Drug products: Cyclophosphamide, Cyklofosfamid Ebb, Sendoxan
ATC code: L01AA01
Substances: cyclophosphamide, cyclophosphamide monohydrate
Female sex is correlated with both better outcome and greater risk of side effects of cyclophosphamide.
Use of cyclophosphamide during pregnancy may cause birth defects.
Chemotherapeutic agents are usually given as combination therapy. Furthermore, chemotherapeutic agents share some adverse effects, and therefore evaluation of a particular agent’s sex-related adverse effects during combination chemotherapy is complicated. Female sex is a favorable prognostic factor in small-cell lung cancer  and Ewing sarcoma .
Pharmacokinetics and dosing
Studies have not been able to verify sex-related discrepancy in pharmacokinetics of cyclophosphamide [3-5].
Small-cell lung cancerA 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 that women have higher overall response rates (80.3% vs 66.9%) and survival (median years 1.3 vs 0.91) compared with men .
SarcomaA randomized noninferiority study (EE99-R1)  compared cyclophosphamide with ifosfamide in sarcoma. In the cyclophosphamide arm there were 258 boys/men and 173 girls/women with a median age of 14.6 (range 0-50) years. Subgroup analysis of this group revealed higher mortality rate in boys/men than in girls/women (OR 1.67) . In a meta-analysis consisted of three randomized clinical trials on sarcoma including EE99-R1 (897 boys/men and 631 girls/women, with a median age of 12 (range 0-50) years), patients were treated with either cyclophosphamide or ifosfamide in combination with vincristine and dactinomycin. Analyses showed a significant heterogeneity of the treatment effect between sexes for cyclophosphamide (higher mortality rate in boys/men than in girls/women, OR 1.43) but not for both treatments together or for ifosfamide alone . Cyclophosphamide and ifosfamide were compared as single drugs in a randomized phase II study including 135 patients (15-70 years old) with advanced or metastatic soft-tissue sarcoma. Overall response rates considering both treatments together were four times higher in girls/women (20% vs. 5%). Sex-related difference in overall response rate was not significant for cyclophosphamide alone (5 of 30 (17%) for girls/women vs 0 of 37 (0%) for boys/men) .
Acute lymphoblastic leukemiaChildren with acute lymphoblastic leukemia recruited to a trial for evaluating a combination chemotherapy called AL90. 58 patients (44 boys, 14 girls) ended up in the high-risk group. The treatment protocol consisted of induction, consolidation, intensification, and maintenance phases. Cyclophosphamide included in the consolidation and maintenance phases. Higher proportion of the girls than the boys in the high-risk group achieved event free survival (86% vs 49%) .
A sex-based retrospective analysis of four small cell lung cancer trials on patients who received cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin (648 men, 358 women) indicated higher incidence of grade 3 and 4 hematological toxicit in women 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%). Women also had significantly more stomatitis and vomiting of all grades .Subgroup analysis of data from a meta-analysis in pediatric and adult sarcoma patients comparing cyclophosphamide with ifosfamide, revealed higher risk of leukopenia/neutropenia associated with cyclophosphamide treatment in girls/women than in boys/men (OR 1.45) .
Reproductive health issues
Fetal defects and miscarriages have been reported. Women of childbearing potential and their partner should be advised against becoming pregnant and advised to use effective contraception during and 6 months after treatment with cyclophosphamide . Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
Date of litterature search: 2022-02-25
- Singh S, Parulekar W, Murray N, Feld R, Evans WK, Tu D et al. Influence of sex on toxicity and treatment outcome in small-cell lung cancer. J Clin Oncol. 2005;23(4):850-6. PubMed
- Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
- Veal GJ, Cole M, Chinnaswamy G, Sludden J, Jamieson D, Errington J et al. Cyclophosphamide pharmacokinetics and pharmacogenetics in children with B-cell non-Hodgkin's lymphoma. Eur J Cancer. 2016;55:56-64. PubMed
- Yule SM, Boddy AV, Cole M, Price L, Wyllie R, Tasso MJ et al. Cyclophosphamide pharmacokinetics in children. Br J Clin Pharmacol. 1996;41(1):13-19. PubMed
- Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D. Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency. Kidney Int 2002 Apr;61(4):1495-501 PubMed
- Le Deley MC, Paulussen M, Lewis I, Brennan B, Ranft A, Whelan J et al. Cyclophosphamide compared with ifosfamide in consolidation treatment of standard-risk Ewing sarcoma: results of the randomized noninferiority Euro-EWING99-R1 trial. J Clin Oncol. 2014;32(23):2440-8. PubMed
- Fresneau B, Hackshaw A, Hawkins DS, Paulussen M, Anderson JR, Judson I et al. Investigating the heterogeneity of alkylating agents' efficacy and toxicity between sexes: A systematic review and meta-analysis of randomized trials comparing cyclophosphamide and ifosfamide (MAIAGE study). Pediatr Blood Cancer. 2017;64(8). PubMed
- Bramwell VH, Mouridsen HT, Santoro A, Blackledge G, Somers R, Verwey J et al. Cyclophosphamide versus ifosfamide: final report of a randomized phase II trial in adult soft tissue sarcomas. Eur J Cancer Clin Oncol. 1987;23(3):311-21. PubMed
- Ishii E, Eguchi H, Matsuzaki A, Koga H, Yanai F, Kuroda H et al. Outcome of acute lymphoblastic leukemia in children with AL90 regimen: impact of response to treatment and sex difference on prognostic factors. Med Pediatr Oncol. 2001;37(1):10-9. PubMed
- Sendoxan (cyclophosphamide). Swedish Medical Products Agency [updated 2016-05-09, cited 2022-02-25]
- Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.] länk
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Approved by: Karin Schenck-Gustafsson