Doxorubicin

Additional information

Men have an increased risk, and a poorer prognosis, than women of most oncologic diseases (common for both sexes) [1, 2]. 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 [1, 2]. The belief that men might present later with more advanced cancer might in part explain the poorer prognosis seen in men [1].

Since chemotherapeutic agents share some adverse effects, evaluation of a particular agent’s sex differences in safety during combination chemotherapy is complicated. Similarly, evaluation of a particular chemotherapeutic agent’s sex differences in effect is also complicated during combination chemotherapy.

Pharmacokinetics and dosing

Doxorubicin has a very large distribution volume with a triphasic elimination and is dosed per body surface area (mg/m2) [3]. In a clinical study, the median doxorubicin clearance was higher in men than in women (1088 mL/min/m2 vs 433 mL/min/m2), but the terminal half-life was also longer in men than in women (54 vs 35 h) (6 men, 21 women) [4]. A higher clearance of doxorubicin in men than in women was also shown in another study (852 mL/min vs 690 mL/min) (15 men, 16 women) [5]. The latter study was done in elderly patients (75-96 years of age) with diffuse large B-cell lymphoma, treated with doxorubicin, vincristine, cisplatine and rituximab [5]. Furthermore, in a third study, the clearance of doxorubicin was higher in men than in women (~1217 mL/min vs 1050 mL/min) with malignant solid tumors, but not when the clearance was normalized to body surface area (34 men, 76 women) [6]. In this study, a positive association between body surface area and doxorubicin clearance was seen, with a stronger correlation in men than in women [6].

The mean clearance of pegylated[TW1]  liposomal doxorubicin was shown to be higher in men than in women in a fourth study (0,9 mL/min/m2 vs 0,4 mL/min/m2) (49 men, 21 women) [7]. Moreover, men <60 years had a higher mean clearance of pegylated liposomal doxorubicin (1 mL/min/m2), compared to men ≥60 years (0,45 mL/min/m2), women <60 (0,46 mL/min/m2) and women ≥60 years (0,35 mL/min/m2) [7]. The patients in this study either had solid tumors (13 men, 21 women) or Kaposi’s sarcoma (36 men, 0 women) [7].

Effects

Different oncologic/tumor diseases may have various sex differences regarding underlying prognoses, which can affect the efficacy results in studies.

Better outcome in men

In a meta-analysis from 1997 based on 14 trials of doxorubicin-based adjuvant chemotherapy to patients with localized resectable soft-tissue sarcoma, the chance of overall survival seemed to be higher in men than in women, in a subgroup analysis (686 men, 847 women) [8]. Male sex was also a prognostic factor for survival in an early clinical study from the 80s in patients with non-Hodgkin’s lymphoma, who received doxorubicin among other oncologic treatments (39 men, 34 women) [9].

Better outcome in women

However, in another early study from the 90s, among patients with high-grade soft tissue sarcomas of the extremities and trunk (treated with adjuvant, post-operative, single-agent chemotherapy with doxorubicin) male sex was shown to be a be a risk factor for developing metastatic disease (79 men, 69 women) [10].

In concordance, female sex was also shown to be a prognostic factor for survival in five studies from 1985-2004 and in pooled data from four other studies from 1987-1999 (soft tissue sarcomas, low-grade lymphoma, small-cell lung cancer, advanced-stage Hodgkin’s disease; doxorubicin given among other oncologic treatment; in total 1827 men, 1152 women) [11-16]. In one of the studies, female sex was shown to be a prognostic factor for complete response [15]. In the pooled data, women also had superior overall response rates and more complete responses [16].

No differences in effect reported between men and women

Although, the patient’s sex was not shown to be a prognostic factor for overall survival or best overall response (complete response and partial response) in eight other studies from 1990-2017 were doxorubicin was a part of the oncologic treatment (advanced soft tissue sarcoma, diffuse large B-cell lymphoma, urothelial cancer, primary CNS lymphoma, Hodgkin’s disease or intermediate- or high-grade lymphoma; in total 825 men, 668 women) [17-24].

