Testmiljö
Observera att detta är en testmiljö för utveckling som inte ska användas som underlag för klinisk bedömning. Besök Janusmed här: https://janusmed.se

4/10/2025

Janusmed kön och genus

Janusmed kön och genus – Doxorubicin SanoSwiss

Janusmed kön och genus är ett kunskapsstöd som tillhandahåller information om köns- och genusaspekter på läkemedelsbehandling. Kunskapsstödet är avsedd främst för hälso- och sjukvårdspersonal. Texterna är generella och ska inte ses som behandlingsriktlinjer. Det är alltid behandlande läkare som ansvarar för patientens medicinering.

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Doxorubicin Testmiljö

Doxorubicin

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Produkter

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Adriamycin, Adriamycin RDF, Caelyx pegylated liposomal, Doxorubicin Ac......

Adriamycin, Adriamycin RDF, Caelyx pegylated liposomal, Doxorubicin Accord, Doxorubicin Ebewe, Doxorubicin Hydrochloride Liposome Injection, Doxorubicin STADA, Doxorubicin SanoSwiss, Doxorubicin Teva, Myocet liposomal, Zolsketil pegylated liposomal
ATC-koder

L01DB01

L01DB01
Substanser

doxorubicin, doxorubicinhydroklorid

doxorubicin, doxorubicinhydroklorid
Sammanfattning

Kvinnor har en ökad risk för hematologisk och kardiologisk toxicitet av doxorubicinbehandling. Vid onkologisk behandling har kvinnor även visat sig ha en ökad risk för kräkning och stomatit.

Utifrån vissa studier kan det finnas könsskillnader i överlevnad (och eventuellt behandlingsfördröjning) men resultaten är svårtolkade då resultaten kan bero på olika faktorer såsom kombinationsbehandling, olika tumörformer etc.

Clearance av doxorubicin har visat sig vara högre hos män än kvinnor, men samtidigt har förlängd terminal halveringstid hos män påvisats.

Observera att dozorubicin kan ha teratogena effekter. För mer information, se kunskapsstödet Janusmed fosterpåverkan.

Kvinnor har en ökad risk för hematologisk och kardiologisk toxicitet av doxorubicinbehandling. Vid onkologisk behandling har kvinnor även visat sig ha en ökad risk för kräkning och stomatit. Utifrån vissa studier kan det finnas könsskillnader i överlevnad (och eventuellt behandlingsfördröjning) men resultaten är svårtolkade då resultaten kan bero på olika faktorer såsom kombinationsbehandling, olika tumörformer etc. Clearance av doxorubicin har visat sig vara högre hos män än kvinnor, men samtidigt har förlängd terminal halveringstid hos män påvisats. Observera att dozorubicin kan ha teratogena effekter. För mer information, se kunskapsstödet Janusmed fosterpåverkan.
Background

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......

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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).
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Läkemedel innehållande doxorubin (ATC-kod L01DB01) används huvudsakligen på sjukhus och därför saknas könsspecifika användningsdata [37].
Referenser

Visa referenser

  1. Radkiewicz, C. Sex differences in cancer risk and survival. [dissertation]. Dept of Medical Epidemiology and Biostatistics: Karolinska Institutet; 2019.

  2. Edgren G, Liang L, Adami HO, Chang ET. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol. 2012;27(3):187-96.

  3. Doxorubicin Accord (doxorubicin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-03-29, cited 2021-06-22]

  4. Doxorubicin Hydrochloride. DailyMed [www]. US National Library of Medicine. [updated 2019-12-31, cited 2021-06-22].

  5. Baudry E, Huguet S, Couderc AL, Chaibi P, Bret F, Verny C et al. Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP. Cancer Chemother Pharmacol. 2019;83(4):775-785.

  6. Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer. 2004;40(8):1170-8.

  7. La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43-50.

  8. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data Sarcoma Meta-analysis Collaboration. Lancet. 1997;350(9092):1647-54.

