Sex Differences in the Drug Therapy for Oncologic Diseases

Abstract

There are clear gender-dependent differences in response rates and the probability of side effects in patients treated with chemotherapy. Sex-biased expression levels of metabolic enzymes and transporters in liver and kidney leading to different pharmacokinetics have been described for most common anti-cancer drugs. In women, half-life is often longer, which is associated with improved survival, but also increased toxicity.Some chemotherapy protocols lead to a better response rate in women without increasing toxicity (e.g., cisplatin and irinotecan), while others only increase toxicity, but do not improve response rates in women (e.g., 5-fluorouracil). The increased toxicity often correlates with different pharmacokinetics, but women also show a higher sensitivity to some agents with shorter half-life (e.g., steroids). Organ-specific toxicities like cardiac toxicity after doxorubicin treatment or neurotoxicity associated with ifosfamide are more severe in women due to gender-specific changes in gene expression. Novel therapies like tyrosine kinase inhibitors or monoclonal antibodies show very complex, but clinical significant differences depending on gender. Antibodies often have a longer half-life in women, which is associated with an improved response to therapy.Side effects appear to be highly dependent on different tissue properties, as women have a higher incidence of oral mucositis, but lower rates of gut toxicity. Nausea and vomiting is a greater problem in females during therapy due to the lower activity of anti-emetic drugs. Nausea and vomiting pose a bigger challenge in female patients, as anti-emetic drugs seem to be less effective.

Increased CDA Expression/Activity in Males Contributes to Decreased Cytidine Analog Half-Life and Likely Contributes to Worse Outcomes with 5-Azacytidine or Decitabine Therapy

“…This is the first demonstration of a gender difference in CDA-expression and its impact on 5-azacytidine or decitabine treatment outcomes, however, greater efficacy, but also greater toxicity in females for a number of other cancer drugs has been documented, associated with lower expression in females of liver or kidney metabolic enzymes and transporters relevant to metabolism of these drugs (reviewed in(46)). The specific mechanisms or reasons underlying this broad gender-bias in expression of metabolic enzymes have not been characterized.…”

Influence Of The Number Of Platelets And Hemoglobin Concentrations In Predicting The Development Of Proteinuria Induced By The Administration Of Bevacizumab

“…All of the above findings suggest that oestrogen has a prominent role in preventing the development of colorectal cancer. Moreover, antibodies have a longer half-life in women, resulting in an improved response to treatment with monoclonal antibody (22). Wakelee and associates examined the effects of age and gender on the survival of patients with NSCLC with and without bevacizumab.…”

Risk factors and model for predicting toxicity‐related treatment discontinuation in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor–targeted therapy: Results from the International Metastatic Renal Cell Carcinoma Database Consortium

“…Pharmacokinetic studies of sunitinib and sorafenib found no clinically relevant differences in sex to warrant dose adjustments, and sorafenib phase 3 trials found no differences in toxicity. 24,25 However, bevacizumab was found to have pharmacokinetic variability based on sex. 26 Although sex has not appeared to affect the efficacy of VEGF-targeted therapies, 25 further research should be performed to determine the true impact of sex on toxicity.…”