the need to include SEX considerations in cancer care

because sex does matter, and we haven’t been paying enough attention.

AUGUST 2023

by Lulu Patterson

The idea that certain diseases do not affect one or the other sex is a problematic misconception that creates a barrier to providing quality care. When breast cancer is passed off as a “women’s cancer,” male patients experience delayed detection and poorer prognosis. The same is true when symptoms of heart disease go unrecognized in women based on the misconception that it is a “men’s disease.”

Underneath these misconceptions is, however, an important kernel of truth: detecting certain diseases requires attention by medical professionals to sex-specific symptoms and diagnostic criteria. A healthcare system that fails to acknowledge the differences in disease presentation in male versus female patients is one that will inevitably fail a large share of a diseased population.

not only are women still underrepresented in clinical trials, but also, most biomedical research has been done on exclusively male animals

Despite tremendous progress toward a personalized approach to cancer care, it is surprising to see how much sex-related considerations have been left out of the conversation about cancer. Aside from a short list of reproductive cancers (cervical, ovarian, prostate, penile, and testicular), cancer does not discriminate on the basis of sex — yet, quality cancer care traditionally does. The path toward truly equitable and quality cancer care begins with eradicating the sex-based biases that have plagued the life sciences research and medical world.

the cancer care gap for women

Historically, women have been underrepresented in our research toward understanding and treating diseases. For numerous years, clinical trials have been recruiting mostly male patients, meaning that our diagnostic criteria, diagnostic tools, and recommended drug uses (including dosage and side effects) have been developed and tested primarily, if not only, for men [link]. This fundamental gap exists in many pockets of the healthcare sector, but it is particularly baffling for us to find it in the oncology space [link].

The path to cancer diagnosis and treatment generally has more obstacles for women than it does for men as we will review here. Albeit the evidence is parsed, women face greater delays between the onset of symptoms and diagnosis and longer times for referrals [link. Women tend to be diagnosed with cancer an average of 2.5 years later than men [link, link]. The discrepancy is even larger in the case of metabolic diseases, which women are generally diagnosed with 4.5 years later than men [link, link]. Women endure longer intervals before diagnosis in most non-sex-specific disease sites than men [link].

Delayed diagnosis also often results in higher treatment costs for patients and payers. Not to mention delayed diagnoses have the potential to result in financial and reputation-damaging legal action for hospitals and doctors.

We identified several underlying issues that often are described as root causes for delayed diagnosis of cancer in women:

• education: during medical studies, doctors have been taught diagnostic criteria that are usually based on a male presentation of cancer and are generalized to women. This leads to misconceptions about routine checkups that may result in delayed diagnosis for women [link, link]
• sex-specific response to pain: studies show men and women respond differently to pain [link], and doctors respond differently to reports of pain by men and women [link]. The result is a delay in cancer diagnosis disproportionally affecting women [link, link].
• diagnostic test accuracy: examples of tests yielding different accuracy for men and women are numerous. While we may be tempted to think that such limitations are a thing of the past, here is a recent example. A 2022 study at University College London found that an algorithm designed to help doctors detect liver disease missed the disease in 23% of men and 44% of women [link]. Liver cancer most often begins as liver disease. The study’s authors conclude that the accuracy gap may be attributed to variances in albumin levels across sex. Albumin levels are a known, fairly accurate early diagnostic indicator of liver disease in men. But, albumin levels are not as accurate an indicator in women. (Incidentally, the disease is less prevalent in women but also generally more aggressive, meaning that accurate early diagnosis is especially important.) There are numerous additional cases in which a diagnostic test has shown lower sensitivity when performed on women. A Spanish study on rectal cancer presented that women experience a delay in the suspected and confirmed diagnosis compared to men, which is attributed to sensitivity bias for rectal cancer diagnostic tests, compounded by differences in referrals based on sex [link]. A study demonstrated that although women more closely followed colon screening protocols and recommendations than men, the sensitivity of screenings was higher for men than women [link].

These studies point to numerous possible interventions that would reduce inequality to access to early diagnosis, starting from enhancing medical curricula to include, at the minimum, awareness of the issue.

sex-specific TREATMENT plans drive better outcomes

Treatment for cancer requires physicians to make numerous critical decisions.

When it comes to treatment type, there are many types of treatment available such as chemotherapy, radiation, immunotherapy, and more. The type of treatment will often depend on the cancer’s characteristics and can include a combination of different types. Sex differences may impact the effectiveness of treatments. An illustration of this gap in sex-focused, cancer-specific treatment occurs in glioblastoma [link]. Sex differences in glioblastoma, the most aggressive form of brain cancer in adults, have been thoroughly studied, showing incidence rates 60% higher in men as well as detailed discrepancies in tumor genetic profiles informing prognosis with greater accuracy. The effectiveness of this treatment process is measured by accounting for tumor growth velocity. Women showed greater slowing of their tumor growth velocity than men–meaning this treatment plan was more effective for women than men. However, treatment guidelines are generally the same for women and men, and the standard treatment for glioblastoma consists of surgery, chemotherapy, and radiation therapy [link]. In a reversal of roles, in the Spanish study referenced above on the differences in the diagnosis of rectal cancer for women and men, it was also shown that women are also less likely to be given preoperative radiotherapy, which the authors argue may contribute to cancer most spreading to other parts of their body in women [link].