  9. Koziner B, Sklaroff R, Little C, Labriola D, Thaler HT, Straus DJ, Young CW, Nisce LZ, Oettgen H, Lee BJ 3rd, et al. NHL-3 protocol Six-drug combination chemotherapy for non-Hodgkin's lymphoma. Cancer. 1984;53(12):2592-600.

  10. Alvegard TA, Berg NO, Baldetorp B, Fernö M, Killander D, Ranstam J et al. Cellular DNA content and prognosis of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol. 1990;8(3):538-47.

  11. Toma S, Canavese G, Grimaldi A, Ravera G, Ugolini D, Percivale P et al. Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa. Oncol Rep. 2003;10(3):641-7.

  12. Dana BW, Dahlberg S, Nathwani BN, Chase E, Coltman C, Miller TP et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol. 1993;11(4):644-51.

  13. Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA et al. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994;12(1):70-6.

  14. Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al. Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial. Ann Oncol. 2004;15(2):276-82.

  15. Maurer LH, Pajak T, Eaton W, Comis R, Chahinian P, Faulkner C et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol. 1985;3(7):969-76.

  16. 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.

  17. Young RJ, Litière S, Lia M, Hogendoorn PCW, Fisher C, Mechtersheimer G et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study. Acta Oncol. 2017;56(7):1013-1020.

  18. Kühnl A, Cunningham D, Counsell N, Hawkes EA, Qian W, Smith P, Chadwick N, Lawrie A, Mouncey P, Jack A, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Rosenwald A, Ott G, Horn H, Ziepert M, Pfreundschuh M, Linch D. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial. Ann Oncol. 2017;28(7):1540-1546.

  19. Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002;20(5):1361-7.

  20. Brada M, Hjiyiannakis D, Hines F, Traish D, Ashley S. Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Int J Radiat Oncol Biol Phys. 1998;40(5):1157-62.

  21. Longo DL, Glatstein E, Duffey PL, Young RC, Ihde DC, Bastian AW et al. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol. 1997;15(11):3338-46.

  22. Köppler H, Pflüger KH, Eschenbach I, Pfab R, Birkmann J, Zeller W, Holle R, Steinhauer UE, Gropp C, Oehl S, et al. Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol. 1994;5(1):49-55.

  23. Igawa M, Ohkuchi T, Ueda M, Usui T. Factors affecting the outcome of patients with advanced urothelial cancer following chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin. Cancer Chemother Pharmacol. 1992;30 Suppl:S77-80.

  24. Schneider AM, Straus DJ, Schluger AE, Lowenthal DA, Koziner B, Lee BJ et al. Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas. J Clin Oncol. 1990;8(1):94-102.

  25. Nakamura N, Hara T, Shibata Y, Matsumoto T, Nakamura H, Ninomiya S, Kito Y, Kitagawa J, Kanemura N, Goto N, Shiraki M, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma. Ann Hematol. 2015;94(12):2043-53.

  26. Rosenblatt E, Abdel-Wahab M, El-Gantiry M, Elattar I, Bourque JM, Afiane M et al. Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency. Radiat Oncol. 2014;9:67.

  27. Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M et al. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol. 1998;16(2):658-63.

  28. Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med. 1987;316(15):912-8.

  29. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.

  30. Martindale: The Complete Drug Reference. Pharmaceutical Press.

  31. ZINECARD (dexrazoxane). Summary of Product Charateristics. Drugs@FDA [www]. Food and Drug Administration (FDA). [updated 2014-04-01, cited 2021-08-23].

  32. Sleijfer S, Rizzo E, Litière S, Mathijssen RHJ, Judson IR, Gelderblom H et al. Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database. Acta Oncol. 2018;57(8):1117-1126.

  33. Paioli A, Luksch R, Fagioli F, Tamburini A, Cesari M, Palmerini E et al. Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age. J Chemother. 2014;26(1):49-56.

  34. Ferrari S, Palmerini E, Staals E, Abate ME, Longhi A, Cesari M et al. Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma. J Chemother. 2009;21(2):205-10.

  35. Pater J, Slamet L, Zee B, Osoba D, Warr D, Rusthoven J. Inconsistency of prognostic factors for post-chemotherapy nausea and vomiting. Support Care Cancer. 1994;2(3):161-6.

