Anthracycline-based chemotherapy may have greater negative effects on particular cognitive domains and brain network connections than nonanthracycline-based regimens, according to a recent study published in JAMA Oncology.1

Researchers analyzed cognitive tests and imaging data from 62 primary breast cancer survivors (mean age 54.7 years) who were more than 2 years off therapy on average. The investigators looked at cognitive status and functional brain connectivity. In this study, 20 patients received anthracycline-based chemotherapy as part of their primary treatment, 19 received nonanthracycline regimens and 23 did not receive any chemotherapy.

“We know chemotherapy is a risk factor for developing cognitive difficulties, but it’s been unclear if one chemotherapy is more toxic than another. Anthracyclines like doxorubicin are widely used to treat breast and other cancers so we examined the different effects of these 2 categories of chemotherapy on cognitive function and brain connections in a group of women with a history of breast cancer,” said study investigator Shelli Kesler, PhD, of The University of Texas MD Anderson Cancer Center in Houston, TX. “The results were consistent with our hypothesis, which was based on a previous study demonstrating that anthracyclines are associated with increased inflammation compared to nonanthracyclines.”

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She and her colleague Douglas Blayney, MD, of the Stanford University School of Medicine, CA, found that the women treated with anthracycline-based chemotherapy had lower verbal memory, including immediate recall and delayed recall, compared with the other 2 groups of women. The anthracycline regimens also were associated with lower default mode brain network connectivity, suggesting a decreased efficiency of information processing.

“This is the first study to show this to my knowledge,” Kesler told Cancer Therapy Advisor. “The most important implications are first that clinical trials of chemotherapy agents need to include cognitive outcomes so that we can better determine the cognitive cost-benefit ratios of various chemotherapies. Secondly, patients should be referred for neuropsychological evaluation prior to beginning chemotherapy if possible, and should have their cognitive function monitored throughout their treatment course and into survivorship.”

Patient-reported outcomes of cognitive dysfunction and psychological distress were elevated in both groups of women treated with chemotherapy compared with patients treated without chemotherapy.

Kesler noted that these results should be considered preliminary given the study limitations of small sample size and retrospective, cross-sectional design. She said larger, prospective studies are warranted and those studies should include pretreatment and posttreatment assessments.

The researchers believe that patients’ individual cognitive and neurobiologic trajectories can be better evaluated with respect to potential ANTHR [anthracycline]-related neurotoxic effects if specific assessments are conducted at baseline.

“Cardiotoxicity is a known side effect of anthracyclines and this is routinely monitored as part of standard of care so that intervention can occur when necessary. We should be doing the same thing for chemotherapy-related neurotoxicity,” said Kesler.

“My group is following-up with preclinical studies to determine if there are agents that can protect against and/or reverse chemotherapy-related neurotoxicities. For example, we just started a study to determine if stem cells can restore cognitive function after cancer treatment.”

Brenna McDonald, PsyD, of the Indiana University School of Medicine in Indianapolis, and co-authors in a related editorial wrote that previous studies have linked chemotherapy and cognitive decline. However, few studies have linked specific treatments with differences in brain connectivity.2

“Seventeen to 70% of patients may experience some (cognitive) problems. But we have been trying to get a better sense of how many have these problems and do they get better over time,” said McDonald in an interview with Cancer Therapy Advisor.

“It appears to be a subset of patients who experience these problems and some patients have these problems and then they go away. We need to identify them early on and we are not yet at that stage to fully identify them.”

McDonald said this is one of the few studies that has looked at whether different chemotherapy regimens may make a difference when it comes to what has been referred to as chemo brain.

“This study makes a contribution toward the understanding of one treatment compared to another, but it is not the whole problem. There are aspects of the cancer disease process involved and other kinds of treatments that may be involved. It is not the whole picture, but it is certainly an important piece,” said Dr McDonald.


  1. Kesler SR, Blayney DW. Neurotoxic effects of anthracycline-vs nonanthracycline-based chemotherapy on cognition in breast cancer survivors [published online ahead of print December 3, 2015]. JAMA Oncol. doi:10.1001/jamaoncol.2015.4333.
  2. Nudelman NKH, McDonald BC, Saykin AJ. Imaging brain networks after cancer and chemotherapy advances toward etiology and unanswered questions [published online ahead of print December 3, 2015]. JAMA Oncol. doi: 10.1001/jamaoncol.2015.4551.