Severe Side Effects of Cancer Treatment Are More Common in Women than Men

, by NCI Staff

Woman laying in bed, hand on chest, in discomfort.

Additional research is needed to understand why women are more likely than men to experience serious side effects from cancer treatments, several researchers said.

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Women are more likely than men to experience severe side effects from cancer treatments such as chemotherapy, targeted therapy, and immunotherapy, a new study suggests.

Overall, women had a 34% higher risk of severe side effects compared with men, the researchers found. The sex disparity in severe side effects was the most pronounced among patients receiving immunotherapy, with women having a nearly 50% increased risk of serious side effects compared with men.

The findings are based on several decades of data from 202 cancer clinical trials conducted within the NCI-sponsored SWOG Cancer Research Network. The trials involved more than 23,000 men and women. 

The greater severity of side effects in women suggests that, when it comes to cancer treatment, “broad-based sex differences exist,” the study team concluded. Findings from the study were published February 4 in the Journal of Clinical Oncology.

Researchers have known that women have an increased risk of side effects from chemotherapy. But few studies have tested whether the pattern holds for newer treatments, such as immunotherapies and targeted therapies. 

“This study is a call to action for researchers to dig deeper” into possible sex differences associated with cancer therapies, said the study’s lead investigator, Joseph Unger, Ph.D., of the Fred Hutchinson Cancer Research Center. The study was conducted by the SWOG Cancer Research Network and was supported in part by NCI.

More research is needed, Dr. Unger continued, to better understand the reasons for the sex differences reported in the study.
  
The new results confirm what has been seen in smaller studies, noted Berna Özdemir, M.D., Ph.D., of Bern University Hospital, Switzerland, who studies sex differences in cancer development and outcomes but was not involved in the research.
 
The results also “underscore the need for personalized treatment approaches that consider the sex of a patient,” Dr. Özdemir added.

Collecting reports of side effects from large clinical trials

To conduct the study, the researchers relied on data from patients who participated in large clinical trials that did not involve sex-specific or sex-dominant (e.g., breast) cancers. Severe side effects, also called acute adverse events, were reported for all trial participants while on treatment.

Of the patients whose data was included in the study, 38% were women and 62% were men—numbers that reflect the overall proportions of women and men with cancers that are not sex-specific, according to Dr. Unger. Nearly three-fourths of the patients had received chemotherapy; the others had been treated with either targeted therapy or immunotherapy.

The researchers collected reports of adverse events that were grade 3 or higher that the patients experienced while on treatment. Collectively, 65% of the patients experienced one or more severe adverse events. 

The study assessed two broad categories of treatment side effects—symptomatic (such as pain or nausea), which are reported by the patient, and objective (such as high blood pressure), which are measured using a laboratory test or a medical instrument or device.
 
Objective side effects were further categorized as hematologic (related to blood or bone marrow) or nonhematologic. The researchers examined 13 symptomatic and 14 objective categories of adverse events. 
 
Women had a higher risk of severe symptomatic side effects and severe objective hematologic side effects (e.g., anemia, neutropenia) compared with men. Women were also more likely than men to experience five or more severe side effects, the researchers found.
  
Among patients receiving immunotherapies, women had a 66% increased risk of symptomatic side effects compared with men. “The differences we found for immunotherapies were quite large,” said Dr. Unger. 
 
Limitations of the study include the fact that participants in clinical trials tended to be younger and in better health than similar patients who are not treated on a clinical trial, according to Dr. Unger and his colleagues.

Making patients’ sex part of personalized medicine?

Although the reasons for the sex differences in the study are not clear, Dr. Unger and his colleagues suggested some possible explanations. These include differences in how men and women perceive or report side effects from therapy, the doses and administration of therapies, and biological differences between the sexes.
 
“There are a lot of intriguing possible explanations for the findings,” said Dr. Unger. 
Understanding the mechanisms underlying sex differences could potentially lead to new ways of developing and delivering therapies that reduce toxicity, particularly among women, he added.
 
The increased risk of side effects among women revealed by the study is “concerning,” said coauthor Lori Minasian, M.D., of NCI’s Division for Cancer Prevention. “We need to figure out why this is happening.”

The new findings, Dr. Minasian continued, could also inform future efforts to develop more individualized forms of cancer medicine. To date, the field of personalized medicine has focused primarily on targeting certain changes in a tumor, such as abnormal proteins. But the new study underscores the need to consider the whole patient and not just the tumor, she said.
 
Dr. Unger agreed. “A patient’s sex has not really been considered a component of individualized approaches to cancer medicine,” he said. “But if the new findings are confirmed by other groups, then perhaps patient sex should be considered.

Gender-based versus sex-based differences

When researchers report a difference between men and women, especially when reporting how a patient feels after a treatment, there may be confusion about what is caused by gender differences versus sex differences, explained Sabra Klein, Ph.D., codirector of the Center for Women’s Health, Sex, and Gender Research at the Johns Hopkins Bloomberg School of Public Health.

Sex refers to biological characteristics. Gender refers to “the behaviors, occupations, access, utilization, or perceptions, in this case, about health care, that can be defined by our societal or cultural norms,” Dr. Klein explained.

Previous studies have suggested that men and women may differ in how and whether they report side effects of treatments. 

“Women may find it more socially acceptable to admit to experiencing pain, discomfort, or malaise following a treatment, which is often perceived as not masculine in our culture,” said Dr. Klein. “As a result, we cannot dismiss the possible role that gender might play in the data collected for this study.”
 
But the disparity by sex in the current study was also seen in objectively reported side effects, including lab test results, which would not be affected by potential differences in how men and women report side effects.
 
“Clearly, reporting differences would not explain all of our findings,” said Dr. Unger. “There seems to be something biological going on there as well.”
 
Biology has been linked to sex differences in other cancer outcomes, including in different treatment responses in brain cancer. Many biological differences between males and females are associated with sex hormones, such as testosterone or estrogen.
  
“There are sex differences in inflammatory immune responses that contribute to adverse drug reactions, as well as sex differences in the metabolism of drugs,” said Dr. Klein.

Other studies have found sex-based disparities in both the response to and side effects of treatments that affect the immune system, including vaccines for the flu and antibody-based treatments for autoimmune diseases like arthritis. 
 
The pattern of increased reporting of adverse events among women in the SWOG study is consistent with the adverse event reporting for vaccines and other drugs, Dr. Klein noted. 

Creating awareness about side effect differences

Interest in sex differences and cancer treatments has been growing among researchers. Dr. Özdemir is a board member of the European Society for Medical Oncology Gender Medicine Task Force, which aims to promote research that could lead to a better understanding of sex differences related to cancer and its treatment. 

“The research by Dr. Unger’s team is very timely,” Dr. Özdemir said. “Our task force is trying to raise awareness of potential sex differences in cancer incidence, the biology of tumors, and treatment effects.” The group is also “encouraging oncology professionals to consider sex and gender issues in their education, research, and practice.” 

One of the main lessons of the SWOG study, Dr. Özdemir noted, is that researchers conducting clinical trials of cancer therapies need to report results on the effectiveness and safety of treatments according to a patient’s sex. 

This knowledge could eventually help inform decisions about which treatments are most appropriate for individual patients and how best to develop and deliver new therapies, she added.

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