  36. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.

  37. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.

  38. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.]

  1. Radkiewicz, C. Sex differences in cancer risk and survival. [dissertation]. Dept of Medical Epidemiology and Biostatistics: Karolinska Institutet; 2019.
  2. Edgren G, Liang L, Adami HO, Chang ET. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol. 2012;27(3):187-96.
  3. Doxorubicin Accord (doxorubicin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-03-29, cited 2021-06-22]
  4. Doxorubicin Hydrochloride. DailyMed [www]. US National Library of Medicine. [updated 2019-12-31, cited 2021-06-22].
  5. Baudry E, Huguet S, Couderc AL, Chaibi P, Bret F, Verny C et al. Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP. Cancer Chemother Pharmacol. 2019;83(4):775-785.
  6. Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer. 2004;40(8):1170-8.
  7. La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43-50.
  8. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data Sarcoma Meta-analysis Collaboration. Lancet. 1997;350(9092):1647-54.
  9. Koziner B, Sklaroff R, Little C, Labriola D, Thaler HT, Straus DJ, Young CW, Nisce LZ, Oettgen H, Lee BJ 3rd, et al. NHL-3 protocol Six-drug combination chemotherapy for non-Hodgkin's lymphoma. Cancer. 1984;53(12):2592-600.
  10. Alvegard TA, Berg NO, Baldetorp B, Fernö M, Killander D, Ranstam J et al. Cellular DNA content and prognosis of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol. 1990;8(3):538-47.
  11. Toma S, Canavese G, Grimaldi A, Ravera G, Ugolini D, Percivale P et al. Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa. Oncol Rep. 2003;10(3):641-7.
  12. Dana BW, Dahlberg S, Nathwani BN, Chase E, Coltman C, Miller TP et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol. 1993;11(4):644-51.
  13. Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA et al. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994;12(1):70-6.
  14. Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al. Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial. Ann Oncol. 2004;15(2):276-82.
  15. Maurer LH, Pajak T, Eaton W, Comis R, Chahinian P, Faulkner C et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol. 1985;3(7):969-76.
  16. 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.
  17. Young RJ, Litière S, Lia M, Hogendoorn PCW, Fisher C, Mechtersheimer G et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study. Acta Oncol. 2017;56(7):1013-1020.
  18. Kühnl A, Cunningham D, Counsell N, Hawkes EA, Qian W, Smith P, Chadwick N, Lawrie A, Mouncey P, Jack A, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Rosenwald A, Ott G, Horn H, Ziepert M, Pfreundschuh M, Linch D. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial. Ann Oncol. 2017;28(7):1540-1546.
  19. Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002;20(5):1361-7.
  20. Brada M, Hjiyiannakis D, Hines F, Traish D, Ashley S. Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Int J Radiat Oncol Biol Phys. 1998;40(5):1157-62.
  21. Longo DL, Glatstein E, Duffey PL, Young RC, Ihde DC, Bastian AW et al. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol. 1997;15(11):3338-46.
  22. Köppler H, Pflüger KH, Eschenbach I, Pfab R, Birkmann J, Zeller W, Holle R, Steinhauer UE, Gropp C, Oehl S, et al. Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol. 1994;5(1):49-55.
  23. Igawa M, Ohkuchi T, Ueda M, Usui T. Factors affecting the outcome of patients with advanced urothelial cancer following chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin. Cancer Chemother Pharmacol. 1992;30 Suppl:S77-80.
  24. Schneider AM, Straus DJ, Schluger AE, Lowenthal DA, Koziner B, Lee BJ et al. Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas. J Clin Oncol. 1990;8(1):94-102.
  25. Nakamura N, Hara T, Shibata Y, Matsumoto T, Nakamura H, Ninomiya S, Kito Y, Kitagawa J, Kanemura N, Goto N, Shiraki M, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma. Ann Hematol. 2015;94(12):2043-53.
  26. Rosenblatt E, Abdel-Wahab M, El-Gantiry M, Elattar I, Bourque JM, Afiane M et al. Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency. Radiat Oncol. 2014;9:67.
  27. Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M et al. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol. 1998;16(2):658-63.
  28. Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med. 1987;316(15):912-8.
  29. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.
  30. Martindale: The Complete Drug Reference. Pharmaceutical Press.
  31. ZINECARD (dexrazoxane). Summary of Product Charateristics. Drugs@FDA [www]. Food and Drug Administration (FDA). [updated 2014-04-01, cited 2021-08-23].
  32. Sleijfer S, Rizzo E, Litière S, Mathijssen RHJ, Judson IR, Gelderblom H et al. Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database. Acta Oncol. 2018;57(8):1117-1126.
  33. Paioli A, Luksch R, Fagioli F, Tamburini A, Cesari M, Palmerini E et al. Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age. J Chemother. 2014;26(1):49-56.
  34. Ferrari S, Palmerini E, Staals E, Abate ME, Longhi A, Cesari M et al. Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma. J Chemother. 2009;21(2):205-10.
  35. Pater J, Slamet L, Zee B, Osoba D, Warr D, Rusthoven J. Inconsistency of prognostic factors for post-chemotherapy nausea and vomiting. Support Care Cancer. 1994;2(3):161-6.
  36. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.
  37. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.
  38. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.]
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Litteratursökningsdatum: 6/22/2021

