Cisplatin

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

Pharmacokinetic data do not indicate sex differences [11].

Effects

Small-cell lung cancer

A sex-based retrospective analysis of four small-cell lung cancer trials on patients (648 men, 358 women) who received similar chemotherapy consisting of cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin showed women have increased overall response rates (80.3%vs 66.9%, respectively) and survival (median years 1.3 vs 0.91, respectively) compared with men [7].

Non‐small cell lung cancer

A systemic review and meta-analysis published in Cochrane library 2015 evaluated the effects of administering chemotherapy following surgery or following surgery plus radiotherapy in patients with early-stage non‐small cell lung cancer.  When surgery plus adjuvant chemotherapy compared to surgery alone, the analyses were based on 8447 participants. Addition of chemotherapy was associated with an absolute increase in survival of 4% at five years. Evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone (n= 2660) revealed a comparable benefit, i.e. 4% increase in survival rate at five years. The study indicated no significant evidence that any patient subgroup defined by age, sex, histology, performance status, or stage benefited more or less from adjuvant chemotherapy. However, a tendency towards a more favorable effect on survival observed for women versus men when the effect of surgery and chemotherapy was compared to the effect of surgery alone [12]. A combined analysis of two parallel phase III trials (418 men, 113 women) conducted to test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non–small-cell lung cancer. The addition of cisplatin to single-agent chemotherapy neither prolonged overall survival nor improve global health status score of quality of life. Subgroup analyses revealed no sex-related differences in this regard [13].

Bladder cancer

A meta-analysis including 15 studies and 3071 patients, reported 2008 to 2019, showed that female patients with bladder cancer had more advanced disease than their male counterparts and had experienced worse oncologic outcomes. However, they benefit from neoadjuvant (but not adjuvant) cisplatin-based combination chemotherapy in addition to radical cystectomy more than do male patients. Female patients who had undergone radical cystectomy and neoadjuvant chemotherapy were likely to have better disease recurrence rate and cancer-specific mortality (but not overall mortality) rates than were the male patients (pooled hazard ratio, 0.66 and 95% CI, 0.44-0.98; and pooled hazard ratio, 0.49 and 95% CI, 0.29-0.81, respectively) [14].

Adverse effects

Emesis

Female sex predicts a greater risk for acute emesis and poor antiemetic control [15]. A study on 301 patients who received cisplatin-based combination chemotherapy, with antiemetic therapy based on metoclopramide, showed that patient’s sex may play an important role in modulating the antiemetic response to metoclopramide in cisplatin-based chemotherapy. Female sex predicted for increased incidence of nausea and vomiting [16].

Nephrotoxicity

Data from a retrospective study on patients (203 men, 197 women) with advanced solid tumors who had been treated with weekly high-dose cisplatin in the period 1990-2001 indicated a higher incidence of nephrotoxicity (defined as over 25% decline in estimated creatinine clearance) among women (OR 1.71, 95%CI 1.09-2.7) [17]. A retrospective study of adult patients (520 men, 301 women) treated with cisplatin from January 1, 2000 to September 21, 2011 showed a higher risk of acute kidney injury (defined as an increase from the baseline creatinine of 25% within 30 days after the first cycle of cisplatin) among women than men [18]. A retrospective nationwide cohort study, using Taiwan's National Health Insurance Research Database reviewed the records of 3973 men and 1154 women who had been treated with cisplatin. The proportion of women who had developed a new diagnosis of kidney disease during the first 90 days following the treatment was 39%. The proportion for men was 37%, but the difference was not statistically significant. However, stratifying patients by age group indicated that only postmenopausal women had a significantly higher risk of kidney injury (hazard ratio: 1.28; 95%CI: 1.02-1.61) than did men [19].

Hematological toxicity

A sex-based retrospective analysis of four small cell lung cancer trials on patients (648 men, 358 women) who received cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin indicated increased grade 3 and 4 hematological toxicity in females compared to men (anemia, 16.3% v 7.6%, leukopenia 80.4% v 69.2%). However, toxic death rates were similar for men and women (1.5% v 1.1%, respectively). Women also had significantly more stomatitis and vomiting of all grades [7].

Ototoxicity

A retrospective chart review of pediatric patients (age <18 years, 58 boys, 44 girls) who had completed cisplatin therapy showed that boys were four times more likely to experience hearing loss than girls (33 boys vs 10 girls). Severity of ototoxicity was inversely related to age [20].

Hiccups

Patients receiving cisplatin-based regimens were evaluated in a crossover study with two arms both including ondansetron and dexamethasone but with different ondansetron dosage intervals (233 men, 130 women in arm A, 228 men, 130 women in arm B). Women had significantly higher rates of vomiting and nausea. Men had a significantly higher incidence of hiccups in both treatment arms (35.2% vs 3.1% in arm A and 36% vs 2.3% in arm B, respectively). Hiccups usually began 24 h after cisplatin administration and persisted for some days [21].

Reproductive health issues

Cisplatin 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 cisplatin [22]. Swedish users, please consult Janusmed Drugs and Birth Defects (Janusmed fosterpåverkan).