In concordance, no significant sex differences in 3-year overall survival or 3-year progression free/disease free survival were seen in two other studies from 2014-2015 were doxorubicin was a part of the oncologic treatment (diffuse large B-cell lymphoma and loco-regionally advanced nasopharyngeal carcinoma; 318 men, 162 women) [25, 26]. In one of these studies, only approximately 50% of the patients received doxorubicin [25].

The proportion of men and women with a complete histologic response (i.e. no viable tumor cells) to chemotherapy-treated osteosarcoma of the extremity (high-dose methotrexate, cisplatin and doxorubicin), was similar in one study from 1998 (149 men, 123 women) [27].

A higher complete-response rate was shown in women than in men, in a study from 1987 among patients with small-cell lung carcinoma (254 men, 145 women) who received doxorubicin among other oncologic treatments, but no sex differences were seen regarding the duration of disease-free survival [28]. Female sex was also shown to be a favorable prognostic factor for failure-free survival [28].

Adverse effects

The risk of cardiac toxicity with doxorubicin treatment is higher in women than in men, and it is also more severe in women [3, 29, 30]. In the US, dexrazoxane is recommended to women as a protective substance against the cardiotoxicity of doxorubicin[31], but this is not recommended in Sweden.

Female sex has also been shown to be a risk factor for grade 3/4 haematological toxicity (neutropenia in particular) in a study with soft tissue sarcoma patients who received doxorubicin monotherapy (272 men, 285 women) [32].

Pooled results from four studies among small-cell lung cancer patients showed that women had more hematologic toxicity, stomatitis and vomiting than men (i.e., anemia and leukopenia) (648 men, 358 women) [16]. More women than men had their treatment delayed for two weeks or more, but there were no sex differences regarding the fraction of patients who received all six treatment cycles [16]. Doxorubicin was a part of the oncologic treatment, but not given as monotherapy in the four studies [16].

In concordance, boys and men had a lower risk of grade 4 leukopenia, hospitalization, febrile neutropenia and red blood cell transfusion, compared to girls and women in another study, both when analyzed as accumulated adverse effects at the end of study and as toxicity per cycle (Ewing sarcoma; doxorubicin among other chemotherapeutic agents; 144 boys and men, 86 girls and women) [33]. More women than men received G-CSF (granulocyte colony-stimulating factors) and had a delayed chemotherapy administration when analyzed per cycle, but this was not significant when analyzed as accumulated adverse effects at the end of study [33]. More women than men received platelet transfusions when toxicities were analyzed as accumulated adverse effects at the end of study, but not when analyzed per cycle [33].

Girls and women were also shown to have a higher risk than boys and men of grade 4 neutropenia, grade 4 thrombocytopenia, hospitalization due to neutropenic fever and need of transfusion support (platelets and red blood cells) and G-CSF in a study with osteosarcoma patients (46 boys and men, 25 girls and women) [34]. In a logistic regression analysis, female sex was confirmed to be associated with worse hematologic toxicity. Doxorubicin was given with other chemotherapeutic agents in this study [34]. A better received dose-intensity was seen in boys and men (as a measurement of protocol compliance), compared to girls and women. The article authors pointed out that this probably was related to the higher reported toxicity among girls and women [34].

In a study based on data from four other trials, the patient’s sex was not shown to be associated with nausea or vomiting in patients receiving chemotherapy containing doxorubicin but not cisplatin (128 men, 323 women) [35]. In a pediatric study, a significant increase in parent-reported nausea over time was seen in boys, but not in girls, among children with acute lymphoblastic leukaemia receiving doxorubicin, among other chemotherapeutic agents (n=874 parent reports) [36].

Reproductive health issues

Fetal defects and miscarriages have been reported [3]. Fertile women should use safe anticonception methods during and up to six months after doxorubicin treatment [3]. Men who want children should, before doxorubicin exposure, save their sperm and refrain from having children during and up to six months after doxorubicin treatment [3]. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).