Litteratursökningsdatum: 6/22/2021
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Adriamycin, Adriamycin RDF, Caelyx pegylated liposomal, Doxorubicin Ac......

Adriamycin, Adriamycin RDF, Caelyx pegylated liposomal, Doxorubicin Accord, Doxorubicin Ebewe, Doxorubicin Hydrochloride Liposome Injection, Doxorubicin STADA, Doxorubicin SanoSwiss, Doxorubicin Teva, Myocet liposomal, Zolsketil pegylated liposomal
ATC-koder

L01DB01

L01DB01
Substanser

doxorubicin, doxorubicinhydroklorid

doxorubicin, doxorubicinhydroklorid
Sammanfattning

Kvinnor har en ökad risk för hematologisk och kardiologisk toxicitet av doxorubicinbehandling. Vid onkologisk behandling har kvinnor även visat sig ha en ökad risk för kräkning och stomatit.

Utifrån vissa studier kan det finnas könsskillnader i överlevnad (och eventuellt behandlingsfördröjning) men resultaten är svårtolkade då resultaten kan bero på olika faktorer såsom kombinationsbehandling, olika tumörformer etc.

Clearance av doxorubicin har visat sig vara högre hos män än kvinnor, men samtidigt har förlängd terminal halveringstid hos män påvisats.

Observera att dozorubicin kan ha teratogena effekter. För mer information, se kunskapsstödet Janusmed fosterpåverkan.

Kvinnor har en ökad risk för hematologisk och kardiologisk toxicitet av doxorubicinbehandling. Vid onkologisk behandling har kvinnor även visat sig ha en ökad risk för kräkning och stomatit. Utifrån vissa studier kan det finnas könsskillnader i överlevnad (och eventuellt behandlingsfördröjning) men resultaten är svårtolkade då resultaten kan bero på olika faktorer såsom kombinationsbehandling, olika tumörformer etc. Clearance av doxorubicin har visat sig vara högre hos män än kvinnor, men samtidigt har förlängd terminal halveringstid hos män påvisats. Observera att dozorubicin kan ha teratogena effekter. För mer information, se kunskapsstödet Janusmed fosterpåverkan.
Background

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......

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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).
Försäljning på recept

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Läkemedel innehållande doxorubin (ATC-kod L01DB01) används huvudsakligen på sjukhus och därför saknas könsspecifika användningsdata [37].
Referenser

Visa referenser

  1. Radkiewicz, C. Sex differences in cancer risk and survival. [dissertation]. Dept of Medical Epidemiology and Biostatistics: Karolinska Institutet; 2019.

