Although an individual’s sex is one of the most important modulators of treatment response and toxicity, it is still not taken into consideration neither when deciding on treatment type and starting dose nor on dose adaptation in oncology (J Clin Oncol: no. 26 (September 10, 2018) 2680-2683). A sex and gender-agnostic decision-making is in glaring contradiction to the contemporary trend for precision oncology, although for the vast majority of the oncology community, including funding bodies and policy makers, precision oncology merely stands for molecular characterisation of tumours. Yet, without incorporation of a patient’s sex in treatment decisions, it is as if you are “practicing oncology with a blind eye”, as one of my surgeon colleagues once put it so nicely.
An ever-increasing body of evidence indicates that female sex is associated with significantly higher risk of experiencing adverse events from anticancer therapies. In a recent report, Unger and colleagues have analysed individual patient data from phase II and III clinical trials performed over 30 years, from 1989 to 2019 (J Clin Oncol. 2022 Feb 4;JCO2102377). Records of 202 trials testing systemic anticancer therapies in over 23,000 patients, of which 38% were women, were assessed with regard to severe treatment-related adverse events (AEs) (grade ≥ 3). Overall, women had a 34% higher risk of severe toxicity compared to men (68.6% vs 62.2%, odds ratio (OR) = 1.34, 95% CI 1.27-1.42), p<0.001). Importantly, this increased risk of AEs was present across treatment type (chemotherapies, targeted therapies, immunotherapies), AE type (symptomatic or hematological) and treatment setting (advanced vs adjuvant). In particular, among patients receiving immune checkpoint inhibitors the risk of symptomatic AEs was 54% higher in women compared to men (19.6% vs 13%, OR 1.54, 95% CI, 1.0-5 – 2.26, p= 0.03) confirming previous data from retrospective analyses as well as preliminary results of a prospective clinical trial presented at the ESMO Congress 2021. These results are not surprising given the differences in body composition, drug metabolism and immune functions between men and women, and emphasise once again that dosing of anticancer therapies needs to be urgently revisited.
Although it has been known for decades that the body surface area (BSA) does not correlate well with drug clearance or toxicity, it is the most widely used parameter for chemotherapy dosing. In clinical practice, dose reductions are often made arbitrarily for old, obese or underweight patients out of fear for excess toxicity, with the use of an idealised body weight or capping of the total dose, although it is well documented that neither the BSA nor the body mass index (BMI) do correlate well with the body composition. A patient with a high BMI can still be sarcopenic and therefore at higher risk of toxicity. The body composition significantly affects drug metabolism - in particular, the metabolically active fat-free body mass (FFM) does so. To measure the FFM and the body composition in an individual patient, a single abdominal CT scan of the L3-L4 region without contrast enhancement is sufficient, as it shows a strong correlation with whole body adipose tissue, muscle and lean tissue mass (Appl Physiol Nutr Metab 33(5): 997-1006).
The FFM is significantly higher in men: comparing a man and a woman of equal weight and height, it accounts for 80% and 65% of the man’s and woman’s body mass respectively. Moreover, the FFM decreases with increasing age of the patient (Eur J Clin Nutr 55(8): 663-672). These findings suggest potentially significant differences in drug metabolism in male vs female and in young vs old patients. Indeed, in a retrospective analysis of the SAKK 75/08 trial, sarcopenia was associated with increased grade ≥ 3 toxicity from chemoradiation for locally advanced esophageal cancer (Radiat Oncol. 2019 Sep 11;14(1):166).
The same findings are reported for targeted therapies, and in a meta-analysis low muscle mass was associated with significantly higher toxicity rate for sunitinib and sorafenib in renal cell carcinoma patients (RCC) (Eur Urol Focus. 2018 Apr;4(3):420-434). Dose reductions or treatment discontinuation due to toxicity are very common for targeted therapies. Cabozantinib, a potent TKI approved for the treatment of RCC with a starting dose of 60 mg once daily, is a prime example for a drug with a significant dose-toxicity relationship. In the CABOSUN and METEOR trials, grade 3-4 adverse events occurred in 68% of the RCC patients, leading to drug reduction in 60%, with a reported median dose of 44 mg in the METEOR trial. Interestingly, the response rate in these trials as assessed by an independent review committee was 20% and 21%, respectively, suggesting that dose reductions do not comprise the efficacy of the drug. This is supported by the subgroup analysis of the METEOR trial according to age. Although patients aged 65-74 years and > 75 years had an average daily median dose of 41 mg and 33 mg, respectively, the response rate was virtually identical (21% vs 19%, respectively) (Eur J Cancer. 2020 Feb;126:1-10).
Drug dosing based on the FFM could be a viable alternative to the current dosing of anticancer treatments as it would take patient characteristics such as sex, age and body composition into consideration and could, therefore, represent a great improvement for the quality of life of both, male and female cancer patients, protecting them from unnecessary toxicity without compromising the efficacy of their treatment.
We can significantly improve the outcome of cancer patients if we start considering a patient’s sex as what it is: an important modulator of treatment effects and not merely a confounder.