Differences in How Men and Women Respond to Radiotherapy?

Fran Lowry

April 08, 2020

Men and women who undergo treatment for cancer react differently to radiotherapy (RT), according to evidence drawn from a literature review.

The study found a small but significant difference in response to RT.

Women generally derive a greater survival benefit and are more likely than men to be cured, but the side effects that they suffer are more severe, say the authors.

However, a radiation oncologist who was approached for comment cautioned that the literature review was selective and that more data from larger studies are needed before claims of a differences between sexes in their response to radiotherapy can be considered "definitive."

The new article, published in Critical Reviews in Oncology/Hematology, highlights the importance of including gender as a variable in clinical trials, say the authors.

"It is clear that gender plays a role in the occurrence and response to therapy of many diseases," coauthor Eva Bezak, PhD, professor of medical radiation and director of translational cancer research, University of South Australia, Adelaide, told Medscape Medical News.

"Gender should definitely be considered in this era of individualized medicine," Bezak said.

"We need to take into account the biological differences between males and females and how these differences can affect responses to treatment and even the propensity to develop certain cancers," she said.

"For example, it is already well established that men are more susceptible to head, neck, and blood cancers and women are more prone to autoimmune diseases as well as osteoporosis. In addition, scientists know that individual responses to radiotherapy are up to 80% determined by genetics," Bezak said.

The differences in responses to radiation are evident from two important historical events, Bezak noted: the Chernobyl nuclear reactor disaster in 1986, and the atomic bombing of Hiroshima and Nagasaki in 1945.

After Chernobyl, women were at increased risk for endocrine imbalance, thyroid cancer, and brain tumors, and the male-to-female birth ratio was slightly increased, probably because, as an effect of low-dose radiation, fewer girls were born to irradiated men, she said.

After Hiroshima and Nagasaki, the risk for solid cancers increased by 35% for men and by 58% for women. "This shows us that there is great cause to suspect a significant difference in the effect of radiation between genders," Bezak said.

Preclinical and Clinical Studies Show the Difference

For the current review, Bezak and her coauthors assessed eight articles on the in vitro and in vivo response to RT, and they categorized the results by gender.

In a preclinical study that involved a rodent model of pediatric RT, cognitive impairment, as measured by novel odor recognition after cranial irradiation, occurred in male mice, but female mice showed cognitive impairment only during certain stages of the estrous cycle.

In another preclinical study that focused on differences in acute lung toxicity between genders, 60% of irradiated male rats developed pneumonitis, compared with 50% of irradiated female rats. Similarly, 80% of irradiated male rats developed vasculitis, compared with 70% of female rats.

Studies conducted in patients with rectal and esophageal cancers also highlight differences in response between men and women, Bezak said.

An in vitro study that investigated gender differences of colonic motility after chemotherapy and RT for rectal cancer showed that colonic samples from males demonstrated a higher sensitivity and greater response to carbachol and histamine stimulation than did samples from females.

And a retrospective cohort study of cardiotoxicity during RT for esophageal cancer showed that women developed cardiac toxicity earlier and at much lower doses than did men.

Other studies show that women have an advantage when it comes to survival, Bezak said.

One study that assessed the impact of gender on progression-free survival (PFS) and overall survival (OS) after RT for esophageal squamous cell carcinoma found that for males, the median PFS was 10.6 months and OS was 15.9 months, whereas for females, the median PFS was 14 months and OS was 20.8 months (P = .0005).

"The increased survival here may be due to the heightened radiosensitivity in women, leading to a greater therapeutic effect," Bezak said.

Many factors could affect a person's response to radiotherapy, said Bezak.

"Obviously, there are differing anatomic and body shapes, lipid distribution, among men and women. There are lifestyle differences, because it is known that males are more likely to drink alcohol and smoke more than women. Then looking internally, we have different hormones and enzymes which dictate how we will respond to radiotherapy. We know that estrogen has some protective effect, especially when it comes to head and neck irradiation. Males can lose their sense of smell, but women don't. We speculate, because we don't have enough evidence as yet, that this could be a protective effect of estrogen," she said.

"Ideally, if we want to improve therapies, we should be developing more gender-specific treatment options," she said.

Consider Gender as a Variable in Clinical Trials

Gender is often not considered to be an independent prognostic factor, but it should be, Bezak said.

"Gender is often not isolated when people do various multivariate analyses, but researchers should start looking a bit more at gender as one of the factors. When we do preclinical research and are using cell lines, we should make sure we are using cell lines that are derived both from males and females. When we are doing animal studies, we should be using male and female animals," she said.

"I am researching head and neck cancer and also pancreatic cancer. In some of my past studies, I admit that we used female mice only, because they were less likely to bite you. At the moment, I am doing research on head and neck cancer, and unfortunately most of our cell lines are from males, so I need to record that as a potential bias. But in my pancreatic cancer research, I have made sure that 50% of the cell lines have been derived from males and 50% from females, so that will mitigate bias," Bezak said.

Poses a Question, but No Answer

Approached for comment, Brian Marples, PhD, professor of radiation oncology at the University of Rochester Medical Center, New York, said this is "a nice review of selective literature."

This article "poses a question, but the answer to this question is unknown," he cautioned.

"This manuscript does not answer that question either but highlights that much more work in this area is needed," Marples told Medscape Medical News.

Marples, who is also vice chair of the American Society of Radiation Oncology's Science Council, said the article is selective in nature.

"It does not describe negative studies, for example, and focuses instead on eight studies that show differences, and most of these are too small for firm or definitive conclusions. For example, the research on atomic bomb survivors showed more female than male cancers, but these were largely breast cancers, and data support induction of radiation-induced breast cancers, so this observation is somewhat expected," Marples said.

He agrees that gender plays a role in diseases generally and that the health of males is generally worse than females for a number of reasons, including weight, smoking history, inactivity, and different hormonal backgrounds.

However, in terms of radiosensitivity, this difference has yet to be definitively demonstrated.

"We know sex differences exist in mice in response to radiation and radiation response for some assays, with female mice less prone to cognitive defects of cranial irradiation and also potentially lung sensitivity, but we need more data from much larger studies for these claims to be definitive," Marples said.

Bezak and Marples report no relevant financial relationships.

Crit Rev Oncol Hematol. 2020 Mar;147:102881. Abstract

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