  2. Edgren G, Liang L, Adami HO, Chang ET. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol. 2012;27(3):187-96.

  3. Doxorubicin Accord (doxorubicin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-03-29, cited 2021-06-22]

  4. Doxorubicin Hydrochloride. DailyMed [www]. US National Library of Medicine. [updated 2019-12-31, cited 2021-06-22].

  5. Baudry E, Huguet S, Couderc AL, Chaibi P, Bret F, Verny C et al. Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP. Cancer Chemother Pharmacol. 2019;83(4):775-785.

  6. Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer. 2004;40(8):1170-8.

  7. La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43-50.

  8. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data Sarcoma Meta-analysis Collaboration. Lancet. 1997;350(9092):1647-54.

  9. Koziner B, Sklaroff R, Little C, Labriola D, Thaler HT, Straus DJ, Young CW, Nisce LZ, Oettgen H, Lee BJ 3rd, et al. NHL-3 protocol Six-drug combination chemotherapy for non-Hodgkin's lymphoma. Cancer. 1984;53(12):2592-600.

  10. Alvegard TA, Berg NO, Baldetorp B, Fernö M, Killander D, Ranstam J et al. Cellular DNA content and prognosis of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol. 1990;8(3):538-47.

  11. Toma S, Canavese G, Grimaldi A, Ravera G, Ugolini D, Percivale P et al. Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa. Oncol Rep. 2003;10(3):641-7.

  12. Dana BW, Dahlberg S, Nathwani BN, Chase E, Coltman C, Miller TP et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol. 1993;11(4):644-51.

  13. Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA et al. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994;12(1):70-6.

  14. Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al. Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial. Ann Oncol. 2004;15(2):276-82.

  15. Maurer LH, Pajak T, Eaton W, Comis R, Chahinian P, Faulkner C et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol. 1985;3(7):969-76.

  16. 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.

  17. Young RJ, Litière S, Lia M, Hogendoorn PCW, Fisher C, Mechtersheimer G et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study. Acta Oncol. 2017;56(7):1013-1020.

  18. Kühnl A, Cunningham D, Counsell N, Hawkes EA, Qian W, Smith P, Chadwick N, Lawrie A, Mouncey P, Jack A, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Rosenwald A, Ott G, Horn H, Ziepert M, Pfreundschuh M, Linch D. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial. Ann Oncol. 2017;28(7):1540-1546.

  19. Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002;20(5):1361-7.

  20. Brada M, Hjiyiannakis D, Hines F, Traish D, Ashley S. Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Int J Radiat Oncol Biol Phys. 1998;40(5):1157-62.

  21. Longo DL, Glatstein E, Duffey PL, Young RC, Ihde DC, Bastian AW et al. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol. 1997;15(11):3338-46.

  22. Köppler H, Pflüger KH, Eschenbach I, Pfab R, Birkmann J, Zeller W, Holle R, Steinhauer UE, Gropp C, Oehl S, et al. Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol. 1994;5(1):49-55.

  23. Igawa M, Ohkuchi T, Ueda M, Usui T. Factors affecting the outcome of patients with advanced urothelial cancer following chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin. Cancer Chemother Pharmacol. 1992;30 Suppl:S77-80.

  24. Schneider AM, Straus DJ, Schluger AE, Lowenthal DA, Koziner B, Lee BJ et al. Treatment results with an aggressive chemotherapeutic regimen (MACOP-B) for intermediate- and some high-grade non-Hodgkin's lymphomas. J Clin Oncol. 1990;8(1):94-102.

  25. Nakamura N, Hara T, Shibata Y, Matsumoto T, Nakamura H, Ninomiya S, Kito Y, Kitagawa J, Kanemura N, Goto N, Shiraki M, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma. Ann Hematol. 2015;94(12):2043-53.

  26. Rosenblatt E, Abdel-Wahab M, El-Gantiry M, Elattar I, Bourque JM, Afiane M et al. Brachytherapy boost in loco-regionally advanced nasopharyngeal carcinoma: a prospective randomized trial of the International Atomic Energy Agency. Radiat Oncol. 2014;9:67.

