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. 

Literature: University of Rochester Medical Center, UR study reveals chemo’s toxicity to brain, possible treatment, December 17, 2009

Study shows deterioration in brain function following breast cancer therapy has negative effects on quality of life

One of the most problematic side effects of cancer treatment, chemobrain – a range of symptoms including memory loss, inability to concentrate, difficulty thinking and other subtle cognitive changes following chemotherapy – seriously diminishes women’s quality of life and daily functioning. As a result, they have to adopt a range of coping strategies to manage their restricted social and professional lives.

Breast cancer survivors tell their story in a descriptive study (1) of the effects that cognitive impairment has on women’s work, social networks and dealings with the health care profession. Dr. Saskia Subramanian from the UCLA Center for Culture and Health in the US and her colleagues have just published their work online in Springer’s Journal of Cancer Survivorship.

An increasing number of women survive breast cancer, yet survival comes at a price. Mild cognitive impairment following chemotherapy, known as “chemobrain” or “chemofog” is one of the most commonly reported post-treatment symptoms by breast cancer survivors. Dr. Subramanian and colleagues’ work shows that this deterioration in brain function has devastating effects on breast cancer survivors’ quality of life.

Through a combination of focus groups and in-depth interviews among 74 women who had completed their course of cancer treatment at least a year earlier, the researchers gathered data on patients’ medical background, treatment experience, post-treatment symptoms, reactions from medical staff and from family and friends, self-management, strength of social networks and their perceptions of themselves.

The women described a variety of cognitive changes which they found both frustrating and upsetting. Some were less able to retain material or to digest new information and recognized that they were not functioning as they once did. Others faced reduced independence, becoming limited in their ability to manage certain responsibilities or get around. These changes made women feel scared, dependent and emotionally drained. For some, coping meant having to cut back on work and social activities. Others had more or less accepted the limitations put on their lives and resigned themselves to a diminished cognitive capacity.

The majority of women complained about the lack of acknowledgement from the medical community when they mentioned their chemobrain symptoms. Many women wished they had received some warning and only a few got answers from their physicians. Some women felt that chemobrain confused their families and friends, and young children in particular.

Chemobrain also affected women’s performance at work. Because they were less able to focus, duties became more difficult and often took longer. This affected their efficiency and reduced their chances of promotion or assignment to projects.

The authors conclude: “These data underscore the very serious ways in which chemobrain can affect the life experiences of cancer survivors – emotionally, psychologically and economically. A clear understanding of the cognitive impairments experienced by survivors will aid researchers in developing targeted therapies and interventions aimed at improving or mitigating these post-treatment side effects.”

Reference:   Boykoff N, Moieni M, Subramanian S (2009). Confronting chemobrain: an in-depth look at survivors’ reports of impact on work, social networks, and health care response. Journal of Cancer Survivorship; DOI: 10.1007/s11764-009-0098-x

Patients with curable early-stage breast cancer died from chemotherapy solvent
A chemotherapy drug that is supposed to help save cancer patients’ lives, instead resulted in life-threatening and sometimes fatal allergic reactions.

A new study from the Research on Adverse Drug Events and Reports (RADAR) pharmacovigilance program at Northwestern University Feinberg School of Medicine identified 287 unique cases of hypersensitivity reactions submitted to the FDA’s Adverse Event Report System between 1997 and 2007 with 109 (38 percent) deaths in patients who received Cremophor-based paclitaxel, a solvent-administered taxane chemotherapy.

Adverse event reports generally only represent from 1 to 10 percent of actual incidence, so the number of hypersensitivity reactions and deaths is likely significantly higher. The severe allergic reactions are believed to be caused by Cremophor, the chemical solvent – a derivative of castor oil — that is used to dissolve some insoluble drugs before they can be injected into the blood stream.

Two patients who died from an allergic reaction had early-stage breast cancer, which had been surgically removed, and were being treated with Cremophor-containing paclitaxel to prevent the cancer from coming back. Both of these patients had received medications before the chemotherapy to reduce the risk of hypersensitivity reactions.

The study was led by Charles Bennett, M.D., RADAR program coordinator and a professor of hematology/oncology at Northwestern’s Feinberg School, and Dennis Raisch, a professor of pharmacy at the University of New Mexico.

“The deaths of women with early-stage breast cancer are particularly disturbing because without the adverse reaction, they could have likely had 40 years of life ahead of them,” Bennett said.

RADAR investigators also found that 22 percent of all fatalities occurred in patients despite patients having received premedication to prevent hypersensitivity reactions, while another 15 percent of such patients experienced life-threatening respiratory arrest.

The report was presented at the 45th Annual Meeting of the American Society of Clinical Oncology held recently in Orlando, Fla.

Cremophor-containing paclitaxel has been associated with hypersensitivity reactions, with responses ranging from mild skin conditions to more severe effects, including anaphylaxis and cardiac collapse. Current U.S. product labeling for Cremophor containing paclitaxel includes a black-box warning alerting physicians and patients of potential toxicity and recommending the use of corticosteroids and other medications before chemotherapy administration to reduce the risk of hypersensitivity reactions.

“The results of our review suggest that physicians should be vigilant in monitoring the safety of their patients undergoing chemotherapy treatment,” said Bennett, who also is the A.C. Buehler Professor in Economics and Aging at the Feinberg School and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

“Patients receiving Cremophor-based paclitaxel should be given medications to prevent hypersensitivity reactions, but what is sobering, as the study has shown and as the black-box warning indicates, women suffer anaphylaxis despite receiving steroid premedication,” Bennett said. “Physicians should be diligent in reporting adverse events to regulatory agencies to better monitor the impact of Cremophor on patient safety. Physicians may also want to consider exploring other alternative chemotherapy options that do not include Cremophor.”

In addition to the two women with early-stage breast cancer who died after treatment with the Cremophor-based paclitaxel, four other women with early-stage breast cancer experienced life-threatening anaphylaxis reactions. Each of them had received prior medications to prevent the reactions.

“The fatal outcomes observed in patients with early-stage breast cancer were particularly striking as this is a patient population with a good prognosis that is generally treated with curative intent,” said Raisch.

For the report, Bennett and Raisch reviewed adverse event reports submitted to regulatory agencies in the U.S., Europe and Japan. The most common cancer diagnosis for these patients with allergic reactions was lung cancer followed by breast cancer and ovarian cancer.

Reference: Northwestern University, Common chemotherapy drug triggers fatal allergic reactions, Press Release, 8-Jun-2009