Paclitaxel

Additional information

Generally, women mount stronger innate and adaptive immune responses than men [1]. Women with lung cancer have a more favorable survival compared to men [2]. The 5-year survival is 17 percent among men, and 24 percent among women, in Sweden [3].

The incidence of lung cancer has decreased among men since from 1980s but has increased significantly among women, which reflects women's changing smoking habits. Now the proportion of smoking women is greater than the proportion of smoking men. In Sweden lung cancer made up 6.1% of all yearly cases of cancer, year 2016. The incidence was higher among women (6.8%, n=2067), compared to men (5.4% , n=1824) [3].

Pharmacokinetics and dosing

A retrospective population analysis on 86 men and 82 women with solid tumors shows patient’s sex to affect paclitaxel distribution and elimination. Women reach saturation of the peripheral compartment at lower plasma levels (0.83 vs. 1.74 mmol/l), have 20% lower plasma maximal elimination capacities and a 20% lower maximal transport rate to the first peripheral compartment than in men. However, women also have  a longer time to saturation of drug elimination (1 vs. 0.5 h) [4]. According to the textbook “Sex and gender differences in pharmacology”, the maximum plasma concentration is higher in females, even after a body-surface-adjusted dose. According to the authors different muscle/fat ratios and transport processes (e.g., due to differing p-glycoprotein activity) may explain the different saturation concentrations and the longer maximal transport rate in females [2]. These pharmacokinetic differences lead to an increased time above the toxicological threshold concentration in women and might explain the increased toxicity compared to male patients [2].

Women on average display higher expression and activity of CYP3A4. Sex-related differences in exposure could be of relevance for several substrates of the CYP3A family [2].

Effects

Eastern Cooperative Oncology Group (ECOG) E1594 trial randomized patients with advanced non-small cell lung cancer (NSCLC) to one of four platinum doublets (two included paclitaxel) and found that all four regimens had comparable efficacy. Eligible patients (726 men and 431 women) were included in an analysis that showed similar response rates (19% for both; p = 0.15). The median survival time for women, however, was significantly longer, 9.2 months for women (95% CI, 8.1–10.4) versus only 7.3 months for men (95% CI, 6.8–8.0 months) (p = 0.004 log-rank test). Men were slightly older. However there was no difference in response, toxicity, or survival by age [5]. 

In another study several factors including patient’s sex obtained retrospectively by medical chart review and their role in outcome were analyzed. Eligible patients (147 men and 80 women) with unresectable stage IIIB-IV NSCLC who received first-line chemotherapy of carboplatin and paclitaxel were included. The median survival time was 11.9 months for men and 22.2 months for women (p < 0.001). The median progression free survival was also longer in women (5.3 vs. 4.4 months, p = 0.0081) [6]. However, according to the authors, other factors like a more aggressive tumor in men and a higher percentage of never-smokers among female patients may have played a role [6]. 

However, a better outcome has been observed for female patients with NSCLC even with regimens not including paclitaxel [7, 8], or when paclitaxel was presented in both arms [9]. In general, female sex and younger age ≤70 years are associated with better prognosis for NSCLC [10]. 

Adverse effects

Toxicity is generally greater in women than in men [5, 6]. Significant higher frequency of toxicity (nausea, vomiting, alopecia, neurosensory, neuropsychiatric and cardiac toxicity grade 3 or higher) among women was observed [5].  Yamamoto et al. noted grade 3–4 leukopenia in 15% of male and 39% of female patients (p <0.001) [6].

Reproductive health issues

Paclitaxel, like other mitosis inhibitors, may be harmful to the fetus and should not be given during early pregnancy. For more information regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).