Portal de Periódicos da CAPES

Sex differences in cancer chemotherapy effects, and why we need to reconsider BSA-based dosing of chemotherapy

2020; Elsevier BV; Volume: 5; Issue: 5 Linguagem: Inglês

10.1136/esmoopen-2020-000770

2059-7029

Dorothea Wagner,

Peptidase Inhibition and Analysis

One sees only what one knows.Johann Wolfgang von Goethe Thus we ignore what we don’t know. In oncology, it is traditionally assumed that men and women are equal. As a result, sex differences in treatment effects and the biology of non-sex-related cancers have largely been ignored in the last decades. However, the observation of increased chemotherapy toxicity in women is not new. Although overall insufficiently studied, available data from different types of tumours1.Cristina V. Mahachie J. Mauer M. et al.Association of patient sex with chemotherapy-related toxic effects: a retrospective analysis of the PETACC-3 trial conducted by the EORTC gastrointestinal group.http://www.ncbi.nlm.nih.gov/pubmed/29800044JAMA Oncol. 2018; 4: 1003-1006doi:10.1001/jamaoncol.2018.1080Google Scholar, 2.Singh S. Parulekar W. Murray N. et al.Influence of sex on toxicity and treatment outcome in small-cell lung cancer.http://www.ncbi.nlm.nih.gov/pubmed/15681530J Clin Oncol. 2005; 23: 850-856doi:10.1200/JCO.2005.03.171Google Scholar, 3.Klimm B. Reineke T. Haverkamp H. et al.Role of hematotoxicity and sex in patients with Hodgkin's lymphoma: an analysis from the German Hodgkin Study Group.http://www.ncbi.nlm.nih.gov/pubmed/16204002J Clin Oncol. 2005; 23: 8003-8011doi:10.1200/JCO.2005.205.60Google Scholar, 4.van den Berg H. Paulussen M. Le Teuff G. et al.Impact of gender on efficacy and acute toxicity of alkylating agent -based chemotherapy in Ewing sarcoma: secondary analysis of the Euro-Ewing99-R1 trial.http://www.ncbi.nlm.nih.gov/pubmed/26271204Eur J Cancer. 2015; 51: 2453-2464doi:10.1016/j.ejca.2015.06.123Google Scholar clearly demonstrate that women are more susceptible to toxicity from various types of chemotherapy. Theoretically, sex differences in drug effects can be broken down into two categories: 1.Differences in pharmacokinetics: sex differences in pharmacokinetics have been reviewed elsewhere5.Soldin O.P. Mattison D.R. Sex differences in pharmacokinetics and pharmacodynamics.http://www.ncbi.nlm.nih.gov/pubmed/19385708Clin Pharmacokinet. 2009; 48: 143-157doi:10.2165/00003088-200948030-00001Google Scholar and affect the different types of pharmacokinetic parameters, such as bioavailability, distribution, metabolism and excretion.6.Gandhi M. Aweeka F. Greenblatt R.M. et al.Sex differences in pharmacokinetics and pharmacodynamics.http://www.ncbi.nlm.nih.gov/pubmed/14744256Annu Rev Pharmacol Toxicol. 2004; 44: 499-523doi:10.1146/annurev.pharmtox.44.101802.121453Google Scholar Examples for chemotherapeutic drugs with significant sex differences in pharmacokinetics are 5-fluouracil7.Mueller F. Büchel B. Köberle D. et al.Gender-Specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study.http://www.ncbi.nlm.nih.gov/pubmed/23139054Cancer Chemother Pharmacol. 2013; 71: 361-370doi:10.1007/s00280-012-2018-4Google Scholar and paclitaxel.8.Joerger M. Kraff S. Huitema A.D.R. et al.Evaluation of a pharmacology-driven dosing algorithm of 3-weekly paclitaxel using therapeutic drug monitoring: a pharmacokinetic-pharmacodynamic simulation study.http://www.ncbi.nlm.nih.gov/pubmed/22804749Clin Pharmacokinet. 2012; 51: 607-617doi:10.1007/BF03261934Google Scholar However, the impact of the patients’ sex is most often not analysed, and/or subgroup analyses according to sex are not reported in pharmacokinetic studies and clinical trials. According to a recent literature survey of population pharmacokinetic studies of anticancer drugs,9.Wagner A.D. Oertelt-Prigione S. Adjei A. et al.Gender medicine and oncology: report and consensus of an ESMO workshop.http://www.ncbi.nlm.nih.gov/pubmed/31613312Ann Oncol. 2019; 30: 1914-1924doi:10.1093/annonc/mdz414Google Scholar among 256 studies identified, only 80 reported sex as a tested covariate.2.Differences in pharmacodynamics: in addition to differences in drug metabolism, the sensitivity of both normal tissues and tumours in men and women may be different. Furthermore, the dose–response and dose-toxicity relationships may not necessarily be the same in both sexes. While differences in incidence and mortality of different types of cancers have initially been attributed to differences in exposure to risk factors, evidence from large epidemiologic studies clearly indicates significant sex differences in susceptibility and survival of non-sex-related cancers, which cannot be explained by differences in behaviour. Clocchiatti and colleagues introduced the term ‘sexual dimorphism in cancer’ to describe this observation.10.Clocchiatti A. Cora E. Zhang Y. et al.Sexual dimorphism in cancer.http://www.ncbi.nlm.nih.gov/pubmed/27079803Nat Rev Cancer. 