  27. Bacci G, Ferrari S, Delepine N, Bertoni F, Picci P, Mercuri M et al. Predictive factors of histologic response to primary chemotherapy in osteosarcoma of the extremity: study of 272 patients preoperatively treated with high-dose methotrexate, doxorubicin, and cisplatin. J Clin Oncol. 1998;16(2):658-63.

  28. Perry MC, Eaton WL, Propert KJ, Ware JH, Zimmer B, Chahinian AP et al. Chemotherapy with or without radiation therapy in limited small-cell carcinoma of the lung. N Engl J Med. 1987;316(15):912-8.

  29. Vera Regitz-Zagrosek. Sex and Gender Differences in Pharmacology. Springer-Verlag Berlin Heidelberg; 2012.

  30. Martindale: The Complete Drug Reference. Pharmaceutical Press.

  31. ZINECARD (dexrazoxane). Summary of Product Charateristics. Drugs@FDA [www]. Food and Drug Administration (FDA). [updated 2014-04-01, cited 2021-08-23].

  32. Sleijfer S, Rizzo E, Litière S, Mathijssen RHJ, Judson IR, Gelderblom H et al. Predictors for doxorubicin-induced hematological toxicity and its association with outcome in advanced soft tissue sarcoma patients; a retrospective analysis of the EORTC-soft tissue and bone sarcoma group database. Acta Oncol. 2018;57(8):1117-1126.

  33. Paioli A, Luksch R, Fagioli F, Tamburini A, Cesari M, Palmerini E et al. Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age. J Chemother. 2014;26(1):49-56.

  34. Ferrari S, Palmerini E, Staals E, Abate ME, Longhi A, Cesari M et al. Sex- and age-related chemotherapy toxicity in patients with non-metastatic osteosarcoma. J Chemother. 2009;21(2):205-10.

  35. Pater J, Slamet L, Zee B, Osoba D, Warr D, Rusthoven J. Inconsistency of prognostic factors for post-chemotherapy nausea and vomiting. Support Care Cancer. 1994;2(3):161-6.

  36. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.

  37. Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G et al. Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 2017;64(11):161-6.

