cancer survival data between the developed world and developing countries are very rare, researchers sifted through 9 years’ worth of information to see what they would find. Their report can be found online in the British Journal of Cancer in a study titled “Cancer survival discrepancies in developed and developing countries: comparisons between the Philippines and the United States.”

Specialists from Germany, Manila, and the United States used information on cancer compiled by the National Cancer Institutes. The NCI makes all these numbers available online, if you want to spend an afternoon in front of your screen. The survey is known by its acronym, SEER, which stands for Surveillance, Epidemiology, and End Results. It’s a rich resource.

In Manila, records were collected by the Philippine Cancer Society-Manila Cancer Registry and the Department of Health-Rizal Cancer Registry. And, although epidemiology may seem like a dry field, burdened by numbers and statistical analysis, that was not the case here.  Working in the Philippines, the researchers also had to comb through death certificates at local registries  and match them with records from a database. In some cases, they had to make personal visits to a patient’s last known address in order to find out whether that person was dead or alive.

philippines1

To see how ethnicity factored in, the researchers made sure they surveyed Filipino-Americans living in the United States, who had access to the same health care system as white Americans. Their reach was broad: in all, they looked at outcomes for more than 600,000 people.

The researchers found that 5-year survival rates were much higher for Filipino-Americans than for those in the Philippines — 20 percent to 30 percent higher for some cancers (colorectal, breast and cervix) and 32 percent for leukemia. The survival gap in the Philippines was the largest for leukemia, the scientists said, because the treatments were the most expensive.

“The differences between the Filipino resident population and Filipino-Americans suggest continued inadequacy of access to or utilization of diagnostic and therapeutic procedures in the Philippines,” Dr. Hermann Brenner, an epidemiologist in Heidelberg, Germany, and his colleagues write. “Although diagnostic and treatment facilities are available, access for a majority of cancer patients is still a problem.”

Call for faster clinical trials

Dr. Mark Thornton, who spent six years as a medical officer at the Food and Drug Administration and is the president of the Sarcoma Foundation of America, calls for speedier clinical trials in this opinion piece in the Wall Street Journal. 

The federal stimulus plan will give the National Institutes of Health $10 billion, with a significant portion going to the National Cancer Institute. But, Dr. Thornton says, we’ve been here before. A surge in spending on cancer research from 1999 to 2003 (complete with a march on Washington) accomplished scant success, he writes. And, despite President Obama’s lofty goals, “it appears that the NCI is not mapping out a specific plan or strategy on how to most effectively use its new money.” Dr. Thornton now works in the biotechnology industry.

Cognition and cancer

drmeyers Dr. Christina Meyers, a nationally recognized neuropsychologist at M.D. Anderson Cancer Center in Houston, has done pioneering work on the effects of cancer and cancer treatment on the central nervous system. (In fact, she created the Neuropsychology Service in the newly formed Department of Neuro-Oncology at M. D. Anderson in 1984. A summary of her work can be found here.)

She edited the first textbook collection of studies on cognition and cancer — the first ever — called, appropriately enough, Cognition and Cancer, recently published by Cambridge University Press, New York. Cognition and Cancer is aimed at the doctor, researcher, or other clinician interested in delving into the science of cancer treatments and their long-term effects on the brain. In other words, it’s not an easy read for those of us who are mere mortals.

But that’s probably beside the point: it’s a significant milestone in the study of chemobrain, and clear, hard-copy evidence of the feverish pace of research into this baffling cluster of symptoms. It also provides a blueprint to the science behind chemobrain for clinicians who might not be convinced.

The preface states the mission of the book beautifully:

“This volume is different from anything that has been published in the fields of oncology and neurosciences. The study of cognitive function in cancer patients is in its infancy, and far behind the research in other diseases.”

Dr. Meyers and her colleagues recognize how important quality of life is for cancer patients and survivors. “…cognitive impairment and other adverse symptoms associated with cancer are becoming increasingly important to patients and are identified as a major source of concern for survivors.”