2016; 16: 330-339doi:10.1038/nrc.2016.30Google Scholar In addition, sex-biassed gene-expression signatures have been described for multiple solid tumours.11.Yuan Y. Liu L. Chen H. et al.Comprehensive characterization of molecular differences in cancer between male and female patients.http://www.ncbi.nlm.nih.gov/pubmed/27165743Cancer Cell. 2016; 29: 711-722doi:10.1016/j.ccell.2016.04.001Google Scholar Sex differences in host factors, especially the immune responses, differentially affect the susceptibility to many diseases, especially autoimmune diseases, but as well infectious diseases and non-reproductive cancers.12.Klein S.L. Flanagan K.L. Sex differences in immune responses.http://www.ncbi.nlm.nih.gov/pubmed/27546235Nat Rev Immunol. 2016; 16: 626-638doi:10.1038/nri.2016.90Google Scholar Understanding sex differences in treatment effects is key for three major reasons: The SEXIE-R- CHOP-14 trial (Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients)13.Pfreundschuh M. Murawski N. Zeynalova S. et al.Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients.http://www.ncbi.nlm.nih.gov/pubmed/28990173Br J Haematol. 2017; 179: 410-420doi:10.1111/bjh.14860Google Scholar prospectively investigated different doses of rituximab in men and women with diffuse large B-cell lymphoma and demonstrated an improved progression-free survival by 32.5% (p=0.039), with a trend for a (30%) better overall survival in the experimental arm. It demonstrates the feasibility and is an example for the potential of rationally designed, sex-specific dose modifications to improve patient outcomes in oncology. Further studies with other classes of drugs with significant sex differences in pharmacokinetics are required. The current process of drug development in oncology does not identify potentially different optimal doses for men and women. Cardiologists recently discovered that optimal doses of drugs to treat heart failure are not the same14.Santema B.T. Ouwerkerk W. Tromp J. et al.Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study.http://www.ncbi.nlm.nih.gov/pubmed/31447116Lancet. 2019; 394: 1254-1263doi:10.1016/S0140-6736(19)31792-1Google Scholar in women as in men. We should learn from them. One example of a recent study with significant differences in treatment efficacy between men and women is the BILCAP (Capecitabine compared with observation in resected biliary tract cancer) study, in which adjuvant treatment with capecitabine after curatively resected biliary cancer was compared with observation alone.15.Primrose J.N. Fox R.P. Palmer D.H. et al.Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study.http://www.ncbi.nlm.nih.gov/pubmed/30922733Lancet Oncol. 2019; 20: 663-673doi:10.1016/S1470-2045(18)30915-XGoogle Scholar The subgroup analysis of this trial demonstrated a HR of 0.93 (0.64–1.35) in women and 0.7 (0.50–0.99) in men. Certainly, the result of the subgroup analysis in women is limited by its small sample size and may be false. This trial was neither designed nor powered to detect a treatment benefit in women. A subgroup analysis is not a sufficient argument to withhold a potentially effective treatment for women with biliary cancer. However, these results should raise doubts about the efficacy of capecitabine as adjuvant treatment in women with biliary cancer as they may as well reflect true biological differences in sensitivity of this type of cancer to capecitabine. Further research and trials specifically addressing this question are necessary to confirm or infirm the efficacy of adjuvant capecitabine for biliary cancer in women. Since we understand the concept of a sexual dimorphism in cancer,10.Clocchiatti A. Cora E. Zhang Y. et al.Sexual dimorphism in cancer.http://www.ncbi.nlm.nih.gov/pubmed/27079803Nat Rev Cancer. 2016; 16: 330-339doi:10.1038/nrc.2016.30Google Scholar we can no longer conclude from the observation of a certain treatment benefit in men that this benefit will be the same in women. The recent ESMO workshop concluded that ‘especially in diseases with significant differences in epidemiology or outcomes, men and women with non-sex-related cancers should be considered as biologically distinct groups of patients, for whom specific treatment approaches merit consideration’.9.Wagner A.D. Oertelt-Prigione S. Adjei A. et al.Gender medicine and oncology: report and consensus of an ESMO workshop.http://www.ncbi.nlm.nih.gov/pubmed/31613312Ann Oncol. 2019; 30: 1914-1924doi:10.1093/annonc/mdz414Google Scholar Another example for a disease with a significant difference in tumour biology between men and women is melanoma: a pooled analysis of 2734 patients included in five randomised trials reported in 201316.Joosse A. Collette S. Suciu S. et al.Sex is an independent prognostic indicator for survival and relapse/progression-free survival in metastasized stage III to IV melanoma: a pooled analysis of five European organisation for research and treatment of cancer randomized controlled trials.http://www.ncbi.nlm.nih.gov/pubmed/23690423J Clin Oncol. 