  38. Conise (INSIKT). Kalmar: eHälsomyndigheten. 2018 [cited 2021-11-18.]

  1. Radkiewicz, C. Sex differences in cancer risk and survival. [dissertation]. Dept of Medical Epidemiology and Biostatistics: Karolinska Institutet; 2019.
  2. Edgren G, Liang L, Adami HO, Chang ET. Enigmatic sex disparities in cancer incidence. Eur J Epidemiol. 2012;27(3):187-96.
  3. Doxorubicin Accord (doxorubicin). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-03-29, cited 2021-06-22]
  4. Doxorubicin Hydrochloride. DailyMed [www]. US National Library of Medicine. [updated 2019-12-31, cited 2021-06-22].
  5. Baudry E, Huguet S, Couderc AL, Chaibi P, Bret F, Verny C et al. Cyclophosphamide dose adjustment based on body weight and albuminemia in elderly patients treated with R-mini-CHOP. Cancer Chemother Pharmacol. 2019;83(4):775-785.
  6. Rudek MA, Sparreboom A, Garrett-Mayer ES, Armstrong DK, Wolff AC, Verweij J, Baker SD. Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer. 2004;40(8):1170-8.
  7. La-Beck NM, Zamboni BA, Gabizon A, Schmeeda H, Amantea M, Gehrig PA, Zamboni WC. Factors affecting the pharmacokinetics of pegylated liposomal doxorubicin in patients. Cancer Chemother Pharmacol. 2012;69(1):43-50.
  8. Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual data Sarcoma Meta-analysis Collaboration. Lancet. 1997;350(9092):1647-54.
  9. Koziner B, Sklaroff R, Little C, Labriola D, Thaler HT, Straus DJ, Young CW, Nisce LZ, Oettgen H, Lee BJ 3rd, et al. NHL-3 protocol Six-drug combination chemotherapy for non-Hodgkin's lymphoma. Cancer. 1984;53(12):2592-600.
  10. Alvegard TA, Berg NO, Baldetorp B, Fernö M, Killander D, Ranstam J et al. Cellular DNA content and prognosis of high-grade soft tissue sarcoma: the Scandinavian Sarcoma Group experience. J Clin Oncol. 1990;8(3):538-47.
  11. Toma S, Canavese G, Grimaldi A, Ravera G, Ugolini D, Percivale P et al. Concomitant chemo-radiotherapy in the treatment of locally advanced and/or metastatic soft tissue sarcomas: experience of the National Cancer Institute of Genoa. Oncol Rep. 2003;10(3):641-7.
  12. Dana BW, Dahlberg S, Nathwani BN, Chase E, Coltman C, Miller TP et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol. 1993;11(4):644-51.
  13. Maksymiuk AW, Jett JR, Earle JD, Su JQ, Diegert FA, Mailliard JA et al. Sequencing and schedule effects of cisplatin plus etoposide in small-cell lung cancer: results of a North Central Cancer Treatment Group randomized clinical trial. J Clin Oncol. 1994;12(1):70-6.
  14. Sieber M, Tesch H, Pfistner B, Rueffer U, Paulus U, Munker R et al. Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial. Ann Oncol. 2004;15(2):276-82.
  15. Maurer LH, Pajak T, Eaton W, Comis R, Chahinian P, Faulkner C et al. Combined modality therapy with radiotherapy, chemotherapy, and immunotherapy in limited small-cell carcinoma of the lung: a Phase III cancer and Leukemia Group B Study. J Clin Oncol. 1985;3(7):969-76.
  16. 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.
  17. Young RJ, Litière S, Lia M, Hogendoorn PCW, Fisher C, Mechtersheimer G et al. Predictive and prognostic factors associated with soft tissue sarcoma response to chemotherapy: a subgroup analysis of the European Organisation for Research and Treatment of Cancer 62012 study. Acta Oncol. 2017;56(7):1013-1020.
  18. Kühnl A, Cunningham D, Counsell N, Hawkes EA, Qian W, Smith P, Chadwick N, Lawrie A, Mouncey P, Jack A, Pocock C, Ardeshna KM, Radford J, McMillan A, Davies J, Turner D, Kruger A, Johnson PW, Gambell J, Rosenwald A, Ott G, Horn H, Ziepert M, Pfreundschuh M, Linch D. Outcome of elderly patients with diffuse large B-cell lymphoma treated with R-CHOP: results from the UK NCRI R-CHOP14v21 trial with combined analysis of molecular characteristics with the DSHNHL RICOVER-60 trial. Ann Oncol. 2017;28(7):1540-1546.
  19. Siefker-Radtke AO, Millikan RE, Tu SM, Moore DF Jr, Smith TL, Williams D, Logothetis CJ. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol. 2002;20(5):1361-7.
  20. Brada M, Hjiyiannakis D, Hines F, Traish D, Ashley S. Short intensive primary chemotherapy and radiotherapy in sporadic primary CNS lymphoma (PCL). Int J Radiat Oncol Biol Phys. 1998;40(5):1157-62.
  21. Longo DL, Glatstein E, Duffey PL, Young RC, Ihde DC, Bastian AW et al. Alternating MOPP and ABVD chemotherapy plus mantle-field radiation therapy in patients with massive mediastinal Hodgkin's disease. J Clin Oncol. 1997;15(11):3338-46.
  22. Köppler H, Pflüger KH, Eschenbach I, Pfab R, Birkmann J, Zeller W, Holle R, Steinhauer UE, Gropp C, Oehl S, et al. Randomised comparison of CHOEP versus alternating hCHOP/IVEP for high-grade non-Hodgkin's lymphomas: treatment results and prognostic factor analysis in a multi-centre trial. Ann Oncol. 1994;5(1):49-55.
  23. Igawa M, Ohkuchi T, Ueda M, Usui T. Factors affecting the outcome of patients with advanced urothelial cancer following chemotherapy with methotrexate, vinblastine, adriamycin, and cisplatin. Cancer Chemother Pharmacol. 1992;30 Suppl:S77-80.
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Litteratursökningsdatum: 6/22/2021

Litteratursökningsdatum: 6/22/2021
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