Dr. Meyers and Dr. James Perry, head of the neurology division at Sunnybrook Health Sciences Centre at the University of Toronto, elaborate in their introduction.

cognition

“Cancer treatment may only be considered successful if these symptoms are managed, but successful management is hampered by insufficient knowledge of mechanisms…. The effect of these symptoms on daly life can be quite profound, depending upon the demands present in the individual’s work and home life. Many patients observe that they can no longer multi-task, and that they may become overwhelmed when too much is happening at once. They are often easily distracted, and find that they may go from project to project without getting them done.”

The impact of cognitive dysfunction can depend on a patient’s stage of life: an older, retired person who can take things at his or her own pace might find it easier to cope than an attorney in a court-room setting, who might have to change jobs or go on disability.

I talked with Dr. Meyers by phone to ask what’s next.

Q: What need is this book fulfilling?

A: The study of cancer and cognition is in its infancy, in one respect. There is a huge amount of information out there already, but it is not filtering down to the practitioners. So there are still people who deny that chemobrain exists, who assume it is some kind of psychiatric issue. In fact, there is a lot of good science behind it.

Q: Why do you think practitioners, particularly oncologists, seem to be slow to recognize this?

A: I think they’re not aware of the scientific literature about it, for one thing. Part of it may be an ego issue for some. They want to put this person in remission, on a path to a cure, and now they’re complaining.

Q: The attitude you’re describing is what some patients experience. They’re told, ‘You should be grateful to be alive.’

A: Right, that’s kind of the attitude. That used to be the attitude toward pain, and we finally got that pretty well taken care of. And also fatigue, which has a lot of scientific background. The bottom line is that there has been this nihilistic attitude, that this is what you expect when you go through cancer treatment. And that is just not enough for the consumer any more.

Q: What about long-term effects?

A: It’s a societal issue. If you can’t return to work effectively, if you have these symptoms that are not being addresed, you are not going to get back to your life like you did before. It’s going to have all kinds of downstream social costs and issues.

I think that cancer patients need to be vocal advocates — like they are with insurance companies and everything else. And that their symptoms should be treated with as much respect as their cancer would be treated.

Q: Talk a little about the  ‘seed, soil, and pesticide’ analogy that you use in the book.

A: You have to take all three issues into account. You have the cancer itself (the seed), you have the body’s reaction to the cancer and your own personal genetic makeup (the soil), and you have specific agents that are used to treat the cancer (the pesticide).

Q: Could the cancer itself be causing some chemobrain effects?

A: Yes. It could be an inflammatory response, where your body knows that something is wrong — just as your body knows something is wrong when it has a virus. And some cancers secrete things that could cause symptoms. Or you might have an autoimmune response to the cancer. People will tell me that they felt funny before their cancer was diagnosed, they couldn’t put their finger on it, but something just wasn’t right.

Q: Where would you like to see the research go?

A: Right now there is a lot of new animal work that is being done, and it is very exciting. It is looking at the precise mechanisms by which these agents cause problems, even if they don’t cross the blood-brain barrier. And we know tht some of these agents certainly can influence the blood-brain barrier. This research will eventually lead us to targeted treatment and to ways to prevent symptoms. The ultimate goal is that you don’t have [chemobrain] symptoms to begin with.

Clinical trial at Memorial Sloan-Kettering Cancer Center

ClinicalTrials.gov reports that researchers are conducting a large clinical trial designed to learn more about how chemotherapy affects the ability to think. Specifically, doctors at Memorial Sloan-Kettering Cancer Center in New York City want to know whether chemotherapy agents damage the DNA of women treated for breast cancer, and whether DNA damage is related to problems thinking.

mskcc2

This kind of research, with a large enough group to be statistically significant and a group of healthy “control” subjects, is ultimately going to drive the science of chemotherapy and cognition to a new level. In other words, trials like this may give doctors new insights into cancer treatment and brain function that could help the millions of breast cancer survivors in the United States. It might also translate to other cancers, too.

