When Crystal Ortner was diagnosed with stage 4 colon cancer, her doctors decided to tackle it with an extremely aggressive chemotherapy regimen that included six drugs, along with numerous surgeries.
During her initial round of treatment, Ortner experienced septic shock, causing her doctors to cease chemotherapy for a period of time because her body was too weak to handle it. Later, she said, her extreme side effects while on chemotherapy — constant vomiting, nausea, an overall feeling of complete debilitation — felt like “going to hell and back.”
“Chemotherapy is like death coursing through your veins. And you feel like you’re going to die, and you’re given just enough time to recover to go back and do it all over again,” said Ortner, a 37-year-old mother of two and clinical psychologist in South Florida.
There’s no telling how other patients may have responded to the treatment. But there’s at least some reason to believe Ortner’s sex could have been a factor.
Research has long shown that women are more likely than men to have severe reactions to chemotherapy treatments. At the same time, emerging evidence suggests that women also experience greater toxicity with targeted therapies and immunotherapies, which aim in part to mitigate the inherent toxicities of chemotherapy.
Overall, women were 34% more likely than men to experience severe adverse effects in response to their cancer treatments, a figure that increased to 49% for women receiving immunotherapies, according to a recent study in the Journal of Clinical Oncology (JCO). The study was based on 30 years of data from the SWOG Cancer Research Network, a global cancer research community that designs and conducts publicly funded clinical trials.
Part of the problem, experts say, is that sex differences are not taken into account in the development of cancer treatments.
“The majority of single-cell studies that are happening right now in 2022 are male single-cell studies,” said Narjust Duma, who treats lung cancer patients at the Dana-Farber Cancer Institute and advocates for more inclusive cancer research.
Duma, who was not involved in the study, explained that most cell lines and animal models used in preclinical studies of investigational cancer drugs have XY chromosomes, not XX. Additionally, Duma said, upward of 70% of participants in Phase 1 trials are men.
As a result, any indicators that, say, an immunotherapy is “very well-tolerated” generally apply only to men, Duma said. Phase 1 trials guide dosing decisions for later-stage trials.
The JCO study examined Phase 2 and 3 trials conducted from 1989-2019, and analyzed the severe treatment-related adverse effects of chemotherapy, targeted therapy, and immunotherapy. Researchers excluded sex-specific breast and prostate cancers. They also focused on adverse effects such as trouble breathing or bone marrow suppression — complications significant enough that they often require hospitalization.
Sixty-two percent of study participants were men; 9% of study participants were Black; and 5% were another or unknown race.
“We need to have better representation in clinical trials — not only males and females, but also making sure we get adequate representation of non-white participants,” said Margaret Gatti-Mays, an immunotherapy specialist at Ohio State’s James Comprehensive Cancer Center.
She said the study “really pointed out that void in the research literature. We have to do better.”
Joseph M. Unger, a biostatistician at the Fred Hutchinson Cancer Research Center and the study’s first author, said that, to his knowledge, the study is the first to look at sex differences in severe adverse events in clinical trials in relation to targeted therapies and immunotherapies.
While Unger’s study focuses on clinical trials specifically, reports of greater adverse reactions to immunotherapies among women have begun to emerge.
In 2019, for example, Duma reported that women receiving immunotherapies for melanoma or non-small cell lung cancer experienced more adverse events than men — sometimes including extensive kidney or liver damage. Gatti-Mays has observed a similar pattern.
Not all of the reasons why women can experience harsher responses to cancer treatments than men are clear, although experts have some likely explanations. Women take longer than men to metabolize drugs, on average, said Sue Haupt of the Peter MacCallum Cancer Centre in Australia. That explains the greater toxicities women often experience during chemotherapy, suggested Haupt, who has studied sex disparities in cancer extensively.
When it comes to immunotherapies, Haupt hypothesized that one reason women could have harsher reactions is because they are more prone to autoimmune diseases than men. The entire purpose of an immunotherapy is to prime someone’s immune system to fight cancer, which may in turn spur some women’s immune systems into overdrive. Haupt said large-scale clinical trials would be necessary to test this hypothesis. She also noted that women might also benefit from their generally stronger immune systems; women are less likely to develop cancer than men in the first place.
Gatti-Mays finds one encouraging glimmer in the JCO data: Despite experiencing more adverse events than men, women maintained their treatment protocols for just as long. This could mean that the adverse events did not impede women’s quality of life as greatly as it might appear at first blush. That’s a question Unger hopes to explore in future work.
“I’m interested to understand whether quality of life, which is the very immediate sort of experience of a patient’s well-being, whether that actually differs by sex. To me that would sort of further develop this idea of sex-based differences in the experience of cancer treatments,” Unger said.
Duma said she fears that some clinicians could pull some women patients off an immunotherapy or targeted therapy once serious adverse events occur, despite the JCO data showing that women can sustain treatment, rather than managing those events so that the women continue to get the benefits of the treatment.
She said she also has some sympathy for physicians who prescribe high doses of chemotherapy or immunotherapies. In the case of chemotherapy, the dogma of “maximum tolerated dose” is entrenched, Duma said. For now immunotherapies are also given at the same dose to everyone regardless of their sex and weight.
It’s ironic, in Duma’s view, that one of the most obvious distinctions between people — right down to their chromosomes — is mostly ignored in cancer drug development. Precision only goes so far, at least for now.
“The beginning of precision oncology is that men and women are different. We’re equal, but we’re different,” Duma said.