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3 Questions on...Paying More Attention to Sex Differences in Cancer Clinical Trials

With Anna Dorothea Wagner, MD, of the Lausanne University Hospital in Switzerland

DiGiulio, Sarah

doi: 10.1097/01.COT.0000549566.90681.ee
Opinion

Precision medicine is a hot topic in oncology right now. Check any oncology meeting schedule and you'll likely find at least one session on the topic. It makes sense. It's the idea that treating different patients with the same therapeutic approach may not result in the same outcome—given their genetics, their previous health status, their psychosocial needs, and numerous other factors.

And one of those factors that deserves a lot more attention is gender, according to Anna Dorothea Wagner, MD, an oncologist at the Lausanne University Hospital in Switzerland. She recently co-authored a comment within the “Comments and Controversies” section of the Journal of Clinical Oncology to bring more awareness to the issue of identifying sex differences in clinical trials (2018;36:2680-2683).

“Sex may have an impact on the efficacy and toxicity of all kinds of drugs,” she told Oncology Times. “We need to learn more about it.”

For some drugs (like 5-fluorouracil [5-FU], for example), evidence clearly shows there's more toxicity when used in women compared with men, she noted. But for other drugs, it's unknown (JAMA Oncol 2018;4:1003-1006). “And we need to learn more about it.”

Other data show that women are at higher risk of things like mucositis, nausea and emesis, and alopecia when they take certain cancer drugs for several types of cancer, Wagner and her coauthors noted in the study. For other drugs, there's evidence sex differences may change how well the drugs work in treating some cancers. And there's more evidence still that gender may affect tumor biology, which could mean that developing sex-specific strategies for treatment (in terms of dose and types of drug) might improve outcomes.

Wagner told Oncology Times why the issue warrants attention and what she suspects effective next steps will be.

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1 Why did you decide to write this editorial with your coauthors and why now?

“I work as a gastrointestinal oncologist and see many patients. I had several women, especially women with pancreatic cancer who had been treated with FOLFIRINOX (but after other treatments, too), who had major side effects—not only nausea and vomiting, but fatigue, diarrhea, and hematological toxicities, too.

“It was those clinical observations, and the suspicion of greater toxicities in women. I wondered why this was the case. These were patients in their 50s, motivated and dynamic, and in many cases managing full-time jobs [and/or] kids, who became too weak to leave [their couches] for at least 1 week after the treatment, and even in the second week they were too tired to do anything.

“They had no other reasons to develop such major side effects. So I suspected finally that it might be their sex. I looked in the literature and found some—but overall little—data on sex differences in side effects from chemotherapy.

“We then did a [secondary] analysis of the PETACC-3 trial, which confirmed the observation of significant higher toxicities in women for both 5-FU and FOLFIRI (JAMA Oncol 2018;4:1003-1006). The more I learned about the topic, the more interesting it became.”

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2 In your opinion, what are some of the reasons that sex differences have not been well-investigated in cancer research, particularly in terms of treatment and treatment efficacy?

“The discipline which systematically analyzes sex differences is gender medicine. For example, in Berlin and Vienna, medical faculties have a chair for Gender Medicine. At Stanford University, there is the Gendered Innovations in Science, Health & Medicine, Engineering, and Environment (to ‘harness the creative power of sex and gender analysis for innovation and discovery,’ according to the department's website).

“I think oncology could benefit significantly from this approach.

“The pioneer in gender medicine, Marianne Legato, MD, PhD, was a cardiologist. Following her initiative, much has been learned in the field of cardiology. In oncology, this work needs to be done. We just have not yet had the pioneers in this field.”

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3 The FDA and NIH have made some efforts in defining guidelines for participation in clinical trials. Why have previous steps not been significant enough to push the needle when it comes to this issue?

“They have certainly made important steps, but more remains to be done. The founding of the U.S. Department of Health and Human Services Office on Women's Health is an important step.

“However, the focus on women's health is not enough. I am not sure if that office will consider the question: for a drug with higher efficacy and a higher, but still acceptable toxicity in women, the dose in men might need to be increased to achieve a similar level of efficacy.

“The point is that what is the optimal treatment for a man might not necessarily be the optimal treatment for a woman. Current medical research needs to take this into account.

“Large databases which analyze systematically the effect of a patient's sex on all types of outcomes—efficacy and toxicity—are needed. If such differences are detected, they need to be correlated with pharmacokinetic data. As a function of the results, dose modifications according to sex may need consideration.”

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