Karboplatin

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].

Since chemotherapeutic agents share some adverse effects, evaluation of a particular agent’s sex-related adverse effects during combination chemotherapy is complicated.

Another factor that complicates the evaluation of chemotherapeutic treatments’ effect is a poorer prognosis in men compared to women of most oncologic diseases that affects both sexes [4, 5]. For instance, and related to this particular context, female sex is a favorable prognostic factor in non-small cell lung cancer (NSCLC) [6-10]. The increased risk of cancer for men has generally been explained by differences in exposure of carcinogenic factors such as smoking, alcohol consumption and exposure of harmful work-related substances [4, 5]. The belief that men might present later with more advanced cancer might in part explain the poorer prognosis seen in men [4].

Pharmacokinetics and dosing

There is a linear correlation between the clearance of the platinum of carboplatin and glomerular filtration rate (GFR) [11]. Therefore, the dose of carboplatin needed to achieve a target AUC has historically been calculated starting with an assessment of GFR. Carboplatin dose in mg can for instance be calculated according to Calvert equation, which is based on GFR. The GFR has traditionally been calculated using the Cockcroft-Gault equation, in which the women’s GFR estimated to be 15% lower than the men’s, if the age, bodyweight and creatinine values are the same [12]. Thus, using Calvert formula, women in general would receive lower doses of carboplatin than men.

There are different sex-related dosing strategies. Either carboplatin doses are decided solely based on body surface area with no dose adjustments for women [13], or the doses are reduced by 15-31 %for women compared to men with comparable characteristics [14-17].

Effects

Whether the sex-related difference in pharmacokinetics plays a role in the effect of carboplatin is not clear. A meta-analysis comparing carboplatin-included cytotoxic regimens’ efficacy in treating NSCLC compared 3-4 cycles of treatment to 6 cycles. A tendency (p=0.18) towards a better overall-survival in women who treated with higher numbers of cycles of platinum-based combination chemotherapies was observed (147 received 6 cycles and 148 received 3-4 cycles). No influence of cycle number on overall survival was observed among men (330 received 6 cycles, 326 received 3-4 cycles) [18].

Eastern Cooperative Oncology Group (ECOG) E1594 trial randomized patients with advanced NSCLC to one of four platinum doublets (one included carboplatin/paclitaxel) (726 men, 431 women). All four regimens had comparable efficacy. Men and women had similar response rates (19% for both; p = 0.15 [19]).

In another study, the role of several factors including patient’s sex 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. The median progression free survival was also longer in women (5.3 vs. 4.4 months) [20]. 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 [20].

A pooled analysis included limited-stage small-cell lung cancer patients (103 men, 97 women) treated with induction chemotherapy followed by concurrent platinum (either cisplatin or carboplatin)-based chemotherapy and daily radiotherapy. The median overall survival for pooled population was about 20 months. Multivariate analysis found younger age and female sex independently associated with improved overall survival [21].

Adverse effects

Women treated with carboplatin and paclitaxel for different types of lung cancer had a higher rate of severe (grade 3–4) leukopenia and a lower median leukocyte nadir [19, 20]. Pooled data of lung cancer patients (156 men, 32 women) from two multicenter, prospective, observational studies were analyzed to identify risk factors for nausea and vomiting following chemotherapy. Multivariate analysis showed that female sex was an independent risk factor for both delayed nausea, and delayed vomiting [22].

Reproductive health issues

Carboplatin like most other anti-cancer drugs is not compatible with pregnancy. Therefore, it is recommended that both men and women use contraceptives during and for at least 6 months after use of carboplatin [13]. For more information regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).