2013; 31: 2337-2346doi:10.1200/JCO.2012.44.5031Google Scholar clearly described a significantly better survival (HR 0.81, 95% CI 0.72 to 0.91, p<0.001) in stage III and stage IV (HR 0.82, 95% CI 0.72 to 0.93, p<0.001). The authors conclude that ‘a biologic sex trait seems to profoundly influence melanoma progression and survival’. Further research is necessary to identify and understand such biological differences. Finally, when thinking about the individualisation of systemic treatments in oncology, we have to keep in mind that the patients’ sex is only one of different host factors, which deserves consideration: a patients’ body composition is an example of another one. Body surface area (BSA)-based dosing of chemotherapy has been introduced in the 1950s and remained the default approach since then. Its inaccuracy has already been discussed nearly 25 years ago,17.Gurney H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.http://www.ncbi.nlm.nih.gov/pubmed/8823340J Clin Oncol. 1996; 14: 2590-2611doi:10.1200/JCO.1996.14.9.2590Google Scholar, 18.Miller A.A. Body surface area in dosing anticancer agents: scratch the surface!.http://www.ncbi.nlm.nih.gov/pubmed/12488468J Natl Cancer Inst. 2002; 94: 1822-1831doi:10.1093/jnci/94.24.1822Google Scholar and more recently by Bins et al,19.Bins S. Ratain M.J. Mathijssen R.H.J. Conventional dosing of anticancer agents: precisely wrong or just inaccurate?.http://www.ncbi.nlm.nih.gov/pubmed/24646486Clin Pharmacol Ther. 2014; 95: 361-364doi:10.1038/clpt.2014.12Google Scholar where paclitaxel is taken as an example to illustrate both the lack of correlation between clearance and BSA, and the impact of the patients’ sex. BSA-based dosing of chemotherapy ignores both the sex differences in fat-free body mass and the large individual variations of body composition, which can easily and precisely be assessed by CT scanning.9.Wagner A.D. Oertelt-Prigione S. Adjei A. et al.Gender medicine and oncology: report and consensus of an ESMO workshop.http://www.ncbi.nlm.nih.gov/pubmed/31613312Ann Oncol. 2019; 30: 1914-1924doi:10.1093/annonc/mdz414Google Scholar In an editorial published in 1998,20.Ratain M.J. Body-Surface area as a basis for dosing of anticancer agents: science, myth, or habit?.http://www.ncbi.nlm.nih.gov/pubmed/9667242J Clin Oncol. 1998; 16: 2297-2298doi:10.1200/JCO.1998.16.7.2297Google Scholar Ratain asked if BSA-based dosing of chemotherapy is ‘science, myth or habit?’ and concluded that myth and habit have gotten in the way of science. Alternatives to chemotherapy dosing according to BSA, such as toxicity-based dosing, genotype-based dosing or therapeutic drug monitoring (TDM) have been developed. However, the complexities of TDM make its universal use impractical,17.Gurney H. Dose calculation of anticancer drugs: a review of the current practice and introduction of an alternative.http://www.ncbi.nlm.nih.gov/pubmed/8823340J Clin Oncol. 1996; 14: 2590-2611doi:10.1200/JCO.1996.14.9.2590Google Scholar genotype-based dosing is possible only for a limited number of drugs and in a limited number of settings, but information about the patients’ host factors, such as sex, age and body composition, as well as treatment-related toxicity, is available wherever oncology is practiced. We are now in 2020 and should put greater efforts in the investigation of alternatives to BSA-based dosing of chemotherapy. Rationally designed concepts for chemotherapy dosing, developed on the basis of the understanding of a drugs’ pharmacokinetics, which integrate information about the relation between host factors, such as sex, age and body composition and drug clearance, as well as genotypes wherever possible, need further development. Furthermore, dose adjustment according to toxicity should not be limited to reductions in presence of toxicity. The potential of uptitration of chemotherapy doses in absence of toxicity in eligible patients to increase treatment efficacy deserves further investigation. Ideally, composite models, which take these different parameters according to their specific relevance for a given drug into account, should be developed. The clinical benefit of such new concepts in terms of reduction of toxicity and improvement of efficacy needs confirmation in randomised clinical trials. Finally, body composition matters not only for chemotherapy dosing, but might also affect the results of immunotherapy.21.Wang Z. Aguilar E.G. Luna J.I. et al.Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade.http://www.ncbi.nlm.nih.gov/pubmed/30420753Nat Med. 2019; 25: 141-151doi:10.1038/s41591-018-0221-5Google Scholar By individualising cancer treatments on the basis of tumour characteristics we made significant progress. We have understood the importance of the microenvironment and are exploring the role of the microbiome. We should now continue and explore the impact of host factors, such as sex and body composition, as well as their interactions with tumour biology and treatment effects, to further individualise the administration of anticancer treatments.