New study explores why females experience more side effects from head and neck cancer radiation

BUFFALO, N.Y. ­—  Radiation used to treat cancers of the head and neck leaves nearly every patient with painful inflammation and mouth ulcers. In roughly a third to more than half — depending on the dose and on whether chemotherapy is included — the damage becomes severe enough to interfere with eating, drinking or the treatment itself

Female patients seem to get the worst of it. Some clinical studies have indicated female sex as a risk factor for more severe oral mucositis (the clinical name for the mouth inflammation and ulcers), though the finding has not held up consistently across different groups of patients.

The stronger evidence, so far, comes from the laboratory, where female mice develop markedly worse radiation damage than males do. The reasons behind these sex differences remain unknown, according to a researcher in the University at Buffalo School of Dental Medicine.

Keith Kirkwood, DDS, PhD, Centennial Endowed Professor and associate dean for research in the Department of Oral Biology, recently received a $440,000, two-year grant from the National Institute of Dental and Craniofacial Research to delve into this mystery.

He’s working with Jonathan Bard, PhD, research assistant professor in the Department of Biochemistry in the Jacobs School of Medicine and Biomedical Sciences, who will handle the bioinformatics part of the study, and Lixia Zhang, MD, a research scientist and pathologist who works with Kirkwood.

They hope to figure out the biological causes for the apparent sex-based difference, with the aim of advancing treatment for radiation-induced oral mucositis, especially in females undergoing treatment for head and neck cancer. These cancers form in the mouth, including tongue, salivary glands, and gums, along with the throat, voice box, and nasal cavity.

“Oral mucositis is really difficult for patients because it makes eating and drinking very painful, which can lead to weight loss and dehydration,” says Kirkwood, whose research includes oral cancer progression. “It also can increase the risk of infection in an already fragile individual.”

While men are more likely than women to develop cancers of the oral cavity and pharynx, one subtype of these types of cancers has been climbing in women over the last several years, possibly tied to an increase in the human papillomavirus (HPV) infections, according to the Centers for Disease Control and Prevention. Other causes of head and neck cancer include tobacco and alcohol use, overexposure to ultraviolent rays and occupational exposure to cancerous substances.

Radiation therapy is relatively effective in treating some of these cancers, especially in the early stages. However, treatments for the resulting mouth sores are limited.

“There isn’t much beyond giving patients ice chips to numb the pain,” Kirkwood says. “One of the reasons the side effects are so severe is that radiation treatments are given in multiple small doses over several weeks — somewhere between 30 and 35 times —depending on the stage or severity of the cancer.”

Guidelines from the Multinational Association of Supportive Care in Cancer  recommend a handful of measures for these patients, including low-level light therapy, and a specific mouthwash, along with rigorous oral care. But none reliably prevents the sores, and no drug is approved to treat them in head and neck cancer patients.

While the standard radiation doses are typically the same for both sexes, women experience more severe reactions. This doesn’t surprise Kirkwood.

Kirkwood first saw the difference a few years ago in mice, working alongside a UB graduate student who happens to be his son, Cameron Kirkwood, on a different research project. The effect was striking: females fared distinctly worse in the oral mucositis model.

To test the hypothesis behind the sex differences for the new study, Kirkwood and his team are conducting complementary tests on mice. The first looks for sex-specific patterns in which genes’ oral tissue switches on and off after radiation.

The second one uses multimodal spectral flow cytometry — an analytical technique that can read dozens of markers on individual cells at once — to reveal which immune cell populations are present and how they shift after treatment. This should reveal whether specific immune cells differ between males and females.

If they are able to ascertain how and why oral mucositis develops differently in males and females, the findings could eventually point toward sex-specific prevention strategies, and toward drugs that work better in both. Kirkwood emphasizes that research is in the early stages.

“Hopefully, we will identify a number of potential targets,” Kirkwood says. “Then we would strategize the best way forward — to look at this in preclinical studies and then validate what we see in preclinical studies with human subjects to understand if it’s true.”

Because there is so little in the existing literature about the sex differences in mouth sores, the UB team will also build a single-cell atlas — initially of mouse tissue — and make it available to other researchers.

“The technologies that we have now with single-cell RNA-sequencing provide an understanding of differential gene expression not just in the tissue, but in the cells within that tissue,” he says. “That’s a huge amount of information. The atlas would also help us to understand how the cells interact with each other. Other investigators can use the information that we acquire, which could lead to more discoveries.”