Women suffer more adverse effects after cancer treatments than men

The picture of adverse effects—rare and frequent— of cisplatin, a common chemotherapy to treat advanced neoplasms, exceeds thirty; and pembrolizumab technical data sheet, an immunotherapy approved for several types of tumors, includes around a hundred possible collateral damages. No drug is harmless. But its side effects are uneven and many factors come into play, such as the patient's previous situation or underlying diseases. Also gender. An American study published in the journal Journal Of Clinical Oncology reveals that, after receiving cancer treatment, women have a 34% higher risk of developing serious symptomatic adverse effects than men. Above all, if the treatment was immunotherapy: when faced with this drug, women experience a 49% higher risk of sequelae than men.

The researchers reviewed phase II and III oncological studies carried out by the SWOG center between 1980 and 2019: excluding those trials on sex-specific tumors (such as breast or prostate), in total, they analyzed about 23.300 patients (38% women). who experienced nearly 275.000 adverse effects. Toxicity was greater in women, explains Joseph M. Unger, a biostatistician at the Fred Hutchinson Cancer Research Center and first author of the study: “We found especially large increases in severe toxicity in women compared to men who received immunotherapies. Given the increasing use of these new and important treatments, it should be a priority to better understand the magnitude and causes underlying these differences,” explains the researcher by email.

The scientific community already knew that there were differences between men and women in the therapeutic approach to cancer. But the studies that evaluated it, Unger clarifies, were limited to the impact of chemotherapy and its clinical results (survival and disease progression). “This is the first study to systematically evaluate, in a large sample, differences in treatment toxicity between men and women for traditional chemotherapeutic approaches, as well as novel therapies, such as targeted treatments and immunotherapies,” the expert points out.

Their research confirmed that women suffered more toxicity than men from the treatments and were also at greater risk of serious hematological adverse effects, especially in patients with colon cancer who received complementary treatment to the main therapy. The study does not specify the reason for these differences, but experts point out several hypotheses. “There may be differences in the extent to which women and men report adverse events, and there may be differences in how well they adhere to medications. Women and men may also differ in the way they physically process medications,” Unger notes. Women, for example, are less able to eliminate fluorouracil, a cancer treatment that kills cells that grow uncontrollably.

The study adds that the intestinal microbiome, which is the ecosystem of microbes that populates the body, may also be involved, “given its function in the regulation of inflammatory, metabolic and immune pathways,” in how women and men metabolize drugs.

The research also does not rule out that there may be a bias when it comes to reporting adverse effects, in the perception of ailments or in women reporting more than men. However, Unger points out, “It is important to note that we also see more severe hematologic toxicity in women, and assessments of such toxicities are based entirely on objective laboratory measures.” Thus, the difference in reporting would explain part of this pattern, “but only part,” adds the expert.

For Rafael López, president of the Foundation for Excellence and Quality in Oncology, the study has opened their eyes with something that they already suspected at the consultation: “We all sensed that women had more side effects, but official science He said no. This is going to make us change the way we test drugs, regulate them and administer them: we have to design the studies taking sex into account,” says the doctor, who is also head of Oncology at the Santiago de Compostela Hospital. Ruth Vera, coordinator of the Women in Oncology Commission of the Spanish Society of Medical Oncology, agrees that Unger's research shows that "there is an influence of sex on the toxicity of treatments and this should be taken into account when administering drugs and when dosing them.”

Both oncologists, who have not participated in the study, also support the hypotheses of the causes. Vera points out, for example, that “adherence to oral treatments is greater in women than in men” and the immune system in both sexes also behaves differently. López defends that “the hormonal system that makes men and women different has implications for the immune system” and it will be necessary to adjust the drugs by sex: “Now the doses are adjusted to weight or body surface area, but in the future they will also do so.” by sex or according to the hormonal situation: a patient of premenopausal or postmenopausal age will not be the same.”

Uneven clinical trials

Narjust Duma, oncologist at the Dana-Farber Cancer Institute and professor at Harvard Health School, goes one step further and warns that there are gender inequalities in oncology and they are there “from the beginning”: the differences in adverse effects , for example, have their origins far back, in preclinical studies, points out the researcher, who has not participated in Unger's study either: “One of the big problems in cancer research is that we use male cells and that means that when You study a drug in the laboratory before testing it in humans, you use animal models, such as mice, and they are usually male mice. “Most of the preclinical data comes from cell lines in animals that are male and the data we have is that the drug is potentially good… for men, but it has not been tested in women.”

And this inequality continues in clinical trials: “More men participate in trials. For example, in immunotherapy trials, only 30% of people participating are women. So why are there these inequities [in adverse effects]? Because we do not test these medications in women until the clinical trials and when these studies arrive, only a small percentage of women are offered to participate in them,” Duma points out. Precisely, In 2019, this researcher published an article in the journal Oncology which also found a higher prevalence of adverse effects in women with melanoma or lung cancer after receiving a type of immunotherapy. The study revealed that they could be at greater risk of sequelae associated with the immune system and more likely to develop endocrinopathies and pneumonitis.

Duma also points out that “there are gender inequalities in the entire cancer care process.” Also in diagnoses and in the beginning of treatments. For example, she points out: “In bladder, lung or kidney tumors, women suffer more delays in diagnosis and treatment because these tumors are normally attributed to older men. So when they go to the doctor, they are not included in the differential diagnosis because of this.” The researcher assures that, in women, the social and media focus is so focused on breast cancer that other types of tumors are “forgotten”: “We live in a bubble where we believe that women are only affected by cancer, Mom's, and that's not true. “More women die from lung cancer.” In an article in the magazine Nature, Duma denounced that “the research community continues to view lung cancer as a disease of older men, and the consequences of this stereotype can be detrimental to women, causing significant delays in diagnosis.”

Unger and his team encourage having “more awareness” of the differences between men and women and better understanding why this happens to improve the therapeutic approach. “Our hope and expectation is that cancer patients will increasingly receive individualized treatments, and that the patient's sex may be an important element when considering individualized treatment options.”

Fuente: El País