Treatment modeling that includes sex considerations accounts for different drug metabolization rates and, consequently, ideal drug dosage based on sex. Not only the choice of the most effective drug for a patient can be influenced by sex, dosage holds equal importance. In 20xx, a study that considered sex differences in cancer described the discrepancies in drug absorption between men and women [link]. According to this study, both enzyme type and enzyme activity levels are different in the two sexes — factors which, in combination with others, determine drug metabolization. Little known fact is most biomedical research today is conducted in male animals [link] and male cells [link], To compound the issue are years of underrepresentation by women in drug clinical trials [link]. As a result, many drug dosages are based on how the male body processes the treatment. Even cases of unexpected toxicity have been recorded, resulting in a drug actually being removed from the market. it is estimated that variations in male versus female drug metabolization (and a lack of understanding of these variations), are responsible for 20% of overexposure in women, according to the aforementioned research [link].

The best treatment plan cannot be found without accounting for patients’ preferences, which are known to vary between men and women and may impact the success rates of their treatment. A study from the Netherlands found that women and men differed in what they looked for in their cancer care [link]. While women placed more value on psychosocial support within their medical team, like the attitudes of their nurses, men more commonly sought support from other individuals, like their wives. Women were also more likely to take advantage of support services, see greater value in confiding in their support, and were more likely to feel that they did not have sufficient support [link]. Another study found that while men were more likely to evaluate the costs and benefits of treatment plans, women were more likely to choose the most aggressive treatment option for fear of recurrence. Women appeared to hold less trust in their doctors and sought support from other women who had similar experiences and expressed their fears, whereas men tended to speak about their emotions and prognosis with more “matter-of-fact” verbiage [link].

While cancer affects fertility regardless of gender, cancer occuring in the reproductive age is more likely to affect women, who are asked to weigh the benefits and risks of fertility preservation procedures [link, link] as part of their treatment plan. Disproportionally for women, cancer care does not just occur within an oncology department but instead often requires the involvement of OBGYNs and fertility specialists, with significant secondary costs on top of cancer treatments [link]. Here, it may be argued that we are placing a higher burden on women — or that we are doing a disservice to men by not offering them enough counseling and options regarding the unintended consequence of treatments on their ability to have children after cancer.

effective SYMPTOMS management must be personalized

Patients often experience cancer in different ways, meaning that symptoms and side effects of their treatment manifest differently. Educating patients about exactly what symptoms to expect during and after treatment and understanding and responding to patients’ symptoms is key to delivering patient-centered medicine.

It is crucial, then, that sex-related considerations are included in modeling cancer development and symptom management. A study on patients with esophageal and gastric cancer found that while men and women had equal rates of toxicity from chemo, women were more likely to experience losing hair, vomiting, diarrhea, feeling nauseous, and mouth ulcers as side effects of treatment; men, on the other hand, displayed higher rates of peripheral neuropathy — a condition characterized by nerve damage which manifests as numbness and weakness in limbs [link]. In a study referenced above, women were more likely to experience “‘serious adverse events’” that could put them in the hospital– after receiving cancer treatment than men due to increased infections which in turn could be linked to women’s generally lower levels of white blood cells [link].

By understanding how the same treatments might manifest as different side effects based on sex, doctors can better prepare their patients for what lies ahead and offer improved symptom management. As symptoms vary in type and severity, patients will have to find different ways to monitor and address them. The burden of symptoms impacts patients’ overall quality of life and can be reduced by establishing different habits. Recognizing the difference in sex-specific symptoms is key to drive adherence and reduce the burden of treatment on patients.

After a cancer diagnosis, managing symptoms requires effective communication between patients and doctors. This, too, can differ depending on whether a patient is a man or woman, a key point for doctors to note in order to guide patients best. Women experience more openness to talking about physical and emotional side effects than their male counterparts. Addressing the psychological side effects is a key aspect in improving the well-being of patients and, with it, the success of their treatments.

Leveling the playing field using technology and adopting personalized, sex-specific tools for symptom management can optimize and inform patient care plans to minimize the detrimental effects of treatment and improve quality of life. This may empower patients who are already experiencing a challenging time and enable them to regain control of their well-being. The improved mental state has been proven to improve the likelihood of success for a given therapy, decreasing the overall load on the health system.

less judgment, more doing

Sex-based inequality extends, unfortunately, also to medicine and healthcare. There are numerous historical reasons why the world looks this way. We are not here to judge. Innovation starts when we recognize that there’s a problem in the world and then decide that we’re going to solve it. We are here to shed light on it and start a conversation.

It is tempting to leverage technology to create valuable sex-specific medical care; however, one must be careful not to introduce new variations of the same biases and disparities that we would like to see eradicated. The successful implementation of technology solutions that are accessible to all and that create better prevention, detection, treatment, and symptom management that is mindful of sex differences may be, from this point of view, the preferred way forward — wherever possible and appropriate. While developing them may (will) be more costly, the jury’s out on the health economics — we simply could not find lots of work being done to understand how much value such investment would yield. We think it would be high and benefit everyone — men and women alike.

pppst.

Sex and gender are occasionally used interchangeably. Both sex and gender affect research results, but they have different meanings. Thus, it is important to know their correct meanings and avoid interchangeable use. According to the US Institute of Medicine (IOM), sex is “the classification of living things, generally as male or female, according to their reproductive organs and functions assigned by chromosomal complement,” while gender is “a person’s self-representation as male or female or how social institutions respond to that person on the basis of the individual’s gender presentation. Gender is shaped by environment and experience.” Thus, sex is related to reproductive organs, sex hormones, gene expression, anatomy, and physiology. Gender refers to socio-culturally constructed roles, norms, identities, and power relations that shape ‘feminine’ and ‘masculine’ behaviors. Sex can be used for both humans and animals as whole organisms or materials derived from them, such as cells and tissues, while gender is, in general, used only for humans. Importantly, sex and gender affect each other, as gender is rooted in biology and can influence biological outcomes.