Gender Differences in Chemo Side Effects

Liam Davenport

October 19, 2018

MUNICH — Women who receive first-line chemotherapy for esophagogastric cancer are more likely to experience a range of adverse effects and toxicities than men treated with the same regimens, despite the fact that outcomes and rates of overall toxicity are similar, say UK researchers.

Michael Davidson, MD, a clinical research fellow at the Royal Marsden Hospital National Health Service Foundation Trust, London, United Kingdom, and colleagues examined data from four trials involving more than 1600 patients treated with one of four chemotherapy regimens.

The study, which is the largest pooled analysis to date of the impact of gender on chemotherapy outcomes and toxicity in advanced esophagogastric cancer, was presented here at the European Society for Medical Oncology (ESMO) 2018 Congress.

It showed that women were significantly more likely than men to report all-grade and severe nausea and vomiting, as well as all-grade diarrhea, mouth ulceration, and hair loss, despite the fact that overall rates of all-grade and severe toxicity are similar.

Rates of peripheral neuropathy were higher in men than women.

There were no significant differences in survival between men and women, although the overall response rate was higher in men than in women. The difference was of borderline statistical significance.

Davidson said in a release that their "key finding" is that men and women "were affected by a number of different toxicities to varying degrees," despite receiving similar chemotherapy combinations.

He added, however, that "the clinical relevance of this remains to be established.

"Whilst there are not enough data here to support alternative chemotherapy dosing strategies for men and women, it is useful for clinicians to be aware of such findings in order to refine their treatment in other ways," he said.

Coauthor David Cunningham, MD, PhD, director of the National Institute of Health Research (NIHR) Biomedical Research Center at the Royal Marsden Hospital and the Institute of Cancer Research, London, agreed.

"This work adds to the growing body of evidence that gender can be an important factor in cancer treatment and that clinicians need to be aware of such differences," he said.

"For example, knowing female patients are more likely to experience side effects such as nausea and vomiting or diarrhea may allow for more tailored chemotherapy education and support to be given in order to optimize the management of these common problems."

Michel Ducreux, MD, PhD, of Institut Gustave Roussy, Villejuif, France, who was not involved in the study, pointed out that the notion that women and men respond differently to treatment is nothing new.

Commenting for ESMO in a release, he said: "Dissimilarities in men's and women's reactions to treatment had already been observed in a number of past clinical trials.

"Until recently, though, because no one could explain why such differences might exist, they tended to be written off as a statistical artifact and remained absent from the discussion."

He continued: "In the clinic, meanwhile, the trends highlighted in this study would have been imperceptible to physicians. Thanks to the large number of patients included, this analysis was able to show statistically significant gender differences in the frequency of several side effects of chemotherapy."

Ducreux said that the challenge now is that "not only must we discuss their implications, we also need to understand the underlying reasons.

"Going forward, we might consider stratifying patients according to their gender in clinical trials, so as to evaluate the efficacy and tolerance of treatments in each sex from the beginning of drug development," he said.

"If further studies systematically confirm that women are more prone than men to a wider range of side effects, then we will also need to think about entirely different prevention and support strategies for female patients," he added.

Study Details

For their study, Davidson and colleagues assessed the toxicity associated with four first-line triplet chemotherapy regimens used in four NIHR multicenter randomized controlled trials in patients with advanced esophagogastric cancer.

The four chemotherapy regimens were ECF (epirubicin, cisplatin, and 5-fluorouracil), ECX (epirubicin, cisplatin, and capecitabine), EOF (epirubixin, oxaliplatin, and 5-fluorouracil), and EOX (epirubicin, oxaliplatin, and capecitabine).

"The four trials we included were large international trials conducted in the UK and Australasia, with comparable patient populations and treatments being used," Davidson noted.

From these four trials, the researchers were able to pool data on 1654 esophageal cancer patients, of whom 1328 (80.3%) were male and 326 (19.7%) were female.

Men and women were comparable with respect to age and performance status. Women were more likely to have gastric tumors than men, at 57.4% vs 34.1%.

Davidson pointed out that these population characteristics "are consistent with the incidence and distribution of esophagogastric cancers in Western populations."

Overall, there was no significant difference in the occurrence of all-grade or grade ≥3 toxicities between women and men, at 67.2% vs 62.8% (P = .19).

In women, however, rates of nausea and vomiting were significantly higher than in men, at 89.3% vs 78.3% (P < .001), for all grades of this adverse effect. They were also higher, at 16.7% vs 9.5% (P = .004), for the most severe, grade ≥3 nausea and vomiting.

In women, rates of all-grade diarrhea were higher than in men, at 53.8% vs 46.9% (P = .027), as were rates of all-grade stomatitis, at 49.5% vs 40.7% (P = .004) and all-grade alopecia, at 81.4% vs 74.3% (P = .009).

The researchers found that for women compared to men, there was a trend toward higher rates of grade ≥3 neutropenia, at 45.1% vs 40.4%, and grade ≥3 febrile neutropenia, at 11.8% vs 7.7%. These differences did not reach significance.

In contrast, men were significantly more likely to experience all-grade peripheral neuropathy than women, at 49.3% vs 42.6% (P = .03).

Crucially, there was no significant difference between women and men with regard to progression-free or overall survival, although the overall response rate was higher in men than in women, at 46.6% vs 40.4%. This differene was of borderline significance (P = .051).

The study was funded by the Royal Marsden's GI and Lymphoma Unit, the NIHR Biomedical Research Center at the Royal Marsden Hospital and the Institute of Cancer Research, and the Royal Marsden Cancer Charity. Dr Cunningham has received research funding from Amgen, AstraZeneca, Bayer, Celgene, Merck-Serono, Medimmune, Merrimack, Novartis, Roche, Sanofi. Coauthor Naureen Starling, BSc, MD(res), reported several financial relationships with industry. The other authors have disclosed no relevant financial relationships.

European Society for Medical Oncology (ESMO) 2018 Congress. Abstract 619PD_PR, presented October 19, 2018.

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