“Some research has shown that chemotherapy can cause changes in cognition [thinking] in breast cancer survivors,” the doctors write. “However, it is not clear why this change occurs. In this study, the investigators will look to see if damage to DNA is related to these changes in cognition.”

Doctors hope to enroll 150 women, all between 50 and 70 years old, at three different MSKCC sites: in New York City, in Commack, New York, and in Rockville Centre, New York.

The study, which began  in June 2007, will be completed by June 2010. Women participating in the trial will be divided into three different groups, according to the information posted on ClinicalTrials.gov:

  • Breast cancer survivors 2-6 years post-treatment who were post-menopausal at the time of diagnosis and treated with a combination of chemotherapy and hormonal therapy.
  • Breast cancer survivors 2-6 years post-treatment who were post-menopausal at the time of diagnosis and treated only with hormonal therapy.
  • Healthy women.

All participants will be given a mini “mental state exam” — a neuropsychological test that takes abou 2 hours to finish. Blood samples will also be drawn. Participants will be matched by age and education, as well — allowing researchers to draw valid, apples-to-apples comparisons.

ahles2The researchers conducting the trial, Dr. Tim Ahles and Dr. Denise Correa, write that “the primary objective of this proposal is to obtain preliminary data regarding the association between DNA damage and cognitive functioning in breast cancer survivors.”

They predict that breast cancer survivors treated with chemotherapy and hormonal therapy will have higher levels of DNA damage, compared with those treated only with hormonal therapy, and compared with the healthy women.

They also expect to find that those who show signs of cognitive impairment on tests will have higher levels of DNA damage.

Crossing the medical/media barrier

 

When I began researching chemobrain in January 2007, it was clear that the field of study was in its infancy. There was a growing body of serious research into what scientists call neurocognitive late effects — and this research was exploding all over the world. But some cancer patients and survivors I talked to still reported that their doctors dismissed their complaints. 

As Dr. Harold Burstein at the Dana-Farber Cancer Institute in Boston told me, chemobrain is part of the lore of breast cancer, and any clinician who sees breast cancer patients has heard the term — and, he says, has heard patients talk about  this bedeviling cluster of symptoms. Preparing a PowerPoint presentation in 2007 for the 10th International Conference on breast cancer therapy in St. Gallen, Switzerland, he did what he calls “a highly unscientific survey” of 24 of his breast cancer patients. Eighty percent of them told him that they believed that chemotherapy had made it harder to concentrate or remember names. Some had particular trouble with numbers, others could not follow a single train of thought for long. Many felt spaced out and easily distracted.

However, he added, the literature is messy — at least, the literature that doctors pay attention to. Think of the difficulty in comparing apples and oranges: some studies follow a group of people over a long period of time, other studies are a snapshot of a particular moment. Cognitive tests are designed differently. (And sometimes the tests themselves are daunting — could you complete a drawing of a geometric figure while stuffed inside a claustrophobic MRI tube?) 

But that is changing. Researchers are designing controlled studies and experimenting in the lab, and publishing scores of new articles in peer-reviewed journals — the gold standard for scientific work. Researchers like Christina A. Meyers, PhD, and Jeffrey Wefel, PhD, at the M.D. Anderson Cancer Center in Texas, Tim Ahles, PhD, at Memorial Sloan Kettering Cancer Center in New York, Sanne Schagen, PhD, at the Netherlands Cancer Institute in Amsterdam, and Robert Butler, PhD, at Oregon Health & Science University in Portland. (Dr. Butler, who specializes in pediatric hematology and oncology, was cited with gratitude by many parents I interviewed. He listened to them. He helped them find answers. More on late side effects in teen-agers in another post.)

113754-prometheus It’s seeping into websites and into the popular press — what the rest of us non-doctors read. Although no one should begin, end, or alter their treatment based on a newspaper article, the media echo chamber helps push patient empowerment movements forward. My colleague at the New York Times, Jane Gross, called attention to chemobrain with an important front-page article in April 2007.

When medical research collides with a burgeoning patient empowerment movement, the results can be powerful